Maternal ingestion of cannabidiol (CBD) in mice leads to sex-dependent changes in memory, anxiety, and metabolism in the adult offspring, and causes a decrease in survival to weaning age.

RATIONALE: The consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement. OBJECTIVE: The objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult. METHODS: Primiparous female C57BL/6 J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut. RESULTS: CBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 ±â€¯1.7 ng/ul) and peaked within 30 min (371.0 ±â€¯34.0 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex. CONCLUSIONS: We conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted.

National Case Volumes and Gender Disparities in Emergency Department Utilization for Psychiatric Emergencies: A Population-Based Claims Data Analysis.

Introduction The utilization of emergency departments (EDs) for managing psychiatric emergencies has significantly increased in the United States because of the increasing prevalence of mental health disorders. This study examined national case volumes and sex disparities in ED visits for psychiatric emergencies using data from the Nationwide Emergency Department Sample (NEDS). Methods This retrospective analysis included adult ED visits for psychiatric emergencies identified using relevant International Classification of Diseases, 10th Revision (ICD-10) codes. Primary endpoints included national case volumes by sex. Hospitalizations with age < 18 years and those with missing data on sex were excluded. Secondary endpoints included inpatient mortality, ED and inpatient costs, admission rates, discharge disposition, length of stay (LOS), and number of procedures. Results In 2021, there were approximately 143.5 million ED visits in the United States, with 7,978,490 of these being for psychiatric emergencies. The most common presentations were substance abuse and intoxication (5,119,086 (64.2%)), severe bipolar disorder (1,912,670 (24%)), and anxiety or panic attacks (1,015,486 (12.7%)). Approximately 3,997,223 (50.1%) were women, and 3,981,267 (49.9%) were men. Men were older (mean age: 45 versus 43 years; P<0.001), were more likely to be uninsured (712,647 (17.9%) versus 497,658 (12.5%); P<0.001), and had a higher Charlson Comorbidity Index (CCI) (CCI ≥ 2: 792,272 (19.9%) versus 643,552 (16.1%); P<0.001). More men than women presented to the ED with acute substance abuse or intoxication (3,196,945 (80.3%) versus 1,922,142 (48.1%)), bipolar disorder with or without psychosis (958,275 (24.1%) versus 954,395 (23.9%); P<0.001), and suicidal ideation (267,638 (6.7%) versus 208,989 (5.2%); P<0.001). More women than men presented with severe depression (455,683 (11.4%) versus 441,921 (11.1%)), anxiety and panic attacks (615,572 (15.4%) versus 402,108 (10.1%)), acute stress reaction (35,975 (0.9%) versus 23,888 (0.6%)), eating disorders (3,997 (0.1%) versus 27,869 (0.07%)), and a history of abuse (21,164 (0.53%) versus 19,569 (0.49%); P<0.001). Women had lower mortality rates (27,980 (0.7%) versus 63,956 (1.6%); P<0.001), lower mean ED costs (adjusted mean difference (AMD): $1,189; P<0.001), fewer in-hospital admissions (1,211,158 (30.3%) versus 1,453,162 (36.5%); P<0.001), and a higher number of prolonged hospitalizations (1,442,998 (36.1%) versus 1,194,380 (30%); P<0.001) compared with men. Conclusion This study highlights significant sex disparities in ED utilization for psychiatric emergencies. Men more frequently present with substance abuse and severe comorbidities, leading to higher healthcare costs and inpatient admissions. Women, while more likely to present with anxiety and depressive disorders, incur lower costs and have better overall outcomes.

Tumor lysate particle only vaccine (TLPO) vs. Tumor lysate particle-loaded, dendritic cell vaccine (TLPLDC) to prevent recurrence in resected stage III/IV melanoma patients: Results of a phase I/IIa trial.

BACKGROUND: The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine. METHODS: Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis. RESULTS: Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0 %, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7 %, p = 0.714) and OS (94.6% vs. 93.8 %, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw. CONCLUSIONS: In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial.

Scientists in exile.

Since 2001, the United Nations has designated 20 June as World Refugee Day. It seeks to raise awareness of refugees-currently estimated to be more than 114 million persons internally displaced, exiled, or on the move-and the often-harsh conditions they confront around the world. Among them are scientists, giving the scientific community a special responsibility to protect and support these colleagues. It is not just scientists and their families whose lives are disrupted, but science as an enterprise as well.

