Summary
Despite their anticholinergic side effects, first-generation antihistamines are widely prescribed to elderly patients. A systematic review was conducted to synthesize real-world evidence. ...First-generation antihistamine use is considerably associated with an increased risk of injurious falls or fracture among the elderly.
Introduction
First-generation antihistamines are considered potentially inappropriate for elderly patients owing to anticholinergic side effects. We aimed to determine whether elderly patients taking antihistamines are at increased risk of injurious falls or fracture.
Methods
We identified studies in MEDLINE, EMBASE, and several local databases through November 2016. Observational studies on the association between antihistamine use and the risk of injurious falls or fracture were selected. Quality of the studies and the level of evidence were assessed. The random-effects model was employed for meta-analysis, and heterogeneity was examined based on I-square and Cochrane’s
Q
test. Subgroup analyses were performed when the heterogeneity among studies could not be explained.
Results
From 473 identified studies, five (three case-control studies, one cohort study, and one case-crossover study) were included in our analysis based on eligibility criteria. First-generation antihistamine use showed significantly increased risk of injurious falls or fracture (odds ratio OR 2.03, 95% confidence interval CI 1.49–2.76, heterogeneity:
p
= 0.41,
I
2
= 0%). Studies including antihistamines of all generations or containing no generation information were dealing with falls during hospitalization. Among these studies, the association was statistically significant without heterogeneity (OR 2.89, 95% CI 1.71–4.89, heterogeneity:
p
= 0.42,
I
2
= 0%). Due to the small number of studies included and unadjusted results, meaningful interpretation based on subgroup analysis was limited.
Conclusions
First-generation antihistamine use is considerably associated with increased risk of injurious falls or fracture among the elderly. Clinicians need to exercise caution when prescribing first-generation antihistamines to elderly patients.
High blood copper (Cu) and homocysteine (Hcy) concentrations have been independently reported as risk factors for cardiovascular diseases. When they are simultaneously measured, a concomitant ...increase in both parameters in association with vascular dysfunction has been observed. Cu chelator penicillamine can significantly diminish the inhibitory effect of Hcy on endothelial function, which has led to the interpretation that Cu mediates the deleterious effect of Hcy. However, Cu itself has been shown to be beneficial to the cardiovascular system. In particular, Cu promotion of angiogenesis has been well documented. Cu stimulates endothelial cell proliferation and differentiation and promotes microtubule formation in cultured saphenous veins. High levels of Hcy do not affect the process of microtubule formation, but the combination of Cu and Hcy leads to a significant inhibitory effect. Under other conditions, Cu does not affect, but Hcy inhibits, the endothelium-dependent relaxation of blood vessels and the combination of both augments the inhibition. Why does Cu produce adverse effects when it co-exists with Hcy? Cu forms complexes with Hcy and the Cu-Hcy complexes possess a deleterious potential due to their redox properties. Cu chelation can remove Cu from the Cu-Hcy complexes, but leaves behind high levels of Hcy and produces Cu deficiency. An alternative approach should focus on the reduction of Hcy, but maintenance of Cu, making detrimental Cu beneficial. A comprehensive understanding of Cu speciation and a development of selective modulation of Cu coordination to Cu-binding molecules to avoid Cu-Hcy complex formation would effectively improve the condition of cardiovascular disease.
•DRW and CRW models are implemented in OpenFOAM for dispersion of particles in a cyclone.•The dispersion model is essential for accurate prediction of the particle collection efficiency.•LES performs ...better than RSTM for the axial velocity of unsteady turbulent flow.•CRW predicts the overall collection efficiency better than DRW in RSTM.•LES gives the better prediction of the overall collection efficiency than RSTM.
