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SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD.sup.+ -dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers. Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity. SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation. SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients.

Background The glial response in multiple sclerosis (MS), especially for recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), predicts the success of remyelination of MS plaques and return of function. As a central player in neuroinflammation, activation and polarization of microglia/macrophages (M/M) that modulate the inflammatory niche and cytokine components in demyelination lesions may impact the OPC response and progression of demyelination and remyelination. However, the dynamic behaviors of M/M and OPCs during demyelination and spontaneous remyelination are poorly understood, and the complex role of neuroinflammation in the demyelination-remyelination process is not well known. In this study, we utilized two focal demyelination models with different dynamic patterns of M/M to investigate the correlation between M/M polarization and the demyelination-remyelination process. Methods The temporal and spatial features of M/M activation/polarization and OPC response in two focal demyelination models induced by lysolecithin (LPC) and lipopolysaccharide (LPS) were examined in mice. Detailed discrimination of morphology, sensorimotor function, diffusion tensor imaging (DTI), inflammation-relevant cytokines, and glial responses between these two models were analyzed at different phases. Results The results show that LPC and LPS induced distinctive temporal and spatial lesion patterns. LPS produced diffuse demyelination lesions, with a delayed peak of demyelination and functional decline compared to LPC. Oligodendrocytes, astrocytes, and M/M were scattered throughout the LPS-induced demyelination lesions but were distributed in a layer-like pattern throughout the LPC-induced lesion. The specific M/M polarization was tightly correlated to the lesion pattern associated with balance beam function. Conclusions This study elaborated on the spatial and temporal features of neuroinflammation mediators and glial response during the demyelination-remyelination processes in two focal demyelination models. Specific M/M polarization is highly correlated to the demyelination-remyelination process probably via modulations of the inflammatory niche, cytokine components, and OPC response. These findings not only provide a basis for understanding the complex and dynamic glial phenotypes and behaviors but also reveal potential targets to promote/inhibit certain M/M phenotypes at the appropriate time for efficient remyelination.

Phage therapy is an emerging therapeutic approach for treating bacterial infections that do not respond to traditional antibiotics. The addition of phage therapy to systemic antibiotics to treat a patient with recurrent E. faecium infections that were non-responsive to antibiotics alone resulted in fewer hospitalizations and improved the patient's quality of life. Combination phage and antibiotic therapy reduced E. faecium and VRE abundance in the patient's stool. Eventually, an anti-phage antibody response emerged that was able to neutralize phage activity, which may have limited clinical efficacy. This study demonstrates the potential of phages as an additional option in the antimicrobial toolbox for treating invasive enterococcal infections and highlights the need for further investigation to ensure phage therapy can be deployed for maximum clinical benefit.

In a study involving 51 patients with electronic-cigarette, or vaping, product use–associated lung injury in 16 states across the United States, vitamin E acetate was detected in samples of bronchoalveolar-lavage fluid from 94% of the patients but not in samples from a healthy comparator group.

Between 15 and 19 March 2022, East Antarctica experienced an exceptional heat wave with widespread 30°–40°C temperature anomalies across the ice sheet. In Part I, we assessed the meteorological drivers that generated an intense atmospheric river (AR) that caused these record-shattering temperature anomalies. Here, we continue our large collaborative study by analyzing the widespread and diverse impacts driven by the AR landfall. These impacts included widespread rain and surface melt that was recorded along coastal areas, but this was outweighed by widespread high snowfall accumulations resulting in a largely positive surface mass balance contribution to the East Antarctic region. An analysis of the surface energy budget indicated that widespread downward longwave radiation anomalies caused by large cloud-liquid water contents along with some scattered solar radiation produced intense surface warming. Isotope measurements of the moisture were highly elevated, likely imprinting a strong signal for past climate reconstructions. The AR event attenuated cosmic ray measurements at Concordia, something previously never observed. Last, an extratropical cyclone west of the AR landfall likely triggered the final collapse of the critically unstable Conger Ice Shelf while further reducing an already record low sea ice extent.

Accumulating evidence suggests that platelet-activating factor (PAF) increases the inflammatory response in demyelinating diseases such as multiple sclerosis. However, PAF receptor (PAFR) antagonists do not show therapeutic efficacy for MS, and its underlying mechanisms remain poorly understood. In the present study, we investigated the effects of PAF on an ex vivo demyelination cerebellar model following lysophosphatidylcholine (LPC, 0.5 mg/mL) application using wild-type and PAFR conventional knockout (PAFR-KO) mice. Demyelination was induced in cerebellar slices that were cultured with LPC for 18 h. Exogenous PAF (1 μM) acting on cerebellar slices alone did not cause demyelination but increased the severity of LPC-induced demyelination in both wild-type and PAFR-KO mice. LPC inhibited the expression of PAF-AH, MBP, TNF-α, and TGF-β1 but facilitated the expression of IL-1β and IL-6 in wild-type preparations. Of note, exogenous PAF stimulated microglial activation in both wild-type and PAFR-KO mice. The subsequent inflammatory cytokines TNFα, IL-1β, and IL-6 as well as the anti-inflammatory cytokine TGF-β1 demonstrated a diverse transcriptional profile with or without LPC treatment. PAF promoted TNF-α expression and suppressed TGF-β1 expression indiscriminately in wild-type and knockout slices; however, transcription of IL-1β and IL-6 was not significantly affected in both slices. The syntheses of IL-1β and IL-6 were significantly increased in LPC-induced demyelination preparations without PAF but showed a redundancy in PAF-treated wild-type and knockout slices. These data suggest that PAF can play a detrimental role in LPC-induced demyelination probably due to a redundant response of PAFR-dependent and PAFR-independent effects on inflammatory cytokines.