Evaluation of flow diverters for cerebral aneurysm therapy: recommendations for imaging analyses in clinical studies, endorsed by ESMINT, ESNR, OCIN, SILAN, SNIS, and WFITN.

BACKGROUND: Multiple studies and meta-analyses have described the technical and clinical outcomes in large cohorts of aneurysm patients treated with flow diverters (FDs). Variations in evaluation methodology complicate making comparisons among studies, hinder understanding of the device behavior, and pose an obstacle in the assessment of further advances in FD therapy. METHODS: A multidisciplinary panel of neurointerventionalists, imaging experts, and neuroradiologists convened with the goal of establishing consensus recommendations for the standardization of image analyses in FD studies. RESULTS: A standardized methodology is proposed for evaluating and reporting radiological outcomes of FD treatment of intracranial aneurysms. The recommendations include general imaging considerations for clinical studies and evaluations of longitudinal changes, such as neointimal lining and stenosis. They cover standards for classification of aneurysm location, morphology, measurements, as well as the assessment of aneurysm occlusion, wall apposition, and neck coverage. These reporting standards further define four specific braid deformation patterns: foreshortening, fish-mouthing, braid bump deformation, and braid collapse, collectively termed 'F2B2'. CONCLUSIONS: When widely applied, standardization of methods of measuring and reporting outcomes will help to harmonize the assessment of treatment outcomes in clinical studies, help facilitate communication of results among specialists, and help enable research and development to focus on specific aspects of FD techniques and technology.

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy.

BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.

Aceite esencial de hojas de Minthostachys mollis [HBK] Griseb. del Ecuador: extracción, composición química, capacidad antioxidante y actividad antimicrobiana / Essential oil of Minthostachys mollis [HBK] Griseb. leaves from Ecuador: extraction, chemical composition, antioxidant capacity and antimicrobial activity

The aim of this study was to optimize by response surface design, the extraction of the leaf essential oil (EO) from Minthostachys mollis [HBK] Griseb., grown in Ecuador, using steam distillation. The factors used were extraction time (XTIE) of 60, 105 and 150 min and plant material/water ratio (XRMA) of 1:3, 1:4 and 1:5. The optimal combination was reached with XRMA 1:5 and XTIE 150 min, obtaining a process yield of 0.67%. The chemical composition of the EO analyzed by GC - MS was determined, where the main compounds were carvacryl acetate (44.01%), carvacrol (16.51%) and menthone (8.20%). The anti oxidant capacity of EO was evaluated using the FRAP and ABTS methodologies, with an IC 50 243.21 µmol Fe 2+ /g and 0.12 mg/mL, respectively. In addition, the antimicrobial activity of EO was found against Pseudomonas aeruginosa , Salmonella enterica , Escherich ia coli and Staphylococcus aureus .

El objetivo del estudio fue optimizar, mediante un diseño de superficie respuesta, la extracción d el aceite esencial (AE) de hojas de Minthostachys mollis [HBK] Griseb. del Ecuador, mediante destilación por arrastre de vapor. Los factores fueron el tiempo de extracción (XTIE) de 60, 105 y 150 min, y relación de material vegetal/ agua destilada (XRMA) d e 1:3, 1:4 y 1:5. La combinación óptima se logró con XTIE 150 min y XRMA 1:5 para un rendimiento de 0,67%. Se determinó la composición química del AE por GC - MS donde los compuestos mayoritarios fueron acetato de carvacrilo (44,01%), carvacrol (16,51%) y me ntona (8,20%). Se evaluó la capacidad antioxidante del AE por las metodologías FRAP y ABTS, con CI 50 de 243,21 µmol Fe 2+ /g y 0,12 mg/mL, respectivamente. Además, se demostró la actividad antimicrobiana contra Pseudomonas aeruginosa , Salmonella enterica , Es cherichia coli y Staphylococcus aureus .

Exploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.

This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites' impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc-mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

Focused update to guidelines for endovascular therapy for emergent large vessel occlusion: basilar artery occlusion patients.