Gas-solid separators have played an important role for process or emission control of many facilities including fluidized bed reactors. The flow field and collection efficiency were investigated for a Stairmand- type cyclone separator by Reynolds stress transport model (RSTM) and large eddy simulation (LES) in this work. RSTM and LES both showed good agreement with measured mean tangential velocity, whereas LES reproduced unsteady flow in the core with better agreement of the mean axial velocity profile. The particle dispersion model is required to obtain an accurate overall collection efficiency in both RSTM and LES. Anisotropy in velocity fluctuation should be taken into account, whereas its effect is more significant in RSTM than in LES. The continuous random walk (CRW) model gave more accurate results than the discrete random walk (DRW) model in RSTM, whereas there was no significant difference in LES resolving most large scale eddies. LES made better prediction of the overall particle collection efficiency than RSTM, although further investigation may be required for deviation in the maximum inlet flow case of the cyclone separator.
Summary
Objective
To describe mesial temporal lobe ablated volumes, verbal memory, and surgical outcomes in patients with medically intractable mesial temporal lobe epilepsy (mTLE) treated with ...magnetic resonance imaging (MRI)–guided stereotactic laser interstitial thermal therapy (LiTT).
Methods
We prospectively tracked seizure outcome in 20 patients at Thomas Jefferson University Hospital with drug‐resistant mTLE who underwent MRI‐guided LiTT from December 2011 to December 2014. Surgical outcome was assessed at 6 months, 1 year, 2 years, and at the most recent visit. Volume‐based analysis of ablated mesial temporal structures was conducted in 17 patients with mesial temporal sclerosis (MTS) and results were compared between the seizure‐free and not seizure‐free groups.
Results
Following LiTT, proportions of patients who were free of seizures impairing consciousness (including those with auras only) are as follows: 8 of 15 patients (53%, 95% confidence interval CI 30.1–75.2%) after 6 months, 4 of 11 patients (36.4%, 95% CI 14.9–64.8%) after 1 year, 3 of 5 patients (60%, 95% CI 22.9–88.4%) at 2‐year follow‐up. Median follow‐up was 13.4 months after LiTT (range 1.3 months to 3.2 years). Seizure outcome after LiTT suggests an all or none response. Four patients had anterior temporal lobectomy (ATL) after LiTT; three are seizure‐free. There were no differences in total ablated volume of the amygdalohippocampus complex or individual volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus between seizure‐free and non–seizure‐free patients. Contextual verbal memory performance was preserved after LiTT, although decline in noncontextual memory task scores were noted.
Significance
We conclude that MRI‐guided stereotactic LiTT is a safe alternative to ATL in patients with medically intractable mTLE. Individualized assessment is warranted to determine whether the reduced odds of seizure freedom are worth the reduction in risk, discomfort, and recovery time. Larger prospective studies are needed to confirm our preliminary findings, and to define optimal ablation volume and ideal structures for ablation.
Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with ...aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here.
Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion).
Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% 95% confidence interval (CI) 12% to 30% and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year.
With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.
•At 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit in patients with aHCC.•ORR was 20% in the sorafenib (SOR)-naive group and 14% in the SOR-experienced group.•3-year OS rates were 28% in the SOR-naive and 20% in the SOR-experienced groups; 5-year rates were 14% and 12%, respectively.•The safety profile of nivolumab monotherapy was manageable and no new safety signals were identified.•Higher ORR and longer OS were noted with baseline PD-L1 ≥1% versus <1% and were more prominent in the SOR-experienced group.
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic ...drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
•NTRK gene fusions are oncogenic drivers in a variety of tumor types including adult and pediatric sarcomas.•TRK inhibitors provide effective treatment options for patients with sarcomas harboring NTRK gene fusions.•Integrating NTRK testing into the management of patients with sarcoma is challenging due to the rarity of this biomarker.•Massive parallel RNA sequencing provides the optimal NTRK fusion test and immunohistochemistry is a valuable screening tool.•We propose a diagnostic strategy that considers histologic and molecular subtypes to facilitate routine NTRK fusion testing.
