C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases.

The proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically eliminated and which molecular characteristics direct them for removal are fundamental questions. We reveal a mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase uses interchangeable substrate receptors to recognize the unusual C termini of abnormal proteins (i.e., C-end degrons). C-end degrons are mostly less than ten residues in length and comprise a few indispensable residues along with some rather degenerate ones. The C-terminal end position is essential for C-end degron function. Truncated selenoproteins generated by translation errors and the USP1 N-terminal fragment from post-translational cleavage are eliminated by DesCEND. DesCEND also targets full-length proteins with naturally occurring C-end degrons. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein "ends" as indicators for protein elimination.

The clinical impacts of lung microbiome in bronchiectasis with fixed airflow obstruction: a prospective cohort study.

BACKGROUND: Airflow obstruction is a hallmark of disease severity and prognosis in bronchiectasis. The relationship between lung microbiota, airway inflammation, and outcomes in bronchiectasis with fixed airflow obstruction (FAO) remains unclear. This study explores these interactions in bronchiectasis patients, with and without FAO, and compares them to those diagnosed with chronic obstructive pulmonary disease (COPD). METHODS: This prospective observational study in Taiwan enrolled patients with either bronchiectasis or COPD. To analyze the lung microbiome and assess inflammatory markers, bronchoalveolar lavage (BAL) samples were collected for 16S rRNA gene sequencing. The study cohort comprised 181 patients: 86 with COPD, 46 with bronchiectasis, and 49 with bronchiectasis and FAO, as confirmed by spirometry. RESULTS: Patients with bronchiectasis, with or without FAO, had similar microbiome profiles characterized by reduced alpha diversity and a predominance of Proteobacteria, distinctly different from COPD patients who exhibited more Firmicutes, greater diversity, and more commensal taxa. Furthermore, compared to COPD and bronchiectasis without FAO, bronchiectasis with FAO showed more severe disease and a higher risk of exacerbations. A significant correlation was found between the presence of Pseudomonas aeruginosa and increased airway neutrophilic inflammation such as Interleukin [IL]-1ß, IL-8, and tumor necrosis factor-alpha [TNF]-α, as well as with higher bronchiectasis severity, which might contribute to an increased risk of exacerbations. Moreover, in bronchiectasis patients with FAO, the ROSE (Radiology, Obstruction, Symptoms, and Exposure) criteria were employed to classify individuals as either ROSE (+) or ROSE (-), based on smoking history. This classification highlighted differences in clinical features, inflammatory profiles, and slight microbiome variations between ROSE (-) and ROSE (+) patients, suggesting diverse endotypes within the bronchiectasis with FAO group. CONCLUSION: Bronchiectasis patients with FAO may exhibit two distinct endotypes, as defined by ROSE criteria, characterized by greater disease severity and a lung microbiome more similar to bronchiectasis without FAO than to COPD. The significant correlation between Pseudomonas aeruginosa colonization and increased airway neutrophilic inflammation, as well as disease severity, underscores the clinical relevance of microbial patterns. This finding reinforces the potential role of these patterns in the progression and exacerbations of bronchiectasis with FAO.

Sex differences in the association between short sleep duration and obesity: A systematic-review and meta-analysis.

AIMS: Obesity is a leading contributor to global morbidity and mortality. Short sleep duration is significantly associated with the incidence of obesity, however, it remains unclear whether this relationship is influenced by sex. The purpose of this meta-analysis was to systematically evaluate the evidence of whether the association between short sleep duration and obesity differs between males and females. DATA SYNTHESIS: The protocol was registered with PROSPERO (CRD42023374205). From inception through June 2023, Medline, Embase and Web of Science databases were searched for longitudinal cohort studies with minimum 12 months of observation. The quality of studies was assessed using the Newcastle-Ottawa Quality Assessment for Cohort Studies. Results were pooled using a random effects model. Results are expressed as ratio of odds ratios (ROR) with 95% confidence interval (CI). ROR directly estimates the relative strength of the association of interest (measured as odds ratio [OR] between females and males). Sensitivity analysis was performed and inconsistency between studies was assessed using I2 statistics. A total of 4582 articles were retrieved with the search strategy, of which 6 were included. The meta-analysis indicated that the association between short sleep duration and obesity incidence was statistically significant in both men [OR 1.26 (95% CI 1.13-1.40)] and women [OR 1.36 (95% CI 1.16-1.59)]. However, it did not differ significantly between sexes ROR (women/men) 1.04 (95%CI 0.79-1.36; I2 20.1%). CONCLUSIONS: This meta-analysis indicates that women and men who subjectively report short sleep duration have similarly increased risks of incident obesity.

