Context:
Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced ...sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus.
Objective:
The objective of the study was to examine associations between AGEs and cognitive functions.
Design, Setting, and Participants:
This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus.
Main Outcome Measures:
We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition.
Results:
After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = −0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = −0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = −0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes.
Conclusion:
We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression.
Background
Data on drug‐induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and ...the safety of drug rechallenge.
Methods
This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge.
Results
Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune‐based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty‐six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0‐1.09; P = .035).
Conclusions
In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.
In modern phase 1 oncology trials, drug‐induced liver injury (DILI) is uncommon and may occur at any time. Drug rechallenge after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and other treatment alternatives.
Basal cell carcinoma (BCC) is the most prevalent type of skin cancer. Histologic analysis of punch biopsy or direct excision specimen is used to confirm clinical diagnosis. In vivo reflectance ...confocal microscopy (RCM) is a non‐invasive imaging modality that could facilitate early diagnosis and minimize unnecessary invasive procedures. We systematically reviewed diagnostic accuracy (sensitivity and specificity) of RCM in diagnosing primary BCCs to judge its usefulness. Eligible studies were reviewed for methodological quality using the QUADAS‐2 tool. We used the bivariate random‐effects model to calculate summary estimates of sensitivity and specificity. Six studies met the selection criteria and were included for analysis. The meta‐analysis showed a summary estimate of sensitivity 0.97 (95% CI, 0.90–0.99) and specificity 0.93 (95% CI, 0.88–0.96). All but one of the QUADAS‐2 items showed a high or unclear risk of bias with regards to patient selection. RCM may be a promising diagnostic tool, but the limited number of available studies and potential risk of bias of included studies do not allow us to draw firm conclusions. Future accuracy studies should take these limitations into account.
Summary
This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6–7 April 2013 (HOME III). The meeting ...addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient‐reported symptoms, long‐term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long‐term control is needed before progress can be made towards recommending a core outcome measure.
What's already known about this topic?
Many different scales have been used to measure eczema, making it difficult to compare trials in meta‐analyses and hampering improvements in clinical practice.
HOME core outcome measures must pass the OMERACT (Outcome Measures in Rheumatology) filter of truth (validity), discrimination (sensitivity to change and responsiveness) and feasibility (ease of use, costs, time to perform and interpret).
It has been previously agreed as part of the consensus process that four domains should be measured by the core outcomes: clinical signs, patient‐reported symptoms, long‐term control and health‐related quality of life.
What does this study add?
Progress was made towards developing a core outcome set for measuring eczema in clinical trials.
The group established the essential items to be included in the outcome measure for the clinical signs of eczema and was able to recommend a scale for the core set.
The remaining three domains of patient‐reported symptoms, long‐term control and health‐related quality of life require further work and meetings to determine the core outcome measures.
Background
Biomarkers to objectively measure disease severity and predict therapeutic responses are needed in atopic dermatitis (AD).
Objective
Primary aim: To identify biomarkers reflecting ...therapeutic response in patients with AD treated systemically.
Secondary aims: (i) To identify a biomarker pattern predicting responsiveness to systemic treatment. (ii) To identify differences in expression of biomarker in filaggrin gene (FLG) mutation carriers vs. non‐FLG mutations carriers.
Methods
Thirty‐eight severe AD patients treated with methotrexate or azathioprine participated. Serum levels of a proliferation‐inducing ligand, B‐cell activating factor of the TNF family, thymus and activation‐regulated chemokine (chemokine (C‐C motif) ligand 17) (TARC (CCl‐17)), interleukin‐1 receptor antagonist (IL‐1RA), interleukin‐1 bèta, IL‐4, IL‐6, IL‐7, IL‐8, IL‐9, IL‐10, IL‐12, IL‐13, IL‐18, IL‐31, interferon gamma, tumour necrosis factor alpha, vascular endothelial growth factor (VEGF), monokine induced by interferon gamma (chemokine (C‐X‐C motif) ligand 9), interferon gamma‐induced protein 10 (C‐X‐C motif chemokine Ligand 10), monocyte chemoattractant protein‐1 (chemokine (C‐C Motif) ligand 2), macrophage inflammatory protein‐1 beta (chemokine (C‐C motif) ligand 4), regulated on activation, normal T cell expressed and secreted (chemokine (C‐C motif) ligand 5), Cutaneous T‐cell‐attracting chemokine (chemokine (C‐C motif) ligand 27) (CTACK (CCL‐27)), thymic stromal lymphopoietin, IL‐5, interleukin‐1 alpha and granulocyte‐colony stimulating factor were analysed by ELISA and Luminex. The primary outcomes were differences in mean absolute change of SCORing Atopic Dermatitis (SCORAD) between groups after 12 weeks compared with baseline. Responders to treatment were defined by a SCORAD reduction in ≥50%. Buccal mucosa swabs were collected to determine FLG genotype status.
Results
Thymus and activation‐regulated chemokine, CTACK, IL‐13 and VEGF showed a significant decrease after treatment with methotrexate or azathioprine. However, no decrease in individual cytokine levels was significantly correlated with a change in any of the outcome parameters. In addition, baseline biomarker levels were not significantly different between responders and non‐responders, and FLG and non‐FLG mutants showed similar biomarker profiles.
