OBJECTIVES:Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced ...detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children.
DESIGN:Nested case-control study.
SETTING:Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia.
PATIENTS:Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia.
CONCLUSIONS:When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.
Asymmetric cell division is a potential means by which cell fate choices during an immune response are orchestrated. Defining the molecular mechanisms that underlie asymmetric division of T cells is ...paramount for determining the role of this process in the generation of effector and memory T cell subsets. In other cell types, asymmetric cell division is regulated by conserved polarity protein complexes that control the localization of cell fate determinants and spindle orientation during division. We have developed a tractable, in vitro model of naive CD8(+) T cells undergoing initial division while attached to dendritic cells during Ag presentation to investigate whether similar mechanisms might regulate asymmetric division of T cells. Using this system, we show that direct interactions with APCs provide the cue for polarization of T cells. Interestingly, the immunological synapse disseminates before division even though the T cells retain contact with the APC. The cue from the APC is translated into polarization of cell fate determinants via the polarity network of the Par3 and Scribble complexes, and orientation of the mitotic spindle during division is orchestrated by the partner of inscuteable/G protein complex. These findings suggest that T cells have selectively adapted a number of evolutionarily conserved mechanisms to generate diversity through asymmetric cell division.
Purpose
To determine the effectiveness of office‐based vergence/accommodative therapy for improving accommodative amplitude and accommodative facility in children with symptomatic convergence ...insufficiency and accommodative dysfunction.
Methods
We report changes in accommodative function following therapy among participants in the Convergence Insufficiency Treatment Trial – Attention and Reading Trial with decreased accommodative amplitude (115 participants in vergence/accommodative therapy; 65 in placebo therapy) or decreased accommodative facility (71 participants in vergence/accommodative therapy; 37 in placebo therapy) at baseline. The primary analysis compared mean change in amplitude and facility between the vergence/accommodative and placebo therapy groups using analyses of variance models after 4, 8, 12 and 16 weeks of treatment. The proportions of participants with normal amplitude and facility at each time point were calculated. The average rate of change in amplitude and facility from baseline to week 4, and from weeks 4 to 16, were determined in the vergence/accommodative therapy group.
Results
From baseline to 16 weeks, the mean improvement in amplitude was 8.6 dioptres (D) and 5.2 D in the vergence/accommodative and placebo therapy groups, respectively (mean difference = 3.5 D, 95% confidence interval (CI): 1.5 to 5.5 D; p = 0.01). The mean improvement in facility was 13.5 cycles per minute (cpm) and 7.6 cpm in the vergence/accommodative and placebo therapy groups, respectively (mean difference = 5.8 cpm, 95% CI: 3.8 to 7.9 cpm; p < 0.0001). Significantly greater proportions of participants treated with vergence/accommodative therapy achieved a normal amplitude (69% vs. 32%, difference = 37%, 95% CI: 22 to 51%; p < 0.0001) and facility (85% vs. 49%, difference = 36%, 95% CI: 18 to 55%; p < 0.0001) than those who received placebo therapy. In the vergence/accommodative therapy group, amplitude increased at an average rate of 1.5 D per week during the first 4 weeks (p < 0.0001), then slowed to 0.2 D per week (p = 0.002) from weeks 4 to 16. Similarly, facility increased at an average rate of 1.5 cpm per week during the first 4 weeks (p < 0.0001), then slowed to 0.6 cpm per week from weeks 4 to 16 (p < 0.0001).
Conclusion
Office‐based vergence/accommodative therapy is effective for improving accommodative function in children with symptomatic convergence insufficiency and coexisting accommodative dysfunction.
Summary
HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The ...HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting.
Abstract
Lung cancer is currently the number one cause of cancer-related deaths worldwide. Five-year survival rates for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are ...still less than twenty percent due to late stage of presentation, treatment failure and lack of biomarkers for personalized therapy. Aim of this study is to identify protein biomarkers that can be used for treatment response prediction and therapy monitoring.
