Acute ampakines increase voiding function and coordination in a rat model of SCI.

Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague-Dawley rats received a unilateral contusion of the T9 spinal cord (n = 10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed 5 d post-SCI under urethane anesthesia. Data were compared to responses in spinal-intact rats (n = 8). The 'low-impact' ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously. The HPCD vehicle had no discernible impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

Role of Histone Deacetylase Inhibitor in Diabetic Painful Neuropathy.

Diabetic painful neuropathy (DPN) is one of the most detrimental complications of diabetes. Alterations in neuroinflammatory mediators play significant roles in the development of DPN. Infiltration of the neutrophils and monocyte/macrophages contributes substantial role in the degenerative process of the distal sciatic nerve by forming neutrophil extracellular traps (NETs) under diabetic condition. Citrullination of histones due to increase in protein arginine deiminase (PAD) enzyme activity under hyperglycemia may promote NET formation, which can further increase the cytokine production by activating macrophages and proliferation of neutrophils. This study reveals that the increase in histone deacetylases (HDAC) is crucial in DPN and inhibition of HDAC using HDAC inhibitor (HDACi) FK228 would suppress NETosis and alleviate diabetic nerve degeneration and pain. FK228, also known as romidepsin, is FDA approved for the treatment of cutaneous T-cell lymphoma yet the molecular mechanisms of this drug are not completely understood in DPN. In this study, type 2 diabetic (T2D) mice with pain were treated with HDACi, FK228 1 mg/kg; I.P. 2 × /week for 3 weeks. The results demonstrate that FK228 treatment can alleviate thermal hyperalgesia and mechanical allodynia significantly along with changes in the expression of HDACs in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons of diabetic animals. The results also indicate that FK228 treatment can alter the expression of neutrophil elastase (NE), extracellular or cell free DNA (cfDNA), citrullinated histone-3 (CitH3), PADI4, growth-associated protein (GAP)-43, and glucose transporter (GLUT)-4. Overall, this study suggests that FK228 could amend the expression of nerve regeneration markers and inflammatory mediators in diabetic animals and may offer an alternative treatment approach for DPN.

A protein kinase C α and ß inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes.

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCß, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/ß inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/ß inhibition to T2D and obesity in humans is warranted.

Assessment of Thoracic Endovascular Aortic Repair Using Relay Proximal Scallop: Results of a French Prospective Multicentre Study.

OBJECTIVE: A proximal scallop design allows aortic arch repair without complex endovascular manipulation in the aortic arch. The aim was to assess the safety and efficacy at one year of the Relay proximal scallop stent graft. METHODS: A prospective multicentre study evaluated consecutive patients treated with the Relay proximal scallop stent graft in 10 French aortic centres. All consecutive patients eligible for elective thoracic endovascular repair with proximal scallop in the 10 participating centres between January 2015 and July 2018 were included. Primary endpoints were 30 day mortality, stroke, and spinal cord ischaemia (SCI) rates. Outcomes including safety and efficacy, technical and clinical success, all cause death, neurological events, vessel patency, and device specific complications were analysed. Survival and survival without severe complications were estimated using Kaplan-Meier estimates. RESULTS: Ten aortic centres treated 40 patients for thoracic aortic aneurysm (45%), penetrating atherosclerotic aneurysm (30%), and dissection (25%). Half of the procedures (50%) targeted zone 0 of the aortic arch (zone 0 in 17.5% and zones 0/1 in 32.5%), 37.5% targeted zone 2 (35% zone 2 alone; 2.5% zones 1/2), and 15% targeted zone 1 (12.5% zone 1 alone). Median follow up was one year. Thirty day mortality, stroke, and SCI rates were 10%, 5%, and 0% respectively. Primary technical success was 95%. Type Ia, Ib, and III endoleaks rates were 5.4%, 0%, and 0% respectively at one month. The overall mortality rate at one year was 17.5%. Aneurysm expansion was > 5 mm in one case at one year associated with type Ia endoleak (3%). There was no supra-aortic trunk thrombosis, one (2%) graft kink, and no migration. CONCLUSION: One year outcomes showed that the Relay proximal scallop stent graft is an acceptable answer to thoracic aortic disease to deal with short proximal landing zones.

