Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Bounding box-based 3D AI model for user-guided volumetric segmentation of pancreatic ductal adenocarcinoma on standard-of-care CTs.

OBJECTIVES: To develop a bounding-box-based 3D convolutional neural network (CNN) for user-guided volumetric pancreas ductal adenocarcinoma (PDA) segmentation. METHODS: Reference segmentations were obtained on CTs (2006-2020) of treatment-naïve PDA. Images were algorithmically cropped using a tumor-centered bounding box for training a 3D nnUNet-based-CNN. Three radiologists independently segmented tumors on test subset, which were combined with reference segmentations using STAPLE to derive composite segmentations. Generalizability was evaluated on Cancer Imaging Archive (TCIA) (n = 41) and Medical Segmentation Decathlon (MSD) (n = 152) datasets. RESULTS: Total 1151 patients [667 males; age:65.3 ± 10.2 years; T1:34, T2:477, T3:237, T4:403; mean (range) tumor diameter:4.34 (1.1-12.6)-cm] were randomly divided between training/validation (n = 921) and test subsets (n = 230; 75% from other institutions). Model had a high DSC (mean ± SD) against reference segmentations (0.84 ± 0.06), which was comparable to its DSC against composite segmentations (0.84 ± 0.11, p = 0.52). Model-predicted versus reference tumor volumes were comparable (mean ± SD) (29.1 ± 42.2-cc versus 27.1 ± 32.9-cc, p = 0.69, CCC = 0.93). Inter-reader variability was high (mean DSC 0.69 ± 0.16), especially for smaller and isodense tumors. Conversely, model's high performance was comparable between tumor stages, volumes and densities (p > 0.05). Model was resilient to different tumor locations, status of pancreatic/biliary ducts, pancreatic atrophy, CT vendors and slice thicknesses, as well as to the epicenter and dimensions of the bounding-box (p > 0.05). Performance was generalizable on MSD (DSC:0.82 ± 0.06) and TCIA datasets (DSC:0.84 ± 0.08). CONCLUSION: A computationally efficient bounding box-based AI model developed on a large and diverse dataset shows high accuracy, generalizability, and robustness to clinically encountered variations for user-guided volumetric PDA segmentation including for small and isodense tumors. CLINICAL RELEVANCE: AI-driven bounding box-based user-guided PDA segmentation offers a discovery tool for image-based multi-omics models for applications such as risk-stratification, treatment response assessment, and prognostication, which are urgently needed to customize treatment strategies to the unique biological profile of each patient's tumor.

Rapid Access Chest Pain Clinics: An Australian Cost-Benefit Study.

OBJECTIVE: Chest pain is a large health care burden in Australia and around the world. Its management requires specialist assessment and diagnostic tests, which can be costly and often lead to unnecessary hospital admissions. There is a growing unmet clinical need to improve the efficiency and management of chest pain. This study aims to show the cost-benefit of rapid access chest pain clinics (RACC) as an alternative to hospital admission. DESIGN: Retrospective cost-benefit analysis for 12 months. SETTING: RACCs in three Sydney tertiary referral hospitals. MAIN OUTCOME MEASURES: Cost per patient. RESULTS: Hospitals A, B and C implemented RACCs but each operating with slightly different staffing, referral patterns, and diagnostic services. All RACCs had similar costs per patient of AUD$455.25, AUD$427.12 and AUD$474.45, hospitals A, B and C respectively, and similar cost benefits per patient of AUD$1,168.75, AUD$1,196.88 and AUD$1,149.55, respectively. At least 28%, 26% and 29% of these RACC patients for hospitals A, B, and C, respectively, would have otherwise had to have been admitted to hospital for the model to be cost-beneficial. CONCLUSION: This study shows that a RACC model of care is cost-beneficial in the state of NSW as an alternative strategy to inpatient care for managing chest pain. Scaling up to a national level could represent an even larger benefit for the Australian health system.

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review.

BACKGROUND: Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. METHODS: We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. FINDINGS: Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. INTERPRETATION: The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. FUNDING: National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

Healthcare resource utilisation by patients with coronary heart disease receiving a lifestyle-focused text message support program: an analysis from the TEXT ME study.

