ABSTRACT
Single-molecule counting is the most accurate and precise method for determining the concentration of a biomarker in solution and is leading to the emergence of digital diagnostic platforms ...enabling precision medicine. In principle, solid-state nanopores—fully electronic sensors with single-molecule sensitivity—are well suited to the task. Here we present a digital immunoassay scheme capable of reliably quantifying the concentration of a target protein in complex biofluids that overcomes specificity, sensitivity, and consistency challenges associated with the use of solid-state nanopores for protein sensing. This is achieved by employing easily-identifiable DNA nanostructures as proxies for the presence (“1”) or absence (“0”) of the target protein captured via a magnetic bead-based sandwich immunoassay. As a proof-of-concept, we demonstrate quantification of the concentration of thyroid-stimulating hormone from human serum samples down to the high femtomolar range. Further optimization to the method will push sensitivity and dynamic range, allowing for development of precision diagnostic tools compatible with point-of-care format.
Serum neurofilament light chain (NfL) is emerging as an important biomarker in multiple sclerosis (MS). Our objective was to evaluate the prognostic value of serum NfL levels obtained close to the ...time of MS onset with long-term clinical outcomes. In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) with more than 15 years of routine clinical follow-up. Levels of serum NfL were quantified in patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Sixty-seven patients had a median follow-up of 18.9 years (range 15.0-27.0). The median serum NfL level in patient baseline samples was 10.1 pg/mL, 38.5% higher than median levels in 37 controls (7.26 pg/mL, p = 0.004). Baseline NfL level was most helpful as a sensitive predictive marker to rule out progression; patients with levels less 7.62 pg/mL were 4.3 times less likely to develop an EDSS score of ≥ 4 (p = 0.001) and 7.1 times less likely to develop progressive MS (p = 0.054). Patients with the highest NfL levels (3rd-tertile, > 13.2 pg/mL) progressed most rapidly with an EDSS annual rate of 0.16 (p = 0.004), remaining significant after adjustment for sex, age, and disease-modifying treatment (p = 0.022). This study demonstrates that baseline sNfL is associated with long term clinical disease progression. sNfL may be a sensitive marker of subsequent poor clinical outcomes.
The process of uterine spiral artery remodeling in the first trimester of human pregnancy is an essential part of establishing adequate blood perfusion of the placenta that will allow optimal ...nutrient/waste exchange to meet fetal demands during later development. Key regulators of spiral artery remodeling are the uterine natural killer cells and the invasive extravillous trophoblasts. The functions of these cells as well as regulation of their activation states and temporal regulation of their localization within the uterine tissue are beginning to be known. In this review, we discuss the roles of these two cell lineages in arterial remodeling events, their interaction/influence on one another and the outcomes of altered temporal, and spatial regulation of these cells in pregnancy complications.
OBJECTIVETo evaluate neurofilament light chain (NfL) levels in serum and CSF of patients with aggressive MS pre- and post-treatment with immunoablation followed by autologous hematopoietic stem cell ...transplantation (IAHSCT) and examine associations with clinical and MRI outcomes.
METHODSPaired serum and CSF in addition to MRI and clinical measures were collected on 23 patients with MS at baseline and 1 and 3 years post-IAHSCT. An additional 33 sera and CSF pairs were taken from noninflammatory neurologic controls. NfL levels were quantitated using the Simoa platform (Quanterix).
RESULTSBaseline MS NfL levels were significantly elevated relative to controls in serum (p = 0.001) and CSF (p = 0.001). Following IAHSCT, high pretreatment NfL levels significantly reduced in serum (p = 0.0023) and CSF (p = 0.0068) and were not significantly different from controls. Serum and CSF NfL levels highly correlated (r = 0.81, p < 0.0001). Baseline NfL levels were associated with worse pretreatment disease measures (Expanded Disability Status Scale EDSS, relapses, MRI lesions, and MR spectroscopy (MRS) N-acetylaspartate/creatine). Elevated baseline NfL levels were associated with persistently worse indices of disease burden post-IAHSCT (sustained EDSS progression, cognition, quality of life, T1 and T2 lesion volumes, MRS, and brain atrophy).