Type 2 Biomarkers and Their Clinical Implications in Bronchiectasis: A Prospective Cohort Study.

PURPOSE: Bronchiectasis is predominantly marked by neutrophilic inflammation. The relevance of type 2 biomarkers in disease severity and exacerbation risk is poorly understood. This study explores the clinical significance of these biomarkers in bronchiectasis patients. METHODS: In a cross-sectional cohort study, bronchiectasis patients, excluding those with asthma or allergic bronchopulmonary aspergillosis, underwent clinical and radiological evaluations. Bronchoalveolar lavage samples were analyzed for cytokines and microbiology. Blood eosinophil count (BEC), serum total immunoglobulin E (IgE), and fractional exhaled nitric oxide (FeNO) were measured during stable disease states. Positive type 2 biomarkers were defined by established thresholds for BEC, total IgE, and FeNO. RESULTS: Among 130 patients, 15.3% demonstrated BEC ≥ 300 cells/µL, 26.1% showed elevated FeNO ≥ 25 ppb, and 36.9% had high serum total IgE ≥ 75 kU/L. Approximately 60% had at least one positive type 2 biomarker. The impact on clinical characteristics and disease severity was variable, highlighting BEC and FeNO as reflective of different facets of disease severity and exacerbation risk. The combination of low BEC with high FeNO appeared to indicate a lower risk of exacerbation. However, Pseudomonas aeruginosa colonization and a high neutrophil-to-lymphocyte ratio (NLR ≥ 3.0) were identified as more significant predictors of exacerbation frequency, independent of type 2 biomarker presence. CONCLUSIONS: Our study underscores the distinct roles of type 2 biomarkers, highlighting BEC and FeNO, in bronchiectasis for assessing disease severity and predicting exacerbation risk. It advocates for a multi-biomarker strategy, incorporating these with microbiological and clinical assessments, for comprehensive patient management.

MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells.

Mammalian cells release different types of vesicles, collectively termed extracellular vesicles (EVs). EVs contain cellular microRNAs (miRNAs) with an apparent potential to deliver their miRNA cargo to recipient cells to affect the stability of individual mRNAs and the cells' transcriptome. The extent to which miRNAs are exported via the EV route and whether they contribute to cell-cell communication are controversial. To address these issues, we defined multiple properties of EVs and analyzed their capacity to deliver packaged miRNAs into target cells to exert biological functions. We applied well-defined approaches to produce and characterize purified EVs with or without specific viral miRNAs. We found that only a small fraction of EVs carried miRNAs. EVs readily bound to different target cell types, but EVs did not fuse detectably with cellular membranes to deliver their cargo. We engineered EVs to be fusogenic and document their capacity to deliver functional messenger RNAs. Engineered fusogenic EVs, however, did not detectably alter the functionality of cells exposed to miRNA-carrying EVs. These results suggest that EV-borne miRNAs do not act as effectors of cell-to-cell communication.

Immunoregulatory Cells and Cytokines Discriminate Disease Activity Score 28-Remission Statuses and Ultrasound Grades in Rheumatoid Arthritis Patients with Non-High Disease Activity.

