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We describe a new set of isotope reagents, 12C4-, 12C213C2-, and 13C4-5-diethylamino-naphthalene-1-sulfonyl chloride (DensCl), in combination with liquid chromatography Fourier-transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS), for improved analysis of the amine- and phenol-containing submetabolome. The synthesis of the reagents is reported, and an optimized derivatization protocol for labeling amines and phenols is described. To demonstrate the utility of the triplex reagents for metabolome profiling of biological samples, urine samples collected daily from a healthy volunteer over a period of 14 days were analyzed. The overall workflow is straightforward, including differential isotope labeling of individual samples and a pooled sample that serves a global internal standard, mixing of the isotope differentially labeled samples and LC-MS analysis for relative metabolome quantification. Comparing to the dansyl chloride (DnsCl) duplex isotope reagents, the new triplex DensCl reagents offer the advantages of improved metabolite detectability due to enhanced sensitivity (i.e., about 1000 peak pairs detected by DensCl labeling vs about 600 peak pairs detected by DnsCl labeling) and analysis speed (i.e., simultaneous analysis of two comparative samples by DensCl vs only one comparative sample analyzed by DnsCl). [ABSTRACT FROM AUTHOR]

We report a new quantitative metabolome profiling technique based on differential 12C-13C-isotope dansylation labeling of metabolites, fast liquid chromatography (LC) separation and electrospray ionization Fourier-transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) detection. An isotope reagent, 13C-dansyl chloride, can be readily synthesized. This reagent, along with 12C-dansyl chloride, provides a simple and robust means of labeling metabolites containing primary amine, secondary amine, or phenolic hydroxyl group(s). It is shown that dansylation labeling offers 1-3 orders of magnitude ESI signal enhancement over the underivatized counterparts. Dansylation alters the chromatographic behaviors of polar and ionic metabolites normally not retainable on a reversed phase (RP) column to an extent that they can be retained and separated by RPLC with high efficiency. There is no isotopic effect on RPLC separation of the differential isotope labeled metabolites, and 12C-13C-labeled isoforms of metabolites are coeluted and detected by MS for precise and accurate quantification and confident metabolite identification. It is demonstrated that, in the analysis of 20 amino acids, a linear response of over 2 orders of magnitude is achieved for relative metabolite quantification with an average relative standard deviation (RSD) of about 5.3% from replicate experiments. A dansylation standard compound library consisting of 121 known amines and phenols has been constructed and is proven to be useful for absolute metabolite quantification and MS-based metabolite identification in biological samples. As an example, the absolute concentrations of 93 metabolites, ranging from 30 nM to 2510 μM, can be determined from a pooled sample of human urines collected in 5 consecutive days labeled with 12C-dansylation and spiked with the 121 13C-dansylated standards. Relative concentration variations of these metabolites in individual urine samples can also be monitored by mixing the 13C-dansylated pooled urine sample with the 12C-dansylated individual sample. With a 12 min fast LC separation combined with FTICR MS, 672 metabolites were detected in a human urine sample with each metabolite peak having a signal-to-noise ratio of greater than 20; the identities of most of the metabolites remain to be determined. This work illustrates that dansylation labeling and fast LC/FTICR MS can be a powerful technique for quantitative profiling of at least 672 metabolites in urine samples in 12 min. [ABSTRACT FROM AUTHOR]

The impacts of the El Niño–Southern Oscillation (ENSO) on the Antarctic region are of special importance in evaluating the variability and change of the climate system in high southern latitudes. In this study, the ENSO signal in modeled precipitation over West Antarctica since 1979 is evaluated using forecast precipitation from several meteorological analyses and reanalyses. Additionally, a dynamical retrieval method (DRM) for precipitation is applied. Over the last two decades, the Southern Oscillation index (SOI) has an overall anticorrelation with precipitation over the West Antarctic sector bounded by 75°–90°S, 120°W–180° while it is positively correlated with precipitation over the South Atlantic sector bounded by 65°–75°S, 30°–60°W. Decadal variations are found as the relationship between the SOI and West Antarctic precipitation is stronger in the 1990s than that in the 1980s. The polar front jet stream, West Antarctic precipitation, and the SOI show a well-ordered correspondence during the 1990s as the jet zonal speed is negatively correlated to the SOI and positively correlated to West Antarctic precipitation. These relationships are weaker during the 1980s, consistent with the change in sign of the correlation between the SOI and West Antarctic precipitation. The decadal variations are apparently related to changes in the quasi-stationary eddies that determine the local onshore and offshore flow over West Antarctica. [ABSTRACT FROM AUTHOR]

