Recurrent and chronic major depressive disorder (MDD) accounts for a substantial part of the disease burden because this course is most prevalent and typically requires long-term treatment. We ...associated blood DNA methylation profiles from 581 MDD patients at baseline with MDD status 6 years later. A resampling approach showed a highly significant association between methylation profiles in blood at baseline and future disease status (P = 2.0 × 10
). Top MWAS results were enriched specific pathways, overlapped with genes found in GWAS of MDD disease status, autoimmune disease and inflammation, and co-localized with eQTLS and (genic enhancers of) of transcription sites in brain and blood. Many of these findings remained significant after correction for multiple testing. The major themes emerging were cellular responses to stress and signaling mechanisms linked to immune cell migration and inflammation. This suggests that an immune signature of treatment-resistant depression is already present at baseline. We also created a methylation risk score (MRS) to predict MDD status 6 years later. The AUC of our MRS was 0.724 and higher than risk scores created using a set of five putative MDD biomarkers, genome-wide SNP data, and 27 clinical, demographic and lifestyle variables. Although further studies are needed to examine the generalizability to different patient populations, these results suggest that methylation profiles in blood may present a promising avenue to support clinical decision making by providing empirical information about the likelihood MDD is chronic or will recur in the future.
In this study involving patients who were at high risk for exacerbations of chronic obstructive pulmonary disease but had no other indication for statin treatment, simvastatin at a daily dose of 40 ...mg did not affect the exacerbation rate.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States.
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It is characterized by acute exacerbations that are associated with increased hospitalizations and costs of care, worsened quality of life, and increased mortality.
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Effective therapies for the treatment or prevention of exacerbations are limited.
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that reduce the risks of acute cardiac events and death.
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Although widely used for their lipid-lowering effects, statins are also reported to have antiinflammatory effects.
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Multiple retrospective studies have shown that statins are beneficial in COPD. Reported benefits include . . .
•Albumin-based nanoparticles have excellent safety profile and targeting properties which facilitates effective drug delivery.•The versatility of albumin-based nanoparticles allows its use in various ...drug delivery routes.•With appropriate formulation of albumin-based nanoparticles, it could potentially be explored for oral delivery.
As a natural polymer, albumin is well-received for being nontoxic, nonimmunogenic, biodegradable and biocompatible. Together with its targeting potential on specific cells, albumin-based nanoparticles appear as an effective carrier for various therapeutics. In recent years, there has been an increasing number of studies investigating the use of albumin-based nanoparticles across different administration routes. Although each route and target tissue presents a distinct anatomical and physiological profile that demands specific consideration, pharmaceuticals could still be delivered effectively via albumin-based nanoparticles. Therefore, this review discusses the features that warrant such applications across various delivery routes and explores their possibilities in other administration routes. The challenges associated with its use will also be elaborated to provide a holistic consideration to realise their clinical potentials.
Summary
Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all‐oral direct‐acting antiviral (DAA) therapy for the genotype 1b HCV‐infected patients. In this study, we investigated how ...resistance‐associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild‐type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans‐complementation of NS5A was demonstrated in our co‐transfection experiments and these results suggest that such a trans‐complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs.
We provide evidence that proton irradiation of energy 2.25 MeV on highly oriented pyrolytic graphite samples triggers ferro- or ferrimagnetism. Measurements performed with a superconducting quantum ...interferometer device and magnetic force microscopy reveal that the magnetic ordering is stable at room temperature.
The Fibromyalgia Impact Questionnaire (FIQ) is a commonly used instrument in the evaluation of fibromyalgia (FM) patients. Over the last 18 years, since the publication of the original FIQ, several ...deficiencies have become apparent and the cumbersome scoring algorithm has been a barrier to widespread clinical use. The aim of this paper is to describe and validate a revised version of the FIQ: the FIQR.
The FIQR was developed in response to known deficiencies of the FIQ with the help of a patient focus group. The FIQR has the same 3 domains as the FIQ (that is, function, overall impact and symptoms). It differs from the FIQ in having modified function questions and the inclusion of questions on memory, tenderness, balance and environmental sensitivity. All questions are graded on a 0-10 numeric scale. The FIQR was administered online and the results were compared to the same patient's online responses to the 36-Item Short Form Health Survey (SF-36) and the original FIQ.
The FIQR was completed online by 202 FM patients, 51 rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients (31 RA and 20 SLE), 11 patients with major depressive disorder (MDD) and 213 healthy controls (HC). The mean total FIQR score was 56.6 +/- 19.9 compared to a total FIQ score of 60.6 +/- 17.8 (P < 0.03). The total scores of the FIQR and FIQ were closely correlated (r = 0.88, P < 0.001). Each of the 3 domains of the FIQR correlated well with the 3 related FIQ domains (r = 0.69 to 0.88, P < 0.01). The FIQR showed good correlation with comparable domains in the SF-36, with a multiple regression analysis showing that the three FIQR domain scores predicted the 8 SF-36 subscale scores. The FIQR had good discriminant ability between FM and the 3 other groups; total FIQR scores were HC (12.1 +/- 11.6), RA/SLE (28.6 +/- 21.2) and MDD (17.3 +/- 11.8). The patient completion time was 1.3 minutes; scoring took about 1 minute.
The FIQR is an updated version of the FIQ that has good psychometric properties, can be completed in less than 2 minutes and is easy to score. It has scoring characteristics comparable to the original FIQ, making it possible to compare past FIQ results with future FIQR results.
This trial involving symptomatic, tobacco-exposed persons with preserved lung function on spirometry showed no benefit to the use of dual bronchodilator therapy.
The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain.
To relate image-based ...measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD.
We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression.
Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV
and peripheral oxygen saturation (
< 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema (
< 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) (
< 0.001).
Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).
Summary
Background
Liver fibrosis is often accompanied by steatosis, particularly in patients with non‐alcoholic fatty liver disease (NAFLD), and its non‐invasive characterisation is of utmost ...importance. Vibration‐controlled transient elastography is the non‐invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis.
Aim
To determine how to use CAP in interpreting liver stiffness measurements.
Methods
This is a secondary analysis of data from an individual patient data meta‐analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology‐specific liver stiffness measurement cut‐offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP.
Results
Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut‐offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity‐optimised cut‐offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity‐optimised cut‐offs for cirrhosis.
Conclusions
Liver stiffness measurement values below aetiology‐specific cut‐offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut‐offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or cirrhosis.
Linked ContentThis article is linked to Hassan and Tapper and Karlas et al papers. To view these articles visit https://doi.org/10.1111/apt.14584 and https://doi.org/10.1111/apt.14632.
Many tissues contain adult mesenchymal stem cells (MSCs), which may be used in tissue regeneration therapies. However, the MSC availability in most tissues is limited which demands expansion in vitro ...following isolation. Like many developing cells, the state of MSCs is affected by the surrounding microenvironment, and mimicking this natural microenvironment that supports multipotent or differentiated state in vivo is essential to understand for the successful use of MSC in regenerative therapies. Many researchers are, therefore, optimizing cell culture conditions in vitro by altering growth factors, extracellular matrices, chemicals, oxygen tension, and surrounding pH to enhance stem cells self-renewal or differentiation. Insulin-like growth factors (IGFs) system has been demonstrated to play an important role in stem cell biology to either promote proliferation and self-renewal or enhance differentiation onset and outcome, depending on the cell culture conditions. In this review, we will describe the importance of IGFs, IGF-1 and IGF-2, in development and in the MSC niche and how they affect the pluripotency or differentiation towards multiple lineages of the three germ layers.
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