The 'Tobacco, Exercise and Diet Messages' (TEXT ME) study was a 6-month, single-centre randomised clinical trial (RCT) that found a text message support program improved levels of cardiovascular risk factors in patients with coronary heart disease (CHD). The current analyses examined whether receipt of text messages influenced participants' engagement with conventional healthcare resources. The TEXT ME study database (N=710) was linked with routinely collected health department databases. Number of doctor consultations, investigations and cardiac medication prescriptions in the two study groups were compared. The most frequently accessed health service was consultations with a General Practitioner (mean 7.1, s.d. 5.4). The numbers of medical consultations, biochemical tests or cardiac-specific investigations were similar between the study groups. There was at least one prescription registered for statin, ACEI/ARBs and ß-blockers in 79, 66 and 50% of patients respectively, with similar refill rates in both the study groups. The study identified TEXT ME text messaging program did not increase use of Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) captured healthcare services. The observed benefits of TEXT ME reflect direct effects of intervention independent of conventional healthcare resource engagement.

Effect of Lifestyle-Focused Text Messaging on Risk Factor Modification in Patients With Coronary Heart Disease: A Randomized Clinical Trial.

IMPORTANCE: Cardiovascular disease prevention, including lifestyle modification, is important but underutilized. Mobile health strategies could address this gap but lack evidence of therapeutic benefit. OBJECTIVE: To examine the effect of a lifestyle-focused semipersonalized support program delivered by mobile phone text message on cardiovascular risk factors. DESIGN AND SETTING: The Tobacco, Exercise and Diet Messages (TEXT ME) trial was a parallel-group, single-blind, randomized clinical trial that recruited 710 patients (mean age, 58 [SD, 9.2] years; 82% men; 53% current smokers) with proven coronary heart disease (prior myocardial infarction or proven angiographically) between September 2011 and November 2013 from a large tertiary hospital in Sydney, Australia. INTERVENTIONS: Patients in the intervention group (n = 352) received 4 text messages per week for 6 months in addition to usual care. Text messages provided advice, motivational reminders, and support to change lifestyle behaviors. Patients in the control group (n=358) received usual care. Messages for each participant were selected from a bank of messages according to baseline characteristics (eg, smoking) and delivered via an automated computerized message management system. The program was not interactive. MAIN OUTCOMES AND MEASURES: The primary end point was low-density lipoprotein cholesterol (LDL-C) level at 6 months. Secondary end points included systolic blood pressure, body mass index (BMI), physical activity, and smoking status. RESULTS: At 6 months, levels of LDL-C were significantly lower in intervention participants, with concurrent reductions in systolic blood pressure and BMI, significant increases in physical activity, and a significant reduction in smoking. The majority reported the text messages to be useful (91%), easy to understand (97%), and appropriate in frequency (86%). [table: see text]. CONCLUSIONS AND RELEVANCE: Among patients with coronary heart disease, the use of a lifestyle-focused text messaging service compared with usual care resulted in a modest improvement in LDL-C level and greater improvement in other cardiovascular disease risk factors. The duration of these effects and hence whether they result in improved clinical outcomes remain to be determined. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12611000161921.

Saphenous vein to internal mammary artery end-to-end composite grafts for coronary artery bypass. Late follow-up.

BACKGROUND: Internal mammary artery (IMA) grafts provide equal or superior graft patency compared to other conduits. The IMA length limits extensive myocardial revascularisation with IMA grafts alone. This study aimed to determine the results of lengthening free IMAs with a short proximal segment of saphenous vein (SV) to enable more extensive myocardial revascularisation. METHODS: Patients (n=92) who underwent end-to-end composite SV-IMA grafts were followed up through cardiology and death register databases. RESULTS: The mean patient age was 57.5 years and median follow up 10.9 years. There was no perioperative mortality and 10-year survival was 89.6%. Thirty-one patients (34%) underwent repeat angiography at a median of 2.8 years postoperatively. The 10-year freedom from angiography showing SV segment occlusion was 89% with a median time to angiography of 2.3 years (nine patients). The number of distal anastomoses was the only independent predictor of SV segment occlusion HR per anastomosis=0.26 (p=0.01). In five sequential grafts to the circumflex and right coronary systems, the IMA portion of the graft remained patent following SV segment occlusion. CONCLUSIONS: Graft patency is improved by a greater number of coronary artery anastomoses.

CSANZ Position Statement on Sedation for Cardiovascular Procedures (2014).