The largest outbreak of severe acute respiratory syndrome (SARS) struck Beijing in spring 2003. Multiple importations of SARS to Beijing initiated transmission in several healthcare facilities. Beijing's outbreak began March 5; by late April, daily hospital admissions for SARS exceeded 100 for several days; 2,521 cases of probable SARS occurred. Attack rates were highest in those 20-39 years of age; 1% of cases occurred in children <10 years. The case-fatality rate was highest among patients >65 years (27.7% vs. 4.8% for those 20--64 years, p < 0.001). Healthcare workers accounted for 16% of probable cases. The proportion of case-patients without known contact to a SARS patient increased significantly in May. Implementation of early detection, isolation, contact tracing, quarantine, triage of case-patients to designated SARS hospitals, and community mobilization ended the outbreak. [ABSTRACT FROM AUTHOR]

A new gadolinium chelating NIR fluorescent molecular probe increases T1relaxivity of water protons, facilitating combined optical and magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To examine the relationship between comorbidities and the development of immediate post-operative complications in patients undergoing oral cavity composite resection (OCCR) with free flap (FF) reconstruction., Materials and Methods: Retrospective analysis was completed on all consecutive OCCRs with FF reconstruction performed at a single quaternary care facility between 1999 and 2020. Comorbidities, immediate post-operative complications, patient demographics, and tumor characteristics were collected. Odds ratios (OR) with 95 % confidence intervals were calculated for associations between comorbidities and immediate post-operative complications., Results: 320 patients who underwent OCCR with FF reconstruction were included. One hundred twenty-one (37.8 %) patients developed a post-operative complication during their initial hospital admission. The most common complications were non-pneumonia cardiopulmonary events (14.1 %), pneumonia (9.4 %), and wound infection (8.4 %). Other complications included flap compromise, bleeding, and fistula. On multivariate analysis, patients without comorbid conditions were less likely to develop a post-operative complication (OR 0.64; 0.41-0.98). Atrial fibrillation (OR 2.94; 1.17-7.39) and cerebrovascular disease (OR 2.28; 1.08-4.84) were associated with increased odds of developing any complications. Furthermore, cerebrovascular disease (OR: 2.33; 1.04-5.39) and peripheral vascular disease (OR: 2.7; 1.2-6.08) were independently associated with pneumonia., Conclusion: In this retrospective review of patients undergoing OCCR with FF reconstruction for oral cavity SCC, lack of identifiable comorbidities appeared to be protective for post-operative complications while atrial fibrillation and cerebrovascular disease were associated with increased odds of any complication. Pre-existing vascular disease was also associated with an increased risk of pneumonia., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The extracellular matrix (ECM) is a critical determinant of tumor fate that reflects the output from myriad cell types in the tumor. Collagens constitute the principal components of the tumor ECM. The changing collagen composition in tumors along with their impact on patient outcomes and possible biomarkers remains largely unknown. The RNA expression of the 43 collagen genes from solid tumors in The Cancer Genome Atlas (TCGA) was clustered to classify tumors. PanCancer analysis revealed how collagens by themselves can identify the tissue of origin. Clustering by collagens in each cancer type demonstrated strong associations with survival, specific immunoenvironments, somatic gene mutations, copy number variations, and aneuploidy. We developed a machine learning classifier that predicts aneuploidy, and chromosome arm copy number alteration (CNA) status based on collagen expression alone with high accuracy in many cancer types with somatic mutations, suggesting a strong relationship between the collagen ECM context and specific molecular alterations. These findings have broad implications in defining the relationship between cancer-related genetic defects and the tumor microenvironment to improve prognosis and therapeutic targeting for patient care, opening new avenues of investigation to define tumor ecosystems., (© 2023. The Author(s).)

Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca 2+ -binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca 2+ overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca 2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca 2+ flux in β cells and in their capacity to adapt to metabolic stress., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis., Methods: We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics., Results: A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T 2  = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T 2  = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC., Conclusion: In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies., Objectives: We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time., Data Sources: The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021., Study Eligibility Criteria: Human observational studies on patients with S. aureus bloodstream infection were included., Participants: The study analyzed data of patients with a positive blood culture for S. aureus., Methods: Two independent reviewers extracted study data and assessed risk of bias using the Newcastle-Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates., Results: A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%-12.1%) at 7 days, 13.3% (95% CI, 11.1%-15.8%) at 2 weeks, 18.1% (95% CI, 16.3%-20.0%) at 1 month, 27.0% (95% CI, 21.5%-33.3%) at 3 months, and 30.2% (95% CI, 22.4%-39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02-1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75-1.03 for 2001-2010; aOR: 0.82; 95% CI, 0.69-0.97 for 2011 onward)., Conclusions: SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix., Methods: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors., Results: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors., Conclusions: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment., (© 2022. The Author(s).)