It is not clear whether immunoregulatory cytokines and cells are associated with Disease Activity Score 28 (DAS28) scores and ultrasound grades/scores. Here, we investigated the relationships between immunoregulatory cytokines or cells and different DAS28 scores or ultrasound grades/scores in patients with rheumatoid arthritis (RA). This study enrolled 50 RA patients (with 147 visits) who had remission/low/moderate DAS28-ESR scores (92% in remission and low disease activity) at baseline. Blood was collected and an ultrasound was performed three times in a year. Percentages of regulatory B cells and T regulatory type 1 cells and M2 macrophage numbers in the blood were examined. Plasma levels of 10 immunoregulatory cytokines IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-35, TGF-ß1, sTNF-R1, and sTNF-R2 and monocyte chemotactic protein-1 (MCP-1) were assessed using ELISA assay. The correlations of cytokines and cells with different DAS28 scores and ultrasound grades were investigated, and cytokines and cells were compared between different categories of DAS28 scores and ultrasound grades. Plasma TGF-ß1 levels were higher in the DAS28-ESR < 2.6 (remission) subgroup than in the DAS28-ESR ≥ 2.6 (nonremission) subgroup (p = 0.037). However, plasma TGF-ß1 levels were higher in the high ultrasound grade subgroup than those in the low ultrasound grade subgroup (p = 0.007). The number of M2 macrophages was lower in the DAS28-MCP-1 < 2.2 subgroup than in the DAS28-MCP-1 ≥ 2.2 subgroup (p = 0.036). The levels of TGF-ß1, sTNF-R2, IL-10, and IL-27 were higher in patients with high ultrasound grades than in those with low ultrasound grades. IL-27 was also higher in the nonremission DAS28-ESR subgroup than the remission one (p = 0.025). Moreover, sTNF-R1 levels in the 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission subgroup were significantly lower than in the 2011 ACR/EULAR nonremission subgroup (p = 0.007). This trend was reflected in that lower sTNF-R1 levels correlated with low DAS28-MCP-1 scores (rho = 0.222, p = 0.007). We conclude that high plasma TGF-ß1 levels indicate the DAS28-ESR remission (<2.6) subgroup and the high ultrasound grade subgroup. IL-27 probably connects the nonremission DAS28-ESR to high ultrasound grades. Low sTNF-R1 levels probably link low DAS28-MCP-1 scores with the 2011 ACR/EULAR remission subgroup. It suggests that incongruent immuno-inflammatory abnormalities exist between DAS28 scores and ultrasound grades, and are also dissimilar among various DAS28-formula categories. Therefore, this study may provide a basis for further research into individual cytokines and immunoregulatory cells behind each DAS28 formula and ultrasound grades/scores.

Overexpression of OsERF106MZ promotes parental root growth in rice seedlings by relieving the ABA-mediated inhibition of root growth under salinity stress conditions.

BACKGROUND: Roots are essential for plant growth and have a variety of functions, such as anchoring the plant to the ground, absorbing water and nutrients from the soil, and sensing abiotic stresses, among others. OsERF106MZ is a salinity-induced gene that is expressed in germinating seeds and rice seedling roots. However, the roles of OsERF106MZ in root growth remain poorly understood. RESULTS: Histochemical staining to examine ß-glucuronidase (GUS) activity in transgenic rice seedlings harboring OsERF106MZp::GUS indicated that OsERF106MZ is mainly expressed in the root exodermis, sclerenchyma layer, and vascular system. OsERF106MZ overexpression in rice seedlings leads to an increase in primary root (PR) length. The phytohormone abscisic acid (ABA) is thought to act as a hidden architect of root system structure. The expression of the ABA biosynthetic gene OsAO3 is downregulated in OsERF106MZ-overexpressing roots under normal conditions, while the expression of OsNPC3, an AtNPC4 homolog involved in ABA sensitivity, is reduced in OsERF106MZ-overexpressing roots under both normal and NaCl-treated conditions. Under normal conditions, OsERF106MZ-overexpressing roots show a significantly reduced ABA level; moreover, exogenous application of 1.0 µM ABA can suppress OsERF106MZ-mediated root growth promotion. Additionally, OsERF106MZ-overexpressing roots display less sensitivity to ABA-mediated root growth inhibition when treated with 5.0 µM ABA under normal conditions or exposed to NaCl-treated conditions. Furthermore, chromatin immunoprecipitation (ChIP)-qPCR and luciferase (LUC) reporter assays showed that OsERF106MZ can bind directly to the sequence containing the GCC box in the promoter region of the OsAO3 gene and repress the expression of OsAO3. CONCLUSIONS: OsERF106MZ may play a role in maintaining root growth for resource uptake when rice seeds germinate under salinity stress by alleviating ABA-mediated root growth inhibition.

Sialic-Acid-Related Enzymes of B Cells and Monocytes as Novel Markers to Discriminate Improvement Categories and to Fulfill Two Remission Definitions in Rheumatoid Arthritis.

The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) responses in patients with rheumatoid arthritis (RA). We measured the ST6Gal1, Neu1, ST3Gal1, and Neu3 levels of B cells and monocytes in RA patients and correlated the cells' enzyme levels/ratios with the improvement in the ACR, EULAR and SDAI responses and with the two remission definitions. The difference in the B-cell Neu1 levels differed between the ACR 70% improvement and non-improvement groups (p = 0.043), between the EULAR good major response (improvement) and non-good response groups (p = 0.014), and also between the SDAI 50% or 70% improvement and non-improvement groups (p = 0.001 and 0.018, respectively). The same held true when the RA patients were classified by positive rheumatoid factor or the use of biologics. The B-cell Neu1 levels significantly indicated 2005 modified American Rheumatism Association and 2011 ACR/EULAR remission definitions (area under the curve (AUC) = 0.674 with p = 0.001, and AUC = 0.682 with p < 0.001, respectively) in contrast to the CRP and ESR (all AUCs < 0.420). We suggest that B-cell Neu1 is superior for discriminating ACR, EULAR, and SDAI improvement and is good for predicting two kinds of remission definitions.