Stricturing Crohn's Disease Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity and Intercellular Interactions.

BACKGROUND & AIMS: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full-thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single-cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. METHODS: We performed scRNAseq of 13 fresh full-thickness CD resections containing noninvolved, inflamed nonstrictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next-generation sequencing, proteomics, and animal models. RESULTS: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and up-regulated, and its profibrotic function was validated using NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and knock-out and antibody-mediated CDH11 blockade in experimental colitis. CONCLUSIONS: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and open potential therapeutic developments. This work has been posted as a preprint on Biorxiv under doi: 10.1101/2023.04.03.534781.

Acute ampakines increase voiding function and coordination in a rat model of SCI.

Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague Dawley rats received a unilateral contusion of the T9 spinal cord (n=10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed five days post-SCI under urethane anesthesia. Data were compared to responses in spinal intact rats (n=8). The "low impact" ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (HPCD) was administered intravenously. The HPCD vehicle had no discernable impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

Cellular and humoral responses after second and third SARS-CoV-2 vaccinations in patients with autoimmune diseases treated with rituximab: specific T cell immunity remains longer and plays a protective role against SARS-CoV-2 reinfections.

Background: Humoral and cellular immune responses are known to be crucial for patients to recover from COVID-19 and to protect them against SARS-CoV-2 reinfection once infected or vaccinated. Objectives: This study aimed to investigate humoral and T cell responses to SARS-CoV-2 vaccination in patients with autoimmune diseases after the second and third vaccine doses while on rituximab and their potential protective role against reinfection. Methods: Ten COVID-19-naïve patients were included. Three time points were used for monitoring cellular and humoral responses: pre-vaccine to exclude virus exposure (time point 1) and post-second and post-third vaccine (time points 2 and 3). Specific IgG antibodies were monitored by Luminex and T cells against SARS-CoV-2 spike-protein by ELISpot and CoVITEST. All episodes of symptomatic COVID-19 were recorded. Results: Nine patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and one with an undifferentiated autoimmune disease were included. Nine patients received mRNA vaccines. The last rituximab infusion was administered for a mean (SD) of 15 (10) weeks before the first vaccine and six patients were CD19-B cell-depleted. After a mean (SD) of 19 (10) and 16 (2) days from the second and third vaccine dose, IgG anti-SARS-CoV-2 antibodies were detected in six (60%) and eight (80%) patients, respectively. All patients developed specific T cell responses by ELISpot and CoVITEST in time points 2 and 3. Previous B cell depletion correlated with anti-SARS-CoV-2 IgG levels. Nine (90%) patients developed mild COVID-19 after a median of 7 months of the third dose. Conclusion: Rituximab in patients with autoimmune diseases reduces humoral responses but does not avoid the development of T cell responses to SARS-CoV-2 vaccination, which remain present after a booster dose. A steady cellular immunity appears to be protective against subsequent reinfections.

Stricturing Crohn's disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions.

Background: Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding it's pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. Methods: We performed scRNAseq of 13 fresh full thickness CD resections containing non-involved, inflamed non-strictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next generation sequencing, proteomics and animal models. Results: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and upregulated, and its pro-fibrotic function was validated by NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and two animal models of experimental colitis. Conclusion: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and opens potential therapeutic developments.

Molecular MR Imaging of Renal Fibrogenesis in Mice.

BACKGROUND: In most CKDs, lysyl oxidase oxidation of collagen forms allysine side chains, which then form stable crosslinks. We hypothesized that MRI with the allysine-targeted probe Gd-oxyamine (OA) could be used to measure this process and noninvasively detect renal fibrosis. METHODS: Two mouse models were used: hereditary nephritis in Col4a3-deficient mice (Alport model) and a glomerulonephritis model, nephrotoxic nephritis (NTN). MRI measured the difference in kidney relaxation rate, ΔR1, after intravenous Gd-OA administration. Renal tissue was collected for biochemical and histological analysis. RESULTS: ΔR1 was increased in the renal cortex of NTN mice and in both the cortex and the medulla of Alport mice. Ex vivo tissue analyses showed increased collagen and Gd-OA levels in fibrotic renal tissues and a high correlation between tissue collagen and ΔR1. CONCLUSIONS: Magnetic resonance imaging using Gd-OA is potentially a valuable tool for detecting and staging renal fibrogenesis.