Background: Recent studies have presented concerning data on the safety of cardioversion for acute atrial fibrillation and flutter. We conducted this meta-analysis to evaluate the effect of oral anticoagulation use on thromboembolic events post-cardioversion of low-risk acute atrial fibrillation and flutter patients of < 48 h in duration., Methods: We searched MEDLINE, Embase, and Cochrane from inception through February 6, 2020 for studies reporting thromboembolic events post-cardioversion of acute atrial fibrillation and flutter. Main outcome was thromboembolic events within 30 days post-cardioversion. Primary analysis compared thromboembolic events based on oral anticoagulation use versus no oral anticoagulation use. Secondary analysis was based on baseline thromboembolic risk. We performed meta-analyses where 2 or more studies were available, by applying the DerSimonian-Laird random-effects model. Risk of bias was assessed with the Quality in Prognostic Studies tool., Results: Of 717 titles screened, 20 studies met inclusion criteria. Primary analysis of seven studies with low risk of bias demonstrated insufficient evidence regarding the risk of thromboembolic events associated with oral anticoagulation use (RR = 0.82 where RR < 1 suggests decreased risk with oral anticoagulation use; 95% CI 0.27 to 2.47; I 2  = 0%). Secondary analysis of 13 studies revealed increased risk of thromboembolic events with high baseline thromboembolic risk (RR = 2.25 where RR > 1 indicates increased risk with higher CHADS 2 or CHA 2 DS 2 -VASc scores; 95% CI 1.25 to 4.04; I 2  = 0%)., Conclusion: Primary analysis revealed insufficient evidence regarding the effect of oral anticoagulation use on thromboembolic events post-cardioversion of low-risk acute atrial fibrillation and flutter, though the event rate is low in contemporary practice. Our findings can better inform patient-centered decision-making when considering 4-week oral anticoagulation use for acute atrial fibrillation and flutter patients.

Aim: Receptor-specific small molecules and nanoparticles are widely used in molecular imaging of tumors. Although some studies have described the relative strengths and weaknesses of the two approaches, reports of a direct comparison and analysis of the two strategies are lacking. Herein, we compared the tumor-targeting characteristics of a small near-infrared fluorescent compound (cypate-peptide conjugate) and relatively large perfluorocarbon-based nanoparticles (250 nm diameter) for imaging alpha(nu)beta(3)-integrin receptor expression in tumors., Materials & Methods: Near-infrared fluorescent small molecules and nanoparticles were administered to living mice bearing subcutaneous or intradermal syngeneic tumors and imaged with whole-body and high-resolution optical imaging systems., Results: The nanoparticles, designed for vascular constraint, remained within the tumor vasculature while the small integrin-avid ligands diffused into the tissue to target integrin expression on tumor and endothelial cells. Targeted small-molecule and nanoparticle contrast agents preferentially accumulated in tumor tissue with tumor-to-muscle ratios of 8 and 7, respectively, compared with 3 for nontargeted nanoparticles., Conclusion: Fluorescent small molecular probes demonstrate greater overall early tumor contrast and rapid visualization of tumors, but the vascular-constrained nanoparticles are more selective for detecting cancer-induced angiogenesis. A combination of both imaging agents provides a strategy to image and quantify integrin expression in tumor tissue and tumor-induced neovascular systems.

The excited state of an organic molecule is a crossroads which can lead to many directions, such as non-radiative emission as heat, fluorescence, intersystem crossing and phosphorescence. Due to the unpredictable nature of the excited molecular structure, manipulation of this represents significant challenges for physicists and chemists. However, the successful management of the excited state provides a number of benefits with innumerable applications to fields like photonics and medicine. One such property of the excited state with powerful ramifications in medical diagnostics is fluorescence lifetime.

Novel near-infrared pyrimidine-fused pH fluorescent probes were prepared by an unusual barbiturate-mediated debenzoindolation and subsequent heteroannulation. A plausible mechanistic pathway is proposed, and the final structures were further elucidated by 2D-NMR. All new compounds are highly fluorescent in the near-infrared region and possess excellent spectral sensitivities to environmental pH changes.