Oral health in an urban slum, Nigeria: residents' perceptions, practices and care-seeking experiences.

BACKGROUND/INTRODUCTION: One of the key recommendations for the new WHO global strategy for oral health is inclusion of disadvantaged populations and their engagement in policy dialogues such that their needs and views are addressed in policy decisions. OBJECTIVES: This study explored oral health perceptions, practices and care-seeking experiences of slum residents in Ibadan, Nigeria. METHOD: Focus group discussions (FGD) were conducted with family health-decision makers in an urban slum site. Oral health perceptions, practices, and care-seeking experiences were discussed. FGDs were recorded, transcribed, and translated. ATLAS.ti qualitative research software was deployed for analysis using thematic analysis. RESULTS: Six FGD sessions, divided by gender and age, were conducted between September-October 2019, (N = total 58 participants, aged 25 to 59 years). Common dental ailments mentioned were dental pain, tooth sensitivity, bleeding gums, tooth decay, mouth odor, gum disease, and tooth fracture. Perceived causes of dental conditions included poor dental hygiene and habits, sugary diets, ignorance, and supernatural forces. Mouth cleaning was mostly done once daily using toothbrush and paste. Other cleaning tools were ground glass, wood ash, charcoal, "epa Ijebu" (a dentrifice), and "orin ata" (a type of chewing stick). Remedies for relieving dental pain included over-the-counter medicines, warm salted water, gin, tobacco (snuff/powdered), cow urine/dung, battery fluid, and various mixtures/ concoctions. Visits to the dentists were mentioned by a few but this was usually as last resort. Main barriers to accessing care from dental care facilities were unaffordability of service charges and fear of extreme treatment measures (extraction). Suggested measures to improve timely access to dental health care included reducing/subsidizing costs of treatments and medications, offering non-extraction treatment options, and oral health education programmes. CONCLUSION: The slum residents experience various forms of dental ailments mostly pain-related. The residents perceived formal dental clinics as unaffordable, thereby engaging in self-care remedies and harmful oral health practices before seeking professional help. Policymakers and decision-makers may leverage this empirical evidence for the people's education on early dental care and address challenges to affordable, available, and acceptable oral healthcare services among slum residents to improve access to care facilities.

α-2,6-sialic acid/IgG anti-dsDNA ratios correlate with human lupus disease activity and possible mechanisms: A pilot study.

OBJECTIVE: To study the association of α2,6-sialic acid (SIA) content in serum IgG anti-dsDNA with human systemic lupus erythematosus disease activity index (SLEDAI) and the effect of sialylated and desialylated (deSIA) IgG anti-dsDNA on lupus B cells. METHODS: Blood from lupus patients was collected to determine the ratio of SIA in isolated IgG anti-dsDNA over serum IgG anti-dsDNA (SIA/IgG anti-dsDNA) ratios, which were plotted against SLEDAI using a receiver-operating-characteristics curve. Lupus B cells were cultured in vitro with chimeric sialylated IgG anti-dsDNA and its deSIA form. Culture supernatants were assayed for anti-inflammatory IL-10 and SIA/IgG anti-dsDNA ratios, which were compared among different pre-treatment groups using t-tests. RESULTS: The area-under-the-curve (AUC) for anti-dsDNA levels against SLEDAI was 0.791 positively (95% confidence interval [C.I.]: 0.699-0.884) and SIA/IgG anti-dsDNA ratios against SLEDAI yielded an AUC of 0.705 inversely (95% C.I: 0.601-0.809): not significantly different. SIA/IgG anti-dsDNA ratios discriminated significantly between patients without and patients with proteinuria (p = .046). SIA/IgG anti-dsDNA ratios correlated significantly and positively with serum C3c and C4 levels. Pre-treatment with IgG anti-dsDNA and its immune complexes (dsDNA/IgG anti-dsDNA IC) induced higher IL-10 from lupus B cells than medium pre-treatment (most p < .01 from day 2 to day 5 culture). DeSIA IgG anti-dsDNA IC induced lower IL-10 (p < .05) and lower SIA/IgG anti-dsDNA ratios (p < .001) from lupus B cells than medium and dsDNA pre-treatment. CONCLUSION: α2,6-SIA/IgG anti-dsDNA ratios inversely forecasted SLEDAI scores. Possible mechanisms may be due to the different effects of sialylated and deSIA IgG anti-dsDNA on lupus B cells in terms of IL-10 secretion and SIA/IgG anti-dsDNA ratios.