BACKGROUND: Endovascular therapy (EVT) dramatically improves clinical outcomes for patients with anterior circulation emergent large vessel occlusion (ELVO) strokes. With recent publication of two randomized controlled trials in favor of EVT for basilar artery occlusions, the Society of NeuroInterventional Surgery (SNIS) Standards and Guidelines Committee provides this focused update for the existing SNIS guideline, 'Current endovascular strategies for posterior circulation large vessel occlusion stroke.' METHODS: A structured literature review and analysis of studies related to posterior circulation large vessel occlusion (basilar or vertebral artery) strokes treated by EVT was performed. Based on the strength and quality of the evidence, recommendations were made by consensus of the writing committee, with additional input from the full SNIS Standards and Guidelines Committee and the SNIS Board of Directors. RESULTS: Based on the results of the most recent randomized, controlled trials on EVT for basilar or vertebral artery occlusion, the expert panel agreed on the following recommendations. For patients presenting with an acute ischemic stroke due to an acute basilar or vertebral artery occlusion confirmed on CT angiography, National Institutes of Health Stroke Scale (NIHSS) score of ≥6, posterior circulation Alberta Stroke Program Early CT Score (PC-ASPECTS) ≥6, and age 18-89 years: (1) thrombectomy is indicated within 12 hours since last known well (class I, level B-R); (2) thrombectomy is reasonable within 12-24 hours from the last known well (class IIa, level B-R); (3) thrombectomy may be considered on a case by case basis for patients presenting beyond 24 hours since last known well (class IIb, level C-EO). In addition, thrombectomy may be considered on a case by case basis for patients aged <18 years or >89 years on a case by case basis (class IIb, level C-EO). CONCLUSIONS: The indications for EVT of ELVO strokes continue to expand and now include patients with basilar artery occlusion. Further prospective, randomized controlled trials are warranted to elucidate the efficacy and safety of EVT in populations not included in this set of recommendations, and to confirm long term outcomes.

Endovascular therapy for anterior circulation emergent large vessel occlusion stroke in patients with large ischemic cores: a report of the SNIS Standards and Guidelines Committee.

BACKGROUND: Early clinical trials validating endovascular therapy (EVT) for emergent large vessel occlusion (ELVO) ischemic stroke in the anterior circulation initially focused on patients with small or absent completed infarctions (ischemic cores) to maximize the probability of detecting a clinically meaningful and statistically significant benefit of EVT. Subsequently, real-world experience suggested that patients with large core ischemic strokes (LCS) at presentation may also benefit from EVT. Several large, retrospective, and prospective randomized clinical trials have recently been published that further validate this approach. These guidelines aim to provide an update for endovascular treatment of LCS. METHODS: A structured literature review of LCS studies available since 2019 and grading the strength and quality of the evidence was performed. Recommendations were made based on these new data by consensus of the authors, with additional input from the full SNIS Standards and Guidelines Committee and the SNIS Board of Directors. RESULTS: The management of ELVO strokes with large ischemic cores continues to evolve. The expert panel agreed on several recommendations: Recommendation 1: In patients with anterior circulation ELVO who present within 24 hours of last known normal with large infarct core (70-149 mL or ASPECTS 3-5) and meet other criteria of RESCUE-Japan LIMIT, SELECT2, ANGEL-ASPECT, TESLA, TENSION, or LASTE trials, thrombectomy is indicated (Class I, Level A). Recommendations 2-7 flow directly from recommendation 1. Recommendation 2: EVT in patients with LCS aged 18-85 years is beneficial (Class I, Level A). Recommendation 3: EVT in patients with LCS >85 years of age may be beneficial (Class I, Level B-R). Recommendation 4: Patients with LCS and NIHSS score 6-30 benefit from EVT in LCS (Class I, Level A). Recommendation 5: Patients with LCS and NIHSS score <6 and >30 may benefit from EVT in LCS (Class IIa, Level A). Recommendation 6: Patients with LCS and low baseline mRS (0-1) benefit from EVT (Class I, Level A). Recommendation 7: Patients with LCS and time of last known well 0-24 hours benefit from EVT (Class I, Level A). Recommendation 8: It is recommended that patients with ELVO LCS who also meet the criteria for on-label or guideline-directed use of IV thrombolysis receive IV thrombolysis, irrespective of whether endovascular treatments are being considered (Class I, Level B-NR). CONCLUSIONS: The indications for endovascular treatment of ELVO strokes continue to expand and now include patients with large ischemic cores on presentation. Further prospective randomized studies, including follow-up to assess the population-based efficacy of treating patients with LCS, are warranted.