The Cardiac Society of Australia and New Zealand (CSANZ) Position Statement describes evidence-based standards of training, pre-procedural assessment, procedural conduct and post-procedure care with respect to sedation for cardiovascular procedures. It also describes the environment in which sedation for electrophysiological and other cardiac procedures may be performed. This Statement was developed by a Working Group of the Cardiac Society of Australia and New Zealand. It was reviewed by the Continuing Education and Recertification Committee and ratified at the CSANZ Board meeting held on Friday 7 March 2014.

Adherence to secondary prevention therapies in acute coronary syndrome.

Despite overwhelming evidence of the effectiveness of secondary prevention therapies, surveys indicate poor adherence to medical treatments and lifestyle recommendations after an acute coronary syndrome. The term adherence is preferred over compliance, as the former suggests a therapeutic alliance, whereas the latter reflects passive patient obedience. Poor adherence results from a complex interplay of multiple factors at patient, practitioner and system levels. Poor adherence among patients with stable coronary artery disease is associated with increased risk of cardiovascular admissions (10%-40%), coronary interventions (10%-30%) and cardiovascular mortality (50%-80%). Improving adherence is a complex process. A range of interventions that target modifiable factors influencing adherence have been explored, but there are no guidelines to guide the choice, and multidisciplinary efforts may be needed. Future research in the area should focus on comparative efficacy of interventions to enhance adherence.

Sedation for electrophysiological procedures.

Administration of intravenous sedation (IVS) has become an integral component of procedural cardiac electrophysiology. IVS is employed in diagnostic and ablation procedures for transcutaneous treatment of cardiac arrhythmias, electrical cardioversion of arrhythmias, and the insertion of implantable electronic devices including pacemakers, defibrillators, and loop recorders. Sedation is frequently performed by nursing staff under the supervision of the proceduralist and in the absence of specialist anesthesiologists. The sedation requirements vary depending on the nature of the procedure. A wide range of sedation techniques have been reported with sedation from the near fully conscious to levels approaching that of general anesthesia. This review examines the methods employed and outcomes associated with reported sedation techniques. There is a large experience with the combination of benzodiazepines and narcotics. These drugs have a broad therapeutic range and the advantage of readily available reversal agents. More recently, the use of propofol without serious adverse events has been reported. The results provide a guide regarding the expected outcomes of these approaches. The complication rate and need for emergency assistance is low in reported series where sedation is administered by nonspecialist anesthesiology staff.

Influence of Carboxymethyl Cellulose as a Thickening Agent for Glauber's Salt-Based Low Temperature PCM.

This work is focused on a novel, promising low temperature phase change material (PCM), based on the eutectic Glauber's salt composition. To allow phase transition within the refrigeration range of temperatures of +5 °C to +12 °C, combined with a high repeatability of melting-freezing processes, and minimized subcooling, the application of three variants of sodium carboxymethyl cellulose (Na-CMC) with distinct molecular weights (700,000, 250,000, and 90,000) is considered. The primary objective is to optimize the stabilization of this eutectic PCM formulation, while maintaining the desired enthalpy level. Preparation methods are refined to ensure repeatability in mixing components, thereby optimizing performance and stability. Additionally, the influence of Na-CMC molecular weight on stabilization is examined through differential scanning calorimetry (DSC), T-history, and rheology tests. The PCM formulation of interest builds upon prior research in which borax, ammonium chloride, and potassium chloride were used as additives to sodium sulfate decahydrate (Glauber's salt), prioritizing environmentally responsible materials. The results reveal that CMC with molecular weights of 250 kg/mol and 90 kg/mol effectively stabilize the PCM without phase separation issues, slowing crystallization kinetics. Conversely, CMC of 700 kg/mol proved ineffective due to the disruption of gel formation at its low gel point, hindering higher concentrations. Calculations of ionic concentration indicate higher Na ion content in PCM stabilized with 90 kg/mol CMC, suggesting increased ionic interactions and gel strength. A tradeoff is discovered between the faster crystallization in lower molecular weight CMC and the higher concentration required, which increases the amount of inert material that does not participate in the phase transition. After thermal cycling, the best formulation had a latent heat of 130 J/g with no supercooling, demonstrating excellent performance. This work advances PCM's reliability as a thermal energy storage solution for diverse applications and highlights the complex relationship between Na-CMC molecular weight and PCM stabilization.