Optogenetic activation of the tongue in spontaneously breathing mice.

Inadequate tongue muscle activation contributes to dysarthria, dysphagia, and obstructive sleep apnea. Thus, treatments which increase tongue muscle activity have potential clinical benefit. We hypothesized that lingual injection of an adeno-associated virus (AAV) encoding channelrhodopsin-2 (ChR2) would enable light-induced activation of tongue motor units during spontaneous breathing. An AAV serotype 9 vector (pACAGW-ChR2-Venus-AAV9, 8.29 × 1011 vg) was injected to the posterior tongue in adult C57BL/6J mice. After 12 weeks, mice were anesthetized and posterior tongue electromyographic (EMG) activity was recorded during spontaneous breathing; a light source was positioned near the injection site. Light-evoked EMG responses increased with the intensity and duration of pulses. Stimulus trains (250 ms) evoked EMG bursts that were comparable to endogenous (inspiratory) tongue muscle activation. Histology confirmed lingual myofiber transgene expression. We conclude that intralingual AAV9-ChR2 delivery enables light evoked lingual EMG activity. These proof-of-concept studies lay the groundwork for clinical application of this novel approach to lingual therapeutics.

School Risk and Protective Factors of Suicide: A Cultural Model of Suicide Risk and Protective Factors in Schools.

There are known cultural variations in correlates of and symptoms related to suicide-related thoughts and behaviors; however, the majority of research that informs suicide prevention in school systems has focused on research based on Euro-American/White students. By exploring school-related risk and protective factors in ethnic-racial minoritized students, we expand existing multicultural models of suicide prevention for school settings. Specifically, this systematic literature review identified 33 studies conducted with American Indian and Alaskan Native, Hispanic and Latinx, Black and African American, and Asian American and Pacific Islander students. Findings underscore the importance of building relationships with the school community and fostering a sense of safety for students, the need to approach school-based suicide prevention and intervention with cultural considerations, and the importance of connecting students and families with providers in culturally sensitive and informed ways. Taken together, schools need to build school-family-community partnerships that promote culturally sensitive approaches to suicide prevention.

Risk Factors for Incomplete Aortic Remodeling With Stent-Assisted Balloon-Induced Intimal Disruption and Relamination in Aortic Dissection Repair for Complicated Aortic Dissection: Results of a Multicenter Study.

PURPOSE: The STABILISE technique has extended the treatment of aortic dissection to the thoracoabdominal aorta to achieve complete aortic remodeling. The aim of this multicenter study was to analyze the short- and midterm anatomical results of the STABILISE technique. MATERIALS AND METHODS: We retrospectively analyzed patients treated with the STABILISE technique for complicated aortic dissection at 3 French academic centers. The aortic diameter at different levels was measured preoperatively, postoperatively, and at 1 year. RESULTS: Between 2018 and 2020, 58 patients, including 47 men (average patient age: 60±11 years), were treated for type B aortic dissection in 34 cases and residual aortic dissection after type A repair in 24 cases. Three (5.2%) patients died postoperatively. Complete aortic remodeling (false lumen thrombosis and complete reapposition of the intimal flap) was achieved in 45/55 patients (81.8%), and false lumen thrombosis in the thoracic aorta was achieved in 52/55 patients (94.5%). At 1 year, with a computed tomographic (CT) scan available for 98.2% (54/55) of patients, we observed a significant decrease in the maximal thoracic aortic diameter and a significant increase in the aortic diameter at the bare-stent level compared with the preoperative CT scan. Severe aortic angulation (p=0.024) was a risk factor for incomplete aortic remodeling and significantly increased the aortic diameter (p=0.032). Chronic aortic dissection was associated with an increased risk of incomplete aortic remodeling (p=0.002). CONCLUSIONS: STABILISE for complicated aortic dissection results in false lumen thrombosis, complete reapposition of the intimal flap, and a decrease in the maximum aortic diameter in most cases. Incomplete reapposition of the intimal flap, which is more frequent in cases of chronic aortic dissection and severe aortic angulation, is a risk factor for a significant increase in the aortic diameter at the bare-stent level, and this risk justifies close follow-up and better patient selection. CLINICAL IMPACT: STABILISE technique for complicated aortic dissection results in false lumen thrombosis, complete aortic remodeling and a decrease in the maximum aortic diameter in most cases. At the bare-stent level, incomplete reapposition of the intimal flap, more frequent in chronic aortic dissection and severe aortic angulation, is a risk factor for an increased aortic diameter. This finding justifies close follow-up and better patient selection; thus, the STABILISE technique should be used with care in chronic aortic dissection and severe aortic angulation.