Conclusion
Thymus and activation‐regulated chemokine and CTACK were confirmed as potential biomarkers. VEGF and IL‐13 have a potential value as well. Biomarkers could not be used to discriminate at baseline between responders and non‐responders, or FLG genotype status.
Reactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney ...disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown.
Subjects with normal glucose metabolism (n=1796; age: 57.9±8.2 years; 43.3% men), prediabetes (n=478; age: 61.6±7.6 years; 54.0% men) and T2DM (n=669; age: 63.0±7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO.
Fasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥30mg/24h fasting: 1.12 (95% CI: 0.97–1.29); post-OGTT: 1.19 (1.01–1.41), eGFR<60mL/min/1.73 m2 fasting: 1.58 (95% CI: 1.38–1.82), post-OGTT: 1.57 (1.34–1.83) and retinopathy fasting: 1.59 (95% CI: 1.01–2.53), post-OGTT: 1.38 (0.77–2.48). No associations with prior CVD were found.
Fasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.
Aims/hypothesis
Methylglyoxal (MGO) is a major precursor for advanced glycation end-products (AGEs), which are thought to play a role in vascular complications in diabetes. Known MGO-arginine-derived ...AGEs are 5-hydro-5-methylimidazolone (MG-H1), argpyrimidine and tetrahydropyrimidine (THP). We studied THP in relation to type 1 diabetes, endothelial dysfunction, low-grade inflammation, vascular complications and atherosclerosis.
Methods
We raised and characterised a monoclonal antibody against MGO-derived THP. We measured plasma THP with a competitive ELISA in two cohort studies: study A (198 individuals with type 1 diabetes and 197 controls); study B (individuals with type 1 diabetes, 175 with normoalbuminuria and 198 with macroalbuminuria >300 mg/24 h). We measured plasma markers of endothelial dysfunction and low-grade inflammation, and evaluated the presence of THP and
N
ε
-(carboxymethyl)lysine (CML) in atherosclerotic arteries.
Results
THP was higher in individuals with type 1 diabetes than in those without (median interquartile range 115.5 U/μl 102.4–133.2 and 109.8 U/μl 91.8–122.3, respectively;
p
= 0.03). THP was associated with plasma soluble vascular cell adhesion molecule 1 in both study A (standardised
β
= 0.48 95% CI 0.38, 0.58;
p
< 0.001) and study B (standardised
β
= 0.31 95% CI 0.23, 0.40;
p
< 0.001), and with secreted phospholipase A2 (standardised
β
= 0.26 95% CI 0.17, 0.36;
p
< 0.001) in study B. We found no association of THP with micro- or macro-vascular complications. Both THP and CML were detected in atherosclerotic arteries.
Conclusions/interpretation
Our results suggest that MGO-derived THP may reflect endothelial dysfunction among individuals with and without type 1 diabetes, and therefore may potentially play a role in the development of atherosclerosis and vascular disease.
Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We ...evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and
exon 14 (
ex14) alterations in DNA sequencing (DNAseq) driver-negative lung cancers.
Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq.
As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%)
ex14 alterations. Among 275 driver-negative cases with available tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected alteration was identified in 14% (36/254) of cases, 33 of which were actionable (27 in-frame fusions, 6
ex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical benefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB 0-5 mutations/Megabase (mut/Mb), 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/Mb, only 7% were positive for fusions (
< 0.0001).
Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq.
.
Summary
In this small cross-sectional study of predominantly well-treated participants with relatively short-term type 2 diabetes duration, HbA1c > 7% (53 mmol/mol) was associated with lower cortical ...density and thickness and higher cortical porosity at the distal radius, lower trabecular thickness at the distal tibia, and higher trabecular number at both sites.
Introduction
To examine the association between diabetes status and volumetric bone mineral density (vBMD), bone microarchitecture and strength of the distal radius and tibia as assessed with HR-pQCT. Additionally—in participants with type 2 diabetes (T2DM), to examine the association between HbA1c, diabetes duration, and microvascular disease (MVD) and bone parameters.
Methods
Cross-sectional data from 410 (radius) and 198 (tibia) participants of The Maastricht Study (mean age 58 year, 51% female). Diabetes status (normal glucose metabolism, prediabetes, or T2DM) was based on an oral glucose tolerance test and medication history.
Results
After full adjustment, prediabetes and T2DM were not associated with vBMD, bone microarchitecture, and strength of the radius and tibia, except for lower trabecular number (Tb.N) of the tibia (− 4%) in prediabetes and smaller cross-sectional area of the tibia (− 7%) in T2DM. In T2DM, HbA1c > 7% was associated with lower cortical vBMD (− 5%), cortical thickness (− 16%), higher cortical porosity (+ 20%) and Tb.N (+ 9%) of the radius, and higher Tb.N (+ 9%) and lower trabecular thickness (− 13%) of the tibia. Diabetes duration > 5 years was associated with higher Tb.N (+ 6%) of the radius. The presence of MVD was not associated with any bone parameters.
Conclusions
In this study with predominantly well-treated T2DM participants with relatively short-term diabetes duration, inadequate blood glucose control was negatively associated with cortical bone measures of the radius. In contrast, trabecular number was increased at both sites. Studies of larger sample size are warranted for more detailed investigations of bone density and bone quality in patients with T2DM.
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