Novel low molecular weight lignins as potential anti-emphysema agents: In vitro triple inhibitory activity against elastase, oxidation and inflammation.

No molecule has been found to be effective against emphysema to date primarily because of its complex pathogenesis that involves elastolysis, oxidation and inflammation. We here describe novel unsulfated or sulfated low molecular weight lignins (LMWLs) chemo-enzymatically prepared from 4-hydroxycinnamic acids monomers, as the first potent triple-action inhibitors of neutrophil elastase, oxidation and inflammation. The inhibitory potencies of three different cinnamic acid-based LMWLs were determined in vitro using chromogenic substrate hydrolysis assays, radical scavenging and lung cellular oxidative biomarker reduced glutathione (rGSH) assays, and lung cellular inflammatory biomarker NFκB and IL-8 assays, respectively. Each LWML uniquely displayed triple-action inhibition, among which CDSO3, a sulfated caffeic acid-based LMWL, was most potent. The half-maximal anti-human neutrophil elastase (HNE) potency of CDSO3 was 0.43 µM. This high potency arose from lignin-like oligomerization, which was further potentiated by 6.6-fold due to sulfation. Mechanistically, this elastase inhibition was of mixed-type, time-dependent and more selective to positively charged elastases. The half-maximal anti-oxidative potency of CDSO3 was 3.52 µM, 4.8-fold potentiated from that of the monomer, caffeic acid (CA). In contrast, the half-maximal inhibitory potency to TNFα-induced inflammation was 5-10 µM, despite no activity with the monomer. More intriguingly, this anti-inflammatory activity was essentially identical with different stimuli, okadaic acid and hydrogen peroxide (H(2)O(2)), which implied that CDSO3 acts directly on inflammatory cascades within the cells. Overall, oligomerization and sulfation produced or significantly potentiated the activity, in comparison to the monomer. Thus, sulfated and unsulfated LMWLs are novel non-peptidic 2.8-4.1 kDa macromolecules that exhibit for the first time potent triple inhibitory activity against elastase, oxidation and inflammation, the three major pathogenic mechanisms known to cause emphysema.

The Pattern and Impact of Hospital-Acquired Infections and Its Outlook in India.

Nosocomial infections form one of the most challenging tasks to deal with in a hospital setting. The burden of hospital-acquired infections (HAI) significantly affects the patient's cost of medical treatment and seriously impacts the economy of a developing country like India. Haphazard antibiotic use for the treatment of these infections has led to the development of resistance among the microbes, and factors that complicate microbial eradication further worsen the scenario. A large percentage of the HAI are preventable by simply following up various protocols which when supported by judicious antibiotic use can declutter the severity of the problem. Organized infection control measures, trained hospital staff, and continuous surveillance of HAI in healthcare settings will help deal with nosocomial infections. Although the ability to deal with HAI in a patient might determine his survival after acquiring a nosocomial infection, prevention remains the best option at all times. Lowering down the burden of nosocomial infections is of utmost importance since it contributes significantly to the overall resource utilization of the hospital and the country. Implementing the use of nanoparticles and nanotechnology in delivering target-specific drugs might be helpful in preventing antibiotic resistance. Taking into account reports of nosocomial infection patterns in various centres of India, the seriousness and consequences of HAI are uncovered in this article.

Sulfated, low molecular weight lignins inhibit a select group of heparin-binding serine proteases.

Sulfated low molecular weight lignins (LMWLs), designed as oligomeric mimetics of low molecular weight heparins (LMWHs), have been found to bind in exosite II of thrombin. To assess whether sulfated LMWLs recognize other heparin-binding proteins, we studied their effect on serine proteases of the coagulation, inflammatory and digestive systems. Using chromogenic substrate hydrolysis assay, sulfated LMWLs were found to potently inhibit coagulation factor XIa and human leukocyte elastase, moderately inhibit cathepsin G and not inhibit coagulation factors VIIa, IXa, and XIIa, plasma kallikrein, activated protein C, trypsin, and chymotrypsin. Competition studies show that UFH competes with sulfated LMWLs for binding to factors Xa and XIa. These results further advance the concept of sulfated LMWLs as heparin mimics and will aid the design of anticoagulants based on their novel scaffold.

A Review of Corneal Transplantation: An Insight on the Overall Global Post-COVID-19 Impact.