CONCLUSIONThese data substantiate that serum and CSF NfL levels reflect disease severity and treatment response in patients with MS and may therefore be a useful biomarker. Baseline serum levels associated with markers of pretreatment disease severity and post-treatment outcomes.
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for patients with aggressive MS, serum NfL levels are associated with disease severity.
Predicting seizure recurrence risk is critical to the diagnosis and management of epilepsy. Routine electroencephalography (EEG) is a cornerstone of the estimation of seizure recurrence risk. ...However, EEG interpretation relies on the visual identification of interictal epileptiform discharges (IEDs) by neurologists, with limited sensitivity. Automated processing of EEG could increase its diagnostic yield and accessibility. The main objective was to develop a prediction model based on automated EEG processing to predict one-year seizure recurrence in patients undergoing routine EEG. We retrospectively selected a consecutive cohort of 517 patients undergoing routine EEG at our institution (training set) and a separate, temporally shifted cohort of 261 patients (testing set). We developed an automated processing pipeline to extract linear and non-linear features from the EEGs. We trained machine learning algorithms on multichannel EEG segments to predict one-year seizure recurrence. We evaluated the impact of IEDs and clinical confounders on performances and validated the performances on the testing set. The receiver operating characteristic area-under-the-curve for seizure recurrence after EEG in the testing set was 0.63 (95% CI 0.55-0.71). Predictions were still significantly above chance in EEGs with no IEDs. Our findings suggest that there are changes other than IEDs in the EEG signal embodying seizure propensity.
Diabetes, Dementia and Hypoglycemia Meneilly, Graydon S., MD, FRCPC, FACP; Tessier, Daniel M., MD, FRCPC
Canadian journal of diabetes,
02/2016, Letnik:
40, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract We are experiencing an epidemic of both diabetes and dementia among older adults in this country. The risk for dementia appears to be increased in patients with diabetes, and patients with ...dementia and diabetes appear to be at greater risk for severe hypoglycemia. In addition, there may be an increased risk for developing dementia by older patients with diabetes who have had episodes of severe hypoglycemia, although this issue is controversial. In this article, we review the factors that contribute to the increased risk for dementia in older adults with diabetes and outline the complex relationships between hypoglycemia and dementia.
No-tillage is an increasing way of management for agricultural soils. The objective of this study was to identify in which extent the chemical properties of a loamy soil could be affected by ...no-tillage under temperate conditions.
Soil chemical properties were investigated on a field subjected to either conventional or no-tillage management of maize (
Zea mays L.) and wheat (
Triticum aestivum L.) with identical fertilization practices and no lime supply since 1970. On no-tilled soil, maize was cropped exactly on the same line every other year, which enabled soil sampling under the row and under the interrow.
Tilled soil had an homogeneous ploughed horizon, whereas soil under no-tillage exhibited strong vertical gradients of pH, exchangeable cations and organic C. No-tilled soil had 11.4% greater organic C than tilled soil, and the difference was concentrated in the upper 5
cm. The proportion of exchangeable cations was highest in the interrow of no-tilled soil and lowest in tilled soil. Tilled soil contained much lower exchangeable K than no-tilled soil, indicating a difference in retention capacity of this cation. The pH of the upper 5
cm of no-tilled soil was low, probably because of surface accumulation of organic residues. Whatever the tillage system, exchangeable Al was significantly related to pH according to the relation: Al
ex
=
76441
×
10
−0.99
pH
(
r
2
=
0.96;
p
<
0.001). An expected complexing effect of organic matter on Al was not observed, probably hidden by the influence of pH.
Since yields were not negatively affected by long-term no-tillage and organic C content was higher, no-tillage appears to be a cost-saving choice for maize and wheat production under these temperate environmental conditions, as well as a way for C sequestration.