Summary Objective Increased activity of histone deacetylase 2 (HDAC2) has been found in patients with osteoarthritis (OA) and cartilage matrix degradation and has been shown to mediate the repression ...of cartilage-specific gene expression in human chondrocytes. We aimed to determine whether microRNA-92a-3p (miR-92a-3p) regulates cartilage-specific gene expression via targeted HDAC2 in chondrogenesis and degradation. Methods miR-92a-3p expression was assessed in vitro in a human mesenchymal stem cells (hMSCs) model of chondrogenesis and in normal and OA primary human chondrocytes (PHCs), and in normal and OA human cartilage by in situ hybridization. hMSCs and PHCs were transfected with miR-92a-3p or its antisense inhibitor (anti-miR-92a-3p), respectively. PHCs were transfected with miR-92a-3p or anti-miR-92a-3p for 24 h before chromatin immunoprecipitation assay was performed with anti-ac-H3 antibody. Direct interaction between miR-92a-3p and its putative binding site in the 3’ untranslated region (3’-UTR) of HDAC2 mRNA was confirmed by luciferase reporter assay. Results miR-92a-3p expression was elevated in chondrogenic and hypertrophic hMSC, while reduced in OA cartilage compared with normal cartilage. The overexpression of miR-92a-3p suppressed the activity of a reporter construct containing the 3’-UTR and inhibited HDAC2 expression in both hMSCs and PHCs, while treatment with anti-miR-92a-3p enhanced HDAC2 expression. Chromatin immunoprecipitation assays showed that miR-92a-3p enhances H3 acetylation on ACAN, COMP and Col2a1 promoter, and also promotes relative cartilage matrix expression. Conclusion Our results suggest that miR-92a-3p regulates cartilage development and homeostasis, which directly targets HDAC2, indicating histone hyperacetylation plays an important role in increased expression of cartilage matrix.
The geometrical flamelet statistics in a turbulent premixed flame are represented by c¯, Σf, 〈n〉f, 〈∇·n〉f and 〈|∇·n|〉f which are respectively mean reaction progress variable, flame surface density, ...mean orientation vector, mean curvature and mean absolute curvature. New conditional transport equations are derived for the listed geometrical statistics of successively higher orders in terms of net normal flame motion from the equation of the reaction progress variable. They are simpler and allow easier closure than the unconditionally averaged formulations involving the tangential velocity component and the turbulent flux term involving countergradient diffusion. Balance is checked for all component terms of those transport equations in two freely propagating, constant density DNS flames in statistical steadiness. Results show that the mean orientation vector and the mean absolute curvature remain approximately uniform in local equilibrium with negligible spatial transport except near the edges of a flame brush. A simple closure strategy is suggested with the flame surface density given in terms of uniform mean absolute curvature and mean orientation vectors, 〈nx〉f and 〈nx〉K, given as the conditional averages weighted by Σf′(=∂c/∂n) and ∂2c/∂n2 respectively. The governing equations and closure models are expected to be valid in planar freely propagating turbulent premixed flames of either constant or variable density with heat release. The suggested closure requires prior knowledge on the magnitude of the mean orientation vector and the mean absolute curvature given as the ratio of laminar and turbulent flame speeds and the inverse characteristic wrinkling scale through a flame brush. Good agreement is shown against DNS results of two constant density flames for closure models of the conditional velocities, 〈u〉f and 〈Sd〉f, and for the predicted profiles of c¯ and Σf except for minor deviation near the edges. The suggested closure scheme may be extended to general turbulent premixed flames, while further work may be required for proper closure relationships under the given circumstances.
Yolk-shell-structured MoSe₂ microspheres were prepared via a simple selenization process of MoO₃ microspheres. The yolk-shell-structured MoSe₂ and MoO₃ microspheres delivered initial discharge ...capacities of 527 and 465 mA h g(-1) in the voltage range of 0.001-3 V vs. Na/Na(+