CoVITEST: A Fast and Reliable Method to Monitor Anti-SARS-CoV-2 Specific T Cells From Whole Blood.

Cellular and humoral immune responses are essential for COVID-19 recovery and protection against SARS-CoV-2 reinfection. To date, the evaluation of SARS-CoV-2 immune protection has mainly focused on antibody detection, generally disregarding the cellular response, or placing it in a secondary position. This phenomenon may be explained by the complex nature of the assays needed to analyze cellular immunity compared with the technically simple and automated detection of antibodies. Nevertheless, a large body of evidence supports the relevance of the T cell's role in protection against SARS-CoV-2, especially in vulnerable individuals with a weakened immune system (such as the population over 65 and patients with immunodeficiencies). Here we propose to use CoVITEST (Covid19 anti-Viral Immunity based on T cells for Evaluation in a Simple Test), a fast, affordable and accessible in-house assay that, together with a diagnostic matrix, allows us to determine those patients who might be protected with SARS-CoV-2-reactive T cells. The method was established using healthy SARS-CoV-2-naïve donors pre- and post-vaccination (n=30), and further validated with convalescent COVID-19 donors (n=51) in a side-by-side comparison with the gold standard IFN-γ ELISpot. We demonstrated that our CoVITEST presented reliable and comparable results to those obtained with the ELISpot technique in a considerably shorter time (less than 8 hours). In conclusion, we present a simple but reliable assay to determine cellular immunity against SARS-CoV-2 that can be used routinely during this pandemic to monitor the immune status in vulnerable patients and thereby adjust their therapeutic approaches. This method might indeed help to optimize and improve decision-making protocols for re-vaccination against SARS-CoV-2, at least for some population subsets.

Initial Study of the Extended STABILISE Technique for Complete Remodeling in Aortic Dissection.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is the standard treatment for acute complicated type B aortic dissection (TBAD). However, long-term results reveal that TEVAR does not achieve a complete aortic remodeling and poses a risk of aneurysmal aortic degeneration. Distal re-entry treatment at the abdominal level seems to be necessary to obtain a complete remodeling in TBAD. Moreover, it is necessary to treat the aortoiliac bifurcation in patients with persistent true lumen collapse or limb ischemia. METHODS: Between January 2018 and October 2019, 11 patients with acute or sub-acute complicated TBAD or non-A non-B aortic dissection were treated in our institution in an endovascular fashion. We performed the stent-assisted, balloon-induced intimal disruption and relamination in aortic dissection repair (STABILISE) technique in all cases, but 2 cases required complementary treatment of the aortoiliac bifurcation with a bifurcated AFX endograft system for limb ischemia due to true lumen collapse. RESULTS: Technical success was obtained in all patients. No procedural complications occurred. No postoperative deaths, stroke, paraplegia, mesenteric, or renal ischemia were observed, and no secondary intervention was necessary. Satisfactory aortic re-modeling was obtained after the follow-up periods with a 57.5% mean true lumen expansion. CONCLUSIONS: Our initial experience using the extended STABILISE (e-STABILISE) technique using a bifurcated AFX endograft did not result in any postoperative mortality or complications. Without additional data, this technique should be reserved for specific patients who require revascularization of the aortoiliac bifurcation.

The roles of school in supporting LGBTQ+ youth: A systematic review and ecological framework for understanding risk for suicide-related thoughts and behaviors.