Combined intravenous immunoglobulin and baricitinib treatment for severe COVID-19 with rhabdomyolysis: A case report.

Since December 2019, the outbreak of coronavirus disease 2019 (COVID-19) has spread rapidly around the world. The severity of COVID-19 ranges from asymptomatic carriers to severe acute respiratory distress syndrome (ARDS). Accumulating evidence has shown that COVID-19 may be associated with multiple organ complications including cardiac injury, viral myositis and neurological deficits. Numerous laboratory biomarkers including lymphocytes, platelets, lactate dehydrogenase and creatine kinase (CK) have been associated with the prognostic outcomes of patients with COVID-19. However, dynamic correlations between levels of biomarkers and clinical course have not been studied. Herein, we report a 74-year-old female patient with severe COVID-19 which progressed to ARDS requiring intubation and mechanical ventilation. The laboratory findings showed lymphopenia, hypogammaglobulinemia, and elevated inflammatory biomarkers and CK. She received intensive therapy with hydroxychloroquine, lopinavir/ritonavir, and azithromycin with limited effects. Immunomodulatory treatments with high dose intravenous immunoglobulin and baricitinib were prescribed with satisfactory biochemical, radiographic and clinical recovery. We found an interesting correlation between serum CK elevation and inflammatory biomarkers, which reflected clinical improvement. This case demonstrates that inflammatory biomarkers, cytokines, and CK level correlated with disease severity and treatment response, and combined use of intravenous immunoglobulin and baricitinib is a potential treatment in patients with severe COVID-19.

Sinularin, an Anti-Cancer Agent Causing Mitochondria-Modulated Apoptosis and Cytoskeleton Disruption in Human Hepatocellular Carcinoma.

Liver cancer remains a leading cause of death, despite advances in anti-cancer therapies. To develop novel drugs, natural products are being considered as a good source for exploration. In this study, a natural product isolated from a soft coral was applied to evaluate its anti-cancer activities in hepatocellular carcinoma SK-HEP-1 cells. Sinularin was determined to have half-maximal inhibitory concentration (IC50) values of ~10 µM after 24, 48, and 72 h. The TUNEL assay and annexin V/PI staining results showed that sinularin induced DNA fragmentation and apoptosis, respectively. An investigation at the molecular level demonstrated that the expression levels of cleaved caspases 3/9 were significantly elevated at 10 µM sinularin. Mitochondrial and intracellular reactive oxygen species (ROS) levels were significantly increased following sinularin treatment, which also affected the mitochondrial membrane potential. In addition, it significantly lowered the mitochondrial respiration parameters and extracellular acidification rates at 10 µM. Further investigation showed that sinularin significantly attenuated wound healing, cell migration, and potential colony formation at 10 µM. Fluorescence microscopic observations showed that the distribution of F-actin filaments was significantly altered at 10 µM sinularin. Supported by Western blot analyses, the expression levels of AKT, p-ERK (extracellular-signal-related kinase), vimentin and VEGF were significantly down-regulated, whereas p-p38, pJNK and E-cadherin were significantly increased. Overall, at the IC50 concentration, sinularin was able to significantly affect SK-HEP-1 cells.

Spatiotemporally Skewed Activation of Programmed Cell Death Receptor 1-Positive T Cells after Epstein-Barr Virus Infection and Tumor Development in Long-Term Fully Humanized Mice.