Aging and family history of type 2 diabetes (T2D) are known risk factors of T2D. Younger first-degree relatives (FDR) of T2D patients have shown early metabolic alterations, which could limit ...exercise’s ability to prevent T2D. Thus, the objective was to determine whether exercise metabolism was altered during submaximal exercise in FDR postmenopausal women. Nineteen inactive postmenopausal women (control: 10, FDR: 9) aged 60 to 75 years old underwent an incremental test on a cycle ergometer with intensity ranging from 40 to 70% of peak power output. Participants consumed 50 mg of 13C-palmitate 2 h before the test. At the end of each stage, glucose, lactate, glycerol, non-esterified fatty acids and 13C-palmitate were measured in plasma, and 13CO2 was measured in breath samples. Gas exchanges and heart rate were both monitored continuously. There were no between-group differences in substrate oxidation, plasma substrate concentrations or 13C recovered in plasma or breath. Interestingly, despite exercising at a similar relative intensity to control, FDR were consistently at a lower percentage of heart rate reserve. Overall, substrate plasma concentration and oxidation are not affected by family history of T2D in postmenopausal women and therefore not a participating mechanism in the altered response to exercise previously reported. More studies are required to better understand the mechanisms involved in this response.
Frailty is a widely used term for a multidimensional syndrome that gives rise to increased vulnerability.1 Frail older patients with diabetes have a median life expectancy of 23 months.2 Therefore, ...it is unlikely that these patients will live long enough to obtain the benefits of tight glycemic control. In addition, attempts at tight glucose control in these patients may be associated with hypoglycemia. Blood glucose levels in this group should be controlled well enough to prevent the effects of uncontrolled hyperglycemia, such as polyuria, infections and confusion. Recent guidelines from the Canadian Diabetes Association and other groups recommend that the target in this population should be a fasting or preprandial blood glucose level of 6-11 mmol/L and a hemoglobin A1C concentration of 7.6%-8.5%.3,4 These guidelines are based on consensus among clinicians, and further studies are needed in this patient population to determine appropriate goals. In this patient's case, it might be reasonable to aim for a fasting blood glucose level of 6-9 mmol/L, a premeal blood glucose level of less than 12 mmol/L and a hemoglobin A1C concentration of 7.6%-8.5%. The risk of severe or fatal hypoglycemia in response to agents administered orally or insulin increases exponentially with age.3 Hypoglycemia is associated with falls, fractures, cardiovascular events and a variety of other adverse events. It is one of the most common reasons for emergency admission to hospital for adverse drug events in older patients.6 Continuous glucose monitoring has shown that asymptomatic hypoglycemia is common and often prolonged in these patients.3 Hypoglycemia is more likely to develop in patients with dementia and, conversely, severe hypoglycemia later in life can predispose people to dementia.3 The increased risk of hypoglycemia with increasing age is due to reduced awareness of autonomic warning symptoms, impaired glucagon secretion (the most important counterregulatory hormone) and altered psychomotor performance during hypoglycemia that prevents the patient from taking steps to return the blood glucose level to normal.10 As noted above, selected oral agents and insulin preparations are associated with a lower frequency of hypoglycemia than other pharmacologic treatments in older patients. The patient had an eGFR of 40 mL/min per 1.73 m2. She was given metformin (500 mg orally twice daily) and will stay on this dose. More frequent blood glucose testing was ordered for three weeks, and she will be re-evaluated in one month. After one month, depending on the level of glycemia, there is an option to start a low dose of add low-dose treatment with gliclazide (preferred to glyburide because the patient's eGFR is less than 50 mL/min per 1.73 m2 and there is a lower risk of hypoglycemia with gliclazide) or a dose of dipeptidyl peptidase IV inhibitor adjusted for the GFR. A single daily dose of basal insulin will be a future option depending on the effects of the oral treatment. With the addition of new agents, it is reasonable to increase the frequency of blood glucose testing for a period of time (e.g., daily or twice daily for 7-10 d) and to decrease the frequency when the blood glucose levels are stable.
PDF