The extant literature on suicide-related thoughts and behaviors (STB) has highlighted increased patterns of risk among specific minoritized populations, including lesbian, gay, bisexual, transgender, questioning, intersex, two spirit, and queer (LGBTQ+) youth. Compared to their heterosexual and cisgender peers, LGBTQ+ youth are at increased risk for having STB. Identity-specific stressors such as homonegativity and anti-queerness are among the unique factors posited to contribute to this risk and inhibit factors that protect against suicide. The school setting has been a focal point for suicide prevention and intervention and may also play a key role in linking students to care; however, schools also hold the potential to provide supports and experiences that may buffer against risk factors for STB in LGBTQ+ students. This systematic literature review presents findings from 44 studies examining school-related correlates of STB in LGBTQ+ students, informing an ecological approach to suicide prevention for school settings. Findings underscore the importance of school context for preventing STB in LGBTQ+ youth. Approaches that prioritize safety and acceptance of LGBTQ+ youth should span multiple layers of a student's ecology, including district and state level policies and school programs and interventions, such as Gender and Sexuality Alliances and universal bullying prevention programs. Beyond their role as a primary access point for behavioral health services, schools offer a unique opportunity to support suicide prevention by combating minority stressors through promoting positive social relationships and a safe community for LGBTQ+ students.

Association of Positive Fluid Balance at Discharge After Sepsis Management With 30-Day Readmission.

Importance: Although early fluid administration has been shown to lower sepsis mortality, positive fluid balance has been associated with adverse outcomes. Little is known about associations in non-intensive care unit settings, with growing concern about readmission from excess fluid accumulation in patients with sepsis. Objective: To evaluate whether positive fluid balance among non-critically ill patients with sepsis was associated with increased readmission risk, including readmission for heart failure. Design, Setting, and Participants: This multicenter retrospective cohort study was conducted between January 1, 2012, and December 31, 2017, among 57 032 non-critically ill adults hospitalized for sepsis at 21 hospitals across Northern California. Kaiser Permanente Northern California is an integrated health care system with a community-based population of more than 4.4 million members. Statistical analysis was performed from January 1 to December 31, 2019. Exposures: Intake and output net fluid balance (I/O) measured daily and cumulatively at discharge (positive vs negative). Main Outcomes and Measures: The primary outcome was 30-day readmission. The secondary outcomes were readmission stratified by category and mortality after living discharge. Results: The cohort included 57 032 patients who were hospitalized for sepsis (28 779 women [50.5%]; mean [SD] age, 73.7 [15.5] years). Compared with patients with positive I/O (40 940 [71.8%]), those with negative I/O (16 092 [28.2%]) were older, with increased comorbidity, acute illness severity, preexisting heart failure or chronic kidney disease, diuretic use, and decreased fluid administration volume. During 30-day follow-up, 8719 patients (15.3%) were readmitted and 3639 patients (6.4%) died. There was no difference in readmission between patients with positive vs negative I/O (HR, 1.00; 95% CI, 0.95-1.05). No association was detected between readmission and I/O using continuous, splined, and quadratic function transformations. Positive I/O was associated with decreased heart failure-related readmission (HR, 0.80 [95% CI, 0.71-0.91]) and increased 30-day mortality (HR, 1.23 [95% CI, 1.15-1.31]). Conclusions and Relevance: In this large observational study of non-critically ill patients hospitalized with sepsis, there was no association between positive fluid balance at the time of discharge and readmission. However, these findings may have been limited by variable recording and documentation of fluid intake and output; additional studies are needed to examine the association of fluid status with outcomes in patients with sepsis to reduce readmission risk.

Quantitative, noninvasive MRI characterization of disease progression in a mouse model of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is an increasing cause of chronic liver disease characterized by steatosis, inflammation, and fibrosis which can lead to cirrhosis, hepatocellular carcinoma, and mortality. Quantitative, noninvasive methods for characterizing the pathophysiology of NASH at both the preclinical and clinical level are sorely needed. We report here a multiparametric magnetic resonance imaging (MRI) protocol with the fibrogenesis probe Gd-Hyd to characterize fibrotic disease activity and steatosis in a common mouse model of NASH. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with advanced fibrosis. Mice fed normal chow and CDAHFD underwent MRI after 2, 6, 10 and 14 weeks to measure liver T1, T2*, fat fraction, and dynamic T1-weighted Gd-Hyd enhanced imaging of the liver. Steatosis, inflammation, and fibrosis were then quantified by histology. NASH and fibrosis developed quickly in CDAHFD fed mice with strong correlation between morphometric steatosis quantification and liver fat estimated by MRI (r = 0.90). Sirius red histology and collagen quantification confirmed increasing fibrosis over time (r = 0.82). Though baseline T1 and T2* measurements did not correlate with fibrosis, Gd-Hyd signal enhancement provided a measure of the extent of active fibrotic disease progression and correlated strongly with lysyl oxidase expression. Gd-Hyd MRI accurately detects fibrogenesis in a mouse model of NASH with advanced fibrosis and can be combined with other MR measures, like fat imaging, to more accurately assess disease burden.