Humanized mice developing functional human T cells endogenously and capable of recognizing cognate human leukocyte antigen-matched tumors are emerging as relevant models for studying human immuno-oncology in vivo. Herein, mice transplanted with human CD34+ stem cells and bearing endogenously developed human T cells for >15 weeks were infected with an oncogenic recombinant Epstein-Barr virus (EBV), encoding enhanced firefly luciferase and green fluorescent protein. EBV-firefly luciferase was detectable 1 week after infection by noninvasive optical imaging in the spleen, from where it spread rapidly and systemically. EBV infection resulted into a pronounced immunologic skewing regarding the expansion of CD8+ T cells in the blood outnumbering the CD4+ T and CD19+ B cells. Furthermore, within 10 weeks of infections, mice developing EBV-induced tumors had significantly higher absolute numbers of CD8+ T cells in lymphatic tissues than mice controlling tumor development. Tumor outgrowth was paralleled by an up-regulation of the programmed cell death receptor 1 on CD8+ and CD4+ T cells, indicative for T-cell dysfunction. Histopathological examinations and in situ hybridizations for EBV in tumors, spleen, liver, and kidney revealed foci of EBV-infected cells in perivascular regions in close association with programmed cell death receptor 1-positive infiltrating lymphocytes. The strong spatiotemporal correlation between tumor development and the T-cell dysfunctional status seen in this viral oncogenesis humanized model replicates observations obtained in the clinical setting.

Publication and related biases in health services research: a systematic review of empirical evidence.

BACKGROUND: Publication and related biases (including publication bias, time-lag bias, outcome reporting bias and p-hacking) have been well documented in clinical research, but relatively little is known about their presence and extent in health services research (HSR). This paper aims to systematically review evidence concerning publication and related bias in quantitative HSR. METHODS: Databases including MEDLINE, EMBASE, HMIC, CINAHL, Web of Science, Health Systems Evidence, Cochrane EPOC Review Group and several websites were searched to July 2018. Information was obtained from: (1) Methodological studies that set out to investigate publication and related biases in HSR; (2) Systematic reviews of HSR topics which examined such biases as part of the review process. Relevant information was extracted from included studies by one reviewer and checked by another. Studies were appraised according to commonly accepted scientific principles due to lack of suitable checklists. Data were synthesised narratively. RESULTS: After screening 6155 citations, four methodological studies investigating publication bias in HSR and 184 systematic reviews of HSR topics (including three comparing published with unpublished evidence) were examined. Evidence suggestive of publication bias was reported in some of the methodological studies, but evidence presented was very weak, limited in both quality and scope. Reliable data on outcome reporting bias and p-hacking were scant. HSR systematic reviews in which published literature was compared with unpublished evidence found significant differences in the estimated intervention effects or association in some but not all cases. CONCLUSIONS: Methodological research on publication and related biases in HSR is sparse. Evidence from available literature suggests that such biases may exist in HSR but their scale and impact are difficult to estimate for various reasons discussed in this paper. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2016 CRD42016052333.

Increased Plasma Acetylcarnitine in Sepsis Is Associated With Multiple Organ Dysfunction and Mortality: A Multicenter Cohort Study.

OBJECTIVES: Recent metabolomic studies of sepsis showed that increased circulatory acylcarnitines were associated with worse survival. However, it is unknown whether plasma carnitine and acylcarnitines can reflect the severity of sepsis, and the role of specific acylcarnitines in prognostic assessment need further confirmation. This study aimed to clarify these questions. DESIGN: Prospective multicenter cohort studies with derivation and validation cohort design. SETTING: ICUs at two medical centers and three regional hospitals in Taiwan. PATIENTS: Patients with sepsis and acute organ dysfunction were enrolled. Recruitment of the derivation (n = 90) and validation cohorts (n = 120) occurred from October 2010 through March 2012 and January 2013 through November 2014, respectively. INTERVENTIONS: Plasma samples were collected immediately after admission, and the levels of carnitine and acylcarnitines were measured by ultra-high performance liquid chromatography-mass spectrometry. MEASUREMENTS AND MAIN RESULTS: In the derivation cohort, increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, acetylcarnitine is the only acylcarnitine significantly correlating with various plasma cytokine concentrations and also associated with blood culture positivity and 28-day mortality risk. The association between plasma acetylcarnitine and multiple organ dysfunction severity, blood culture positivity, and 28-day mortality, was confirmed in the validation cohort. Patients with high plasma acetylcarnitine (≥ 6,000 ng/mL) had significantly increased 28-day mortality compared with those with plasma acetylcarnitine less than 6,000 ng/mL (52.6% vs 13.9%; hazard ratio, 5.293; 95% CI, 2.340-11.975; p < 0.001 by Cox proportional hazard model). CONCLUSIONS: We confirm that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis and can serve as a prognostic biomarker for mortality prediction.