Predictors and benefits of multiagent chemotherapy for pancreatic adenocarcinoma: Timing matters.

INTRODUCTION: Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). METHODS: The National Cancer Database was queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. RESULTS: A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%; odds ratio [OR]: 0.59; p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18; 95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95% CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). CONCLUSION: Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.

Dietary Nitrate from Plant Foods: A Conditionally Essential Nutrient for Cardiovascular Health.

Under specific conditions, such as catabolic stress or systemic inflammation, endogenous nutrient production becomes insufficient and exogenous supplementation (for example, through dietary intake) is required. Herein, we propose consideration of a dietary nitrate from plant foods as a conditionally essential nutrient for cardiovascular health based on its role in nitric oxide homeostasis. Nitrate derived from plant foods may function as a conditionally essential nutrient, whereas nitrate obtained from other dietary sources, such as drinking water and cured/processed meats, warrants separate consideration because of the associated health risks. We have surveyed the literature and summarized epidemiological evidence regarding the effect of dietary nitrate on cardiovascular disease and risk factors. Meta-analyses and population-based observational studies have consistently demonstrated an inverse association of dietary nitrate with blood pressure and cardiovascular disease outcomes. Considering the available evidence, we suggest 2 different approaches to providing dietary guidance on nitrate from plant-based dietary sources as a nutrient: the Dietary Reference Intakes developed by the National Academies of Sciences, Engineering, and Medicine, and the dietary guidelines evaluated by the Academy of Nutrition and Dietetics. Ultimately, this proposal underscores the need for food-based dietary guidelines to capture the complex and context-dependent relationships between nutrients, particularly dietary nitrate, and health.

Evaluation of Topical Off-the-Shelf Therapies to Reduce the Need to Evacuate Battlefield-Injured Warfighters.

INTRODUCTION: Immediate evacuation of burn casualties can be challenging in austere environments, and it is predicted to be even more difficult in future multi-domain battlespaces against near-peer foes. Therefore, a need exists to treat burn wounds at the point of injury to protect the exposed injury for an extended period. In this study, we compare two commercially available FDA-approved therapies to the current gold standard of care (GSOC), excisional debridement followed by the application of split-thickness skin graft, and the standard for prolonged field care, silver sulfadiazine (SSD) cream. The shelf-stable therapies evaluated were irradiated human skin (IHS) allograft and polylactic acid (PLA). Our objective was to study whether they have the potential capability to reduce the need for evacuation to a burn center for surgical intervention so that the combat power can be preserved in the field. MATERIALS AND METHODS: Sixteen burns (50 cm2) were created on the dorsum of four anesthetized swine. All materials were sterile, but a sterile field was not utilized in order to simulate the prolonged field care setting. The wounds were then treated with PLA, IHS, and SSD cream, and the remaining wounds (designated GSOC) were also treated with SSD cream. On post-operative day (POD) 3, sterile surgical debridement and skin grafting (1:4) were performed on the GSOC wounds. Burn healing was followed for either PODs 10, 14, 21, or 28, wherein one animal was humanely euthanized at each time point; each represented a time point of the healing process. A full-thickness excisional biopsy was taken from each wound immediately after euthanasia to give a cross-section view of the wound edge to edge. Wound healing was determined by the histological analysis of wound re-epithelialization, epidermal thickness, rete ridges, and scar elevation index and macroscopically using noninvasive imaging systems. RESULTS: The PLA and IHS treatments did not need to be reapplied to the wounds during the course of the experiment, unlike SSD, which was reapplied at each assessment time point. In terms of re-epithelialization, on POD 10, IHS and SSD were similar to the GSOC; on POD 14, all treatments were similar; on POD 21, PLA and IHS were similar to SSD; finally, on POD 28, re-epithelialization was similar in all groups. On POD 28, scar elevation index and rete ridges/mm were similar to all groups, and epidermal and dermal thickness for PLA and IHS were similar to GSOC. CONCLUSIONS: This preclinical study demonstrated that the use of the PLA and the IHS dressings resulted in similar outcomes to the GSOC-treated burns in several key metrics of wound healing. These therapies represent a potentially useful tool in current and future battlespaces, where surgical intervention is not possible. The products are lightweight and, more importantly, stable at room temperature for their entire shelf lives. This would allow for easy storage and transport by medical practitioners in the field.

Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis.