Rather than following a broad strategy by analyzing the proteome of whole cell or tissue lysates, we chose to use a more specific approach based on the assumption that the best tumor markers are shed or secreted by the tumor and can be detected in blood. Secretome (i.e. all proteins shed from or secreted by a cell or tissue) proteomics (Piersma SR et al. J Proteome Res. 2010 Apr 5;9(4):1913-22.) was performed on a set of tumors from conditional mouse models for SCLC and NSCLC (Meuwissen R et al. Oncogene. 2001 Oct 4;20(45):6551-8; Meuwissen R et al. Cancer Cell. 2003 Sep;4(3):181-9.), a set of human and mouse SCLC and NSCLC cell lines and a series of human NSCLC cell lines with a range of IC50-values for cisplatin (1.5 – 15 µM). Secretomes were obtained by collecting serum-free media from the cell lines or collecting PBS in which a tumor tissue piece had been incubated.
In the secretome samples, up to 2,000 proteins can be identified with 80% reproducibility by label-free, shotgun nanoLC tandem mass spectrometry and quantified by spectral counting. The beta-binomial test (Pham TV et al. Bioinformatics. 2010 Feb 1;26(3):363-9.) is used to find significant differences in protein expression between the different secretomes and network analysis is performed to provide insight into the underlying cellular mechanisms. The secretomes from the mouse models are used to find proteins specifically secreted by either NSCLC or SCLC, while the comparison between the secretomes of the several human and mouse cell lines allows extrapolation of the results from the mouse models to the human situation. Furthermore, the analysis of the cell lines with various cisplatin IC50-values permits selection of the protein markers that are indicative of sensitivity or resistance. The results of the different proteomics analyses will be presented along with the most promising biomarker candidates and an overview of the functional network analysis.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5100. doi:10.1158/1538-7445.AM2011-5100
Overexpression of
squamous cell carcinoma–related oncogene (SCCRO) is associated with invasive progression and poor outcomes in non–small cell lung cancer. We assessed the role of SCCRO as a tumor ...marker in bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma exhibiting evidence of histologic tumor progression. We hypothesized that SCCRO expression would correlate with invasive tumor phenotypes and worse survival in BAC.
We classified 150 tumors as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. A tissue microarray was constructed from areas of benign lung, BAC, and invasive adenocarcinoma in these tumors. Squamous cell carcinoma–related oncogene expression was graded by immunohistochemistry from 0 to 3 (absent, low, moderate, or high), with positive SCCRO phenotype defined as grade 3. Squamous cell carcinoma–related oncogene specificity was determined by Wilcoxon rank test and area under the receiver-operator curve, survival by the Kaplan-Meier method, and correlation with prognostic factors by log-rank test.
Of the 86.0% (129 of 150) of specimens suitable for analysis, positive SCCRO phenotype was seen in 16.3% (21 of 129) and was 100.0% specific for tumor versus benign tissue (area under receiver-operator curve, 0.92). Positive SCCRO phenotype was greater in tumors with increasing degrees of invasive histologic type (7.0% pure BAC, 13.6% BAC with focal invasion, and 28.6% adenocarcinoma with BAC features;
p = 0.02). Low-level SCCRO expression was present in 83.9% (99 of 118) of benign tissues and correlated with tobacco use and poor survival (
p = 0.05).
Squamous cell carcinoma–related oncogene is a marker of invasive tumor progression in BAC. Low-level expression in adjacent benign lung predicts worse survival, and may represent field cancerization or host–tumor effects.
Asymmetric cell division is a potential means by which cell fate choices during an immune response are orchestrated. Defining the molecular mechanisms that underlie asymmetric division of T cells is ...paramount for determining the role of this process in the generation of effector and memory T cell subsets. In other cell types, asymmetric cell division is regulated by conserved polarity protein complexes that control the localization of cell fate determinants and spindle orientation during division. We have developed a tractable,
in vitro
model of naïve CD8
+
T cells undergoing initial division while attached to dendritic cells during antigen presentation to investigate whether similar mechanisms might regulate asymmetric division of T cells. Using this system, we show that direct interactions with antigen presenting cells provide the cue for polarization of T cells. Interestingly, the immunological synapse disseminates before division even though the T cells retain contact with the antigen presenting cell. The cue from the antigen presenting cell is translated into polarization of cell fate determinants via the polarity network of the Par3 and Scribble complexes and orientation of the mitotic spindle during division is orchestrated by the Pins/G protein complex. These findings suggest that T cells have selectively adapted a number of evolutionarily conserved mechanisms to generate diversity through asymmetric cell division.
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