Fewer-Angle SPECT/CT Blood Pool Imaging for Infection and Inflammation.

A new protocol for rapid SPECT/CT blood pool imaging consisting of fewer image-angle acquisitions (fewer-angle SPECT/CT, or FASpecT/CT) was evaluated for localization of focal sites of soft-tissue inflammation, infection, and osteomyelitis. Methods: Immediately after dynamic flow and standard planar blood pool imaging with 99mTc-methylene diphosphonate, FASpecT/CT was performed with a dual-head γ-camera consisting of 6 steps over 360°, 12 total images with 30° of separation between angles, and 30 s per image, requiring a total imaging time of approximately 3 min. Images were reconstructed using iterative ordered-subset expectation maximization. Before use in a patient-care setting, various FASpecT/CT acquisition protocols were modeled using a phantom to determine the minimum number of stops and the stop duration required to produce a reliable image. Results: FASpecT/CT images provided excellent 3-dimensional localization of spine osteomyelitis, soft-tissue infection of the foot, and tendonitis of the hand and foot using a 3-min image acquisition time. The FASpecT/CT acquisition protocol required 1.3-3.5 min, including camera movement time. This was a reduction of 72%-90% from the time required for the standard 60-angle, 20-s SPECT/CT acquisition. Conclusion: The ability of FASpecT/CT blood pool images to help localize focal sites of hyperemia and inflammation can increase exam sensitivity and specificity. Additionally, using a FASpecT/CT protocol decreases imaging time by up to 90%.

Improved Beta Cell Glucose Sensitivity Plays Predominant Role in the Decrease in HbA1c with Cana and Lira in T2DM.

AIM: To examine the effect of combination therapy with canagliflozin plus liraglutide versus each agent alone on beta cell function in type 2 diabetes mellitus (T2DM) patients. RESEARCH DESIGN AND METHODS: A total of 45 poorly controlled (HbA1c = 7%-11%) T2DM patients received an oral glucose tolerance test (OGTT) before and after 16 weeks of treatment with: (i) liraglutide (LIRA); (ii) canagliflozin (CANA); (iii) liraglutide plus canagliflozin (CANA/LIRA). RESULTS: Both liraglutide and canagliflozin significantly lowered HbA1c with no significant additive effect of the combination on HbA1c (0.89%, 1.43%, and 1.67% respectively). Insulin secretion during the OGTT, measured with (∆C-Pep/∆G)0-120, increased in the 3 groups (from 0.30 ± 0.06 to 0.48 ± 0.10; 0.29 ± 0.05 to 0.98 ± 0.23; and 0.24 ± 0.06 to 1.09 ± 0.12 in subjects receiving CANA, LIRA and CANA/LIRA respectively; P = 0.02 for CANA vs LIRA, P < 0.0001, CANA/LIRA vs CANA), and the increase in insulin secretion was associated with an increase in beta cell glucose sensitivity (29 ± 5 to 55 ± 11; 33 ± 6 to 101 ± 16; and 28 ± 6 to 112 ± 12, respectively; P = 0.01 for CANA vs LIRA, P < 0.0001, CANA/LIRA vs CANA). No significant difference in the increase in insulin secretion or beta cell glucose sensitivity was observed between subjects in LIRA or CANA/LIRA groups. The decrease in HbA1c strongly and inversely correlated with the increase in beta cell glucose sensitivity (r = 0.71, P < 0.001). In multivariate regression model, improved beta cell glucose sensitivity was the strongest predictor of HbA1c decrease with each therapy. CONCLUSION: Improved beta cell glucose sensitivity with canagliflozin monotherapy and liraglutide monotherapy or in combination is major factor responsible for the HbA1c decrease. Canagliflozin failed to produce an additive effect to improve beta cell glucose sensitivity above that observed with liraglutide.