Clinical factors associated with treatment outcomes in EGFR mutant non-small cell lung cancer patients with brain metastases: a case-control observational study.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations often develop brain metastases. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) has shown the effectiveness; however, knowledge of the clinical factors associated with outcomes in NSCLC patients with EGFR mutations remains limited. METHODS: Treatment-naive patients diagnosed with advanced non-squamous NSCLC with brain metastases harboring EGFR mutations and treated with an EGFR-TKI as first-line therapy were enrolled with analysis of their medical records. RESULTS: A total of 134 advanced NSCLC patients with brain metastases harboring EGFR mutations received an EGFR-TKI (gefitinib: 62, erlotinib: 49, and afatinib: 23) as the first-line therapy. Sixty-nine had exon 19 deletions (51.5%), and 56 (41.8%) had L858R mutations. There was no statistically significant difference in progression-free survival (PFS) and overall survival (OS) among the EGFR-TKIs. Significantly shorter OS was noted in patients with multiple brain metastases (hazard ratio [HR]: 2.43, p = 0.007), uncommon EGFR mutations (HR: 3.75, p = 0.009), and liver metastases. Thirty-eight patients (29.1%) received brain radiotherapy for brain metastases before disease progression, and had a significantly longer time until intracranial progression. However, the brain radiotherapy had no statistically significant impact on PFS or OS. CONCLUSIONS: Patients with uncommon mutations, multiple brain metastases, and concomitant liver metastases tended to have shorter OS. Brain radiotherapy could delay the time to intracranial disease progression but had no impact on survival. The different first-line EGFR-TKIs achieved similar treatment responses in terms of PFS and OS in the EGFR-mutated NSCLC patients with brain metastases.

Ranking Hospitals Based on Preventable Hospital Death Rates: A Systematic Review With Implications for Both Direct Measurement and Indirect Measurement Through Standardized Mortality Rates.

Policy Points The use of standardized mortality rates (SMRs) to profile hospitals presumes differences in preventable deaths, and at least one health system has suggested measuring preventable death rates of hospitals for comparison across time or in league tables. The influence of reliability on the optimal review number per case note or hospital for such a program has not been explored. Estimates for preventable death rates using implicit case note reviews by clinicians are quite low, suggesting that SMRs will not work well to rank hospitals, and any misspecification of the risk-adjustment models will produce a high risk of mislabelling outliers. Most studies achieve only fair to moderate reliability of the direct assessment of whether a death is preventable, and thus it is likely that substantial numbers of reviews of deaths would be required to distinguish preventable from nonpreventable deaths as part of learning from individual cases, or for profiling hospitals. Furthermore, population- and hospital system-specific data on the variation in preventable deaths or adverse events across the hospitals and providers to be compared are required in order to design a measurement procedure and the number of reviews needed to distinguish between the patients or hospitals. CONTEXT: There is interest in monitoring avoidable or preventable deaths measured directly or indirectly through standardized mortality rates (SMRs). While there have been numerous studies in recent years on adverse events, including preventable deaths, using implicit case note reviews by clinicians, no systematic reviews have aimed to summarize the estimates or the variations in methodologies used to derive these estimates. We reviewed studies that use implicit case note reviews to estimate the range of preventable death rates observed, the measurement characteristics of those estimates, and the measurement procedures used to generate them. We comment on the implications for monitoring SMRs and illustrate a way to calculate the number of reviews needed to establish a reliable estimate of the preventability of one death or the hospital preventable death rate. METHODS: We conducted a systematic review of the literature supplemented by a reanalysis of authors' previously published and unpublished data and measurement design calculations. We conducted initial searches in PubMed, MEDLINE (OvidSP), and ISI Web of Knowledge in June 2010 and updated them in June 2012 and December 2017. Eligibility criteria included studies of hospital-wide admissions from general and acute medical wards where preventable death rates are provided or can be estimated and that can provide interobserver variations. FINDINGS: Twenty-three studies were included from 1985 to 2017. Recent larger studies suggest consistently low rates of preventable deaths (interquartile range of 3.0%-6.0% since 2008). Reliability of a single review for distinguishing between individual cases with regard to the preventability of death had a Kappa statistic of 0.10-0.50 for deaths and 0.21-0.76 for adverse events. A Kappa of 0.35 would require an average of 8 to 17 reviews of a single case to be precise enough to have confidence in high-stakes decisions to change care procedures or impose sanctions within a hospital as a result. No study estimated the variation in preventable deaths across hospitals, although we were able to reanalyze one study to obtain an estimate. Based on this estimate, 200 to 300 total case note reviews per hospital could be required to reliably distinguish between hospitals. The studies displayed considerable heterogeneity: 13/23 studies defined preventable death with a threshold of greater than or equal to four in a six-category Likert scale and 11/24 involved a two-stage screening process with nurses at the first stage and physicians at the second. Fifteen studies provided expert clinical review support for reviewer disagreements, advice, and quality control. A "generalist/internist" was the modal physician specialty for reviewers and they received one to three days of generic tools orientation and case note review practice. Methods did not consider the influence of human or environmental factors. CONCLUSIONS: The literature provides limited information about the measurement characteristics of preventable deaths, suggesting that substantial numbers of reviews may be needed to create reliable estimates of preventable deaths at the individual or hospital level. Any operational program would require population-specific estimates of reliability. Preventable death rates are low, which is likely to make it difficult to use SMRs based on all deaths to validly profile hospitals. The literature provides little information to guide improvements in the measurement procedures.