Abstract Background In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through upregulation of efflux pumps and transcriptional downregulation of the porin OprD. Evidence of this effect among hematologic malignancy (HM) patients or hematopoietic cell transplant (HCT) recipients receiving fluoroquinolone prophylaxis for neutropenia is lacking. Methods We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. We determined the association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem nonsusceptibility. Whole-genome sequencing (WGS) and phenotypic assessments of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance. Results We analyzed 55 episodes of P. aeruginosa bacteremia among 51 patients. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with nonsusceptibility to meropenem, but not to antipseudomonal β-lactams or aminoglycosides. The receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate. All meropenem-nonsusceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem-nonsusceptible isolates tested demonstrated reductions in the meropenem minimum inhibitory concentration in the presence of an efflux pump inhibitor. A phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients. Conclusions Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population. Fluoroquinolone prophylaxis in neutropenic, hematologic malignancy patients and hematopoietic-transplant recipients is associated with breakthrough bacteremia with meropenem–non-susceptible P. aeruginosa strains. These findings require validation in larger studies and may have implications for the empirical management of febrile neutropenia.

BackgroundThe neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.MethodsA retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS.Results509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8–33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1–16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9–9.1).ConclusionsWe confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.

Extensively drug-resistant Acinetobacter baumannii (XDR-Ab) has emerged as a major nosocomial pathogen, but optimal treatment regimens are unknown. Although solid organ transplant (SOT) recipients are particularly susceptible to XDR-Ab infections, studies in this population are limited. Our objectives were to determine the epidemiology, clinical characteristics and outcomes of XDR-Ab infections among SOT patients. A retrospective study of SOT recipients at our center who were colonized or infected with XDR-Ab between November 2006 and December 2011 was conducted. Among infected patients, the primary outcome was survival at 28 days. Secondary outcomes included survival at 90 days and clinical success at 28 days, and XDR-Ab infection recurrence. XDR-Ab was isolated from 69 SOT patients, of whom 41% (28) and 59% (41) were colonized and infected, respectively. Infections were significantly more common among cardiothoracic than abdominal transplant recipients (p=0.0004). Ninety-eight percent (40/41) of patients had respiratory tract infections, most commonly ventilator-associated pneumonia (VAP; 88% [36/41]). Survival rates at 28 and 90 days were 54% (22/41) and 46% (19/41), respectively. Treatment with a colistin-carbapenem regimen was an independent predictor of 28-day survival (p=0.01; odds ratio=7.88 [95% CI: 1.60-38.76]). Clinical success at 28 days was achieved in 49% (18/37) of patients who received antimicrobial therapy, but 44% (8/18) of successes were associated with infection recurrence within 3 months. Colistin resistance emerged in 18% (2/11) and 100% (3/3) of patients treated with colistin-carbapenem and colistin-tigecycline, respectively (p=0.03). XDR-Ab causes VAP and other respiratory infections following SOT that are associated with significant recurrence and mortality rates. Cardiothoracic transplant recipients are at greatest risk. Results from this retrospective study suggest that colistin-carbapenem combinations may result in improved clinical responses and survival compared to other regimens and may also limit the emergence of colistin resistance.

Suicidal behavior and demand for services have been increasing in adolescents. Many of the current treatments are focused on symptom mitigation, crisis management, and safety planning; however, few are aimed at remediating underlying vulnerabilities that may be contributing to suicide risk. Dynamic Deconstructive Psychotherapy (DDP) has been found to be effective for suicidal adults but has never been studied for adolescents. The present study examined real-world outcomes of 65 suicidal adolescents, aged 13–17 years, receiving weekly DDP in an outpatient clinic. The primary outcome was change in suicide ideation from baseline to 6 months of treatment as assessed by the Suicide Ideation Subscale of the Columbia Suicide Severity Rating Scale. In intent-to-treat analyses, suicide ideation significantly decreased over the 6 months with a large treatment effect (d = 1.19). Secondary measures, such as suicide attempts, self-harm, depression, anxiety, disability, self-compassion, and inpatient utilization, also improved significantly. Among the 42 adolescents (65%) who completed at least 6 months of treatment, suicide attempts decreased by 84%. DDP may be effective in reducing suicide ideation and other risk factors in suicidal adolescents and may be cost-effective given reduced inpatient utilization. These initial promising findings warrant further research and development.