BACKGROUND: The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients. METHODS: Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS). RESULTS: After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002). CONCLUSIONS: The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial. TRIAL REGISTRATION NUMBER: NCT02301611.

The effect of rice residue management on rice paddy Si, Fe, As, and methane biogeochemistry.

Rice production results in residues of straw and husk, and the management of these residues has implications for the sustainability of the rice agroecosystem. Rice straw is typically incorporated into soil either as fresh residue or is burned prior to incorporation. Rice husk is not typically returned to rice fields. However, rice husk contains high levels of silicon, which has been shown to decrease rice accumulation of arsenic. In this work, we studied the resulting biogeochemical changes in rice paddy soils when paddies were amended with either straw or burned straw and either no husk, husk, or burned husk over two years. Using a full-factorial design, we observed that the higher lability of rice straw carbon controlled redox-sensitive processes despite the application of husk and straw at similar carbon rates. Amending paddies with straw, rather than burned straw, increased porewater Fe and As, plant As, and methane emissions regardless of husk amendment. Husk addition provided insignificant Si to the plant despite its high concentration of Si, suggesting limited short-term mobility of Si and that long-term additions of husk or higher rates may need to be studied.

Topical Synthetic Platelets Loaded With Gentamicin Decrease Bacteria in Deep Partial-Thickness Burns.

INTRODUCTION: Prolonged inflammation and infection in burns may cause inadequate healing. Platelet granules contain anti-inflammatory mediators that impact wound healing. Synthetic platelets (SPs) avoid portability and storage difficulties of natural platelets and can be loaded with bioactive agents. We evaluated wound healing outcomes in deep partial-thickness (DPT) burns treated topically with SP loaded with antibiotics. MATERIALS AND METHODS: Thirty DPT burns were created on the dorsum of two Red Duroc hybrid pigs. Six wounds were randomized into five groups: SP alone, SP loaded with gentamicin vesicles, SP with gentamicin mixture, vehicle control (saline), or dry gauze. Wounds were assessed from postburn days 3-90. Primary outcome was re-epithelialization percentage at postburn day 28. Secondary outcomes included wound contraction percentage, superficial blood flow relative to normal skin controls, and bacterial load score. RESULTS: Results showed that re-epithelialization with the standard of care (SOC) was 98%, SP alone measured 100%, SP loaded with gentamicin vesicles was 100%, and SP with gentamicin mixture was 100%. Wound contraction was 5.7% in the SOC and was ∼10% in both the SP loaded with gentamicin vesicles and SP with gentamicin mixture groups. Superficial blood flow in the SOC was 102.5%, SP alone was 170%, the SP loaded was 155%, and gentamicin mixture 162.5%. Bacterial load score in the SOC was 2.2/5.0 and was significantly less at 0.8/5.0 in SP loaded with gentamicin vesicles (P > 0.05). SP and gentamicin mixture scored 2.7 and 2.3/5.0. CONCLUSIONS: Topical SP treatment did not significantly improve outcomes. However, SP loaded with gentamicin-infused vesicles decreased bacterial load.

Unraveling the Mechanisms of Fe Oxidation and Mn Reduction on Mn Indicators of Reduction in Soil (IRIS) Films.

Indicators of reduction in soil (IRIS) devices are low-cost soil redox sensors coated with Fe or Mn oxides, which can be reductively dissolved from the device under suitable redox conditions. Removal of the metal oxide coating from the surface, leaving behind the white film, can be quantified and used as an indicator of reducing conditions in soils. Manganese IRIS, coated with birnessite, can also oxidize Fe(II), resulting in a color change from brown to orange that complicates the interpretation of coating removal. Here, we studied field-deployed Mn IRIS films where Fe oxidation was present to unravel the mechanisms of Mn oxidation of Fe(II) and the resulting minerals on the IRIS film surface. We observed reductions in the Mn average oxidation state when Fe precipitation was evident. Fe precipitation was primarily ferrihydrite (30-90%), but lepidocrocite and goethite were also detected, notably when the Mn average oxidation state decreased. The decrease in the average oxidation state of Mn was due to the adsorption of Mn(II) to the oxidized Fe and the precipitation of rhodochrosite (MnCO3) on the film. The results were variable on small spatial scales (<1 mm), highlighting the suitability of IRIS in studying heterogeneous redox reactions in soil. Mn IRIS also provides a tool to bridge lab and field studies of the interactions between Mn oxides and reduced constituents.