The coronavirus disease 2019 (COVID-19) pandemic made us reframe a lot of the strategies followed in medical practice and ophthalmological services and procedures were also not spared, including corneal transplantation or keratoplasty, the most routine procedure performed worldwide. The prevalence of viral presence in the ocular tissue necessitates a focus on the handling of donor ocular tissue and the functioning of eye banks, ensuring it doesn't risk the patient and the doctor's safety. Restrictions in the movement of people during the pandemic limited the number of donations, causing a shortage of tissues, with a large number of people already waitlisted for tissue needs. The lesson from the COVID-19 pandemic directs us to look for long-term corneal storage techniques taking into consideration the tissue viability time and the possibility of post-pandemic shortages. Although there is not a significant number of reports, the cases of corneal graft rejection post-vaccination against COVID-19 are highlighted and thus should form a part of the lookout while evaluating the possible cause of rejection of grafts. This article summarises the overall impact of the pandemic on corneal transplantation and the possible future of storage techniques, which need to evolve and be adapted.

Selective adsorption of butenes over butanes on isoreticular Ni-IRMOF-74-I and Ni-IRMOF-74-II.

The separation of butanes and butenes using MOF-74 (with two reticular MOFs with different pore sizes, Ni-IRMOF-74-I and Ni-IRMOF-74-II) was evaluated computationally using density functional theory. We identified that C4 alkene versus alkane selectivity stems from π-d chemical interactions, whereas selectivity differences among butenes stem from steric implications.

Ventricular Septal Rupture Following Acute Myocardial Infarction.

ST-segment elevation myocardial infarction (STEMI) is a known medical exigency that has seen considerable advances in medical treatment, dramatically boosting survival rates. Post myocardial infarction ventricular rupture is a major serious mechanical complication following myocardial infarction. We present a case of a 68-year-old male admitted to the emergency department with heaviness in the chest, for which electrocardiography was done and it was suggestive of anterior and lateral wall myocardial infarction. After six hours he experienced breathlessness, jugular venous pressure (JVP) was raised, and auscultation revealed early systolic murmur at apex suggestive of ventricular septal rupture. An urgent echocardiogram was done and it confirmed the diagnosis of ventricular septal rupture (VSR). To enhance the prognosis, early identification and appropriate care are required, which necessitate a thorough clinical evaluation that raises the possibility of mechanical problem, as late presentation is one of the major risk factors for developing VSR. VSR can manifest itself in numerous ways, based on the patient's condition. Right clinical judgement and ECG are required to establish a quick diagnosis, as a result, to determine the most appropriate treatment at the appropriate time.

Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury.

OBJECTIVE: Sepsis-induced lung injury is a persisting clinical problem with no direct therapy. Recent work suggests that intravenously infused ascorbic acid improves the circulatory dysfunction of sepsis. We used a model of endotoxin-induced acute lung injury to determine whether parenteral ascorbic acid modulates the dysregulated proinflammatory, procoagulant state that leads to lung injury. DESIGN: C57BL/6 mice were exposed to lethal lipopolysaccharide doses (10 µg/g of body weight) to induce acute lung injury. SETTING: Laboratory investigation. SUBJECTS: Wild-type C57BL/6 mice. INTERVENTIONS: Ascorbic acid or its oxidized form (dehydroascorbic acid) was administered intraperitoneally at 200 mg/kg 30 mins after the lethal lipopolysaccharide dose. MEASUREMENTS AND MAIN RESULTS: We quantified survival, lung capillary leak, proinflammatory chemokine expression, and lung microvascular thrombosis. Lipopolysaccharide induced 100% lethality in mice within 28 hrs of exposure and in lung we observed intense neutrophil sequestration, loss of capillary barrier function, exuberant pulmonary inflammation, and extensive microthrombus formation. A time-delayed infusion protocol of both ascorbic acid and dehydroascorbic acid significantly prolonged survival. Both ascorbic acid and dehydroascorbic acid preserved lung architecture and barrier function while attenuating proinflammatory chemokine expression and microvascular thrombosis. Ascorbic acid and dehydroascorbic acid attenuated nuclear factor kappa B activation and normalized coagulation parameters. CONCLUSIONS: Ascorbic acid administered in an interventional manner following lipopolysaccharide infusion attenuates proinflammatory, procoagulant states that induce lung vascular injury in an animal model of sepsis.