Major comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long-acting bronchodilators: a case-control study.

BACKGROUND: While inhaled bronchodilators reduce symptoms and acute exacerbations of chronic obstructive pulmonary disease (COPD), their use is associated with increased cardiovascular events in some studies. This study investigates the risk of adverse events associated with the use of inhaled bronchodilators in COPD patients with multimorbidity. METHODS: A case-control study was conducted between January 2015 and December 2017, and patients with spirometry-confirmed diagnosis of COPD (N = 1565) using inhaled long-acting bronchodilators were enrolled. Medical records were reviewed and clinical data, including age, gender, smoking status, major comorbidities, lung function stage, history of exacerbations, bronchodilator regimens, and treatment duration were analyzed. Major adverse cardiovascular events occurring during long-acting bronchodilator use were recorded. RESULTS: The most common comorbidities were cardiovascular disease (CVD) (53.6%) and chronic kidney disease (CKD) (25.8%). We observed that CVD (odds ratio [OR], 5.77), CKD (OR, 2.02) and history of frequent exacerbations (OR, 2.37) were independent risk factors for cardiovascular events, regardless of the type of bronchodilators use. Moreover, COPD patients with both CKD and CVD had higher risk (6.32-fold) of adverse cardiovascular effects than those with neither comorbidity. Eighty-seven of 1565 (5.56%) COPD patients died during this study period. Of them, 21.8% (19/87) were cardiovascular-related and 73.6% (64/87) patients were respiratory-related mortality. Among COPD patients using long-acting bronchodilators, CKD was the only risk factor to predict cardiovascular events and cardiovascular-related mortality (OR, 4.87; 95% confidence interval [CI], 1.75-13.55]. CONCLUSIONS: COPD patients had higher risk of cardiovascular events were associated with their CVD and/or CKD comorbidities and history of frequent exacerbations, rather than associated with their use of inhaled bronchodilators.

MMP-12 activates protease-activated receptor-1, upregulates placenta growth factor, and leads to pulmonary emphysema.

Because of the expansion of aging and smoking populations, chronic obstructive pulmonary disease (COPD) is predicted to be the third leading cause of death worldwide in 2030. Therefore, it is pertinent to develop effective therapy to improve management for COPD. Cigarette smoke-mediated protease-antiprotease imbalance is a major pathogenic mechanism for COPD and results in massive pulmonary infiltration of neutrophils and macrophages, releasing excessive neutrophil elastase (NE) and matrix metalloproteinases (MMPs). Our previous studies indicated that placenta growth factor (PGF) and PGF-triggered downstream signaling molecules mediate NE-induced lung epithelial cell apoptosis, which is a major pathogenic mechanism for pulmonary emphysema. However, the relationship between MMP-directed COPD and PGF remains elusive. We hypothesize that MMPs may upregulate PGF expression and be involved in MMP-mediated pathogenesis of COPD. In this study, we demonstrate that only MMP-12 can increase the expression of PGF by increasing early-growth response protein 1 (Egr-1) level through the activation of protease-activated receptor 1 (PAR-1). The PGF-mediated downstream signaling molecules drive caspase-3 and caspase-9-dependent apoptosis in bronchial epithelial cells. Both the upregulation of PGF by MMP-12 and PGF downstream signaling molecules with pulmonary apoptosis and emphysema were also demonstrated in animals. Given these findings, we suggest that both human COPD-associated elastases, NE, and MMP-12, upregulate PGF expression and promote the progression of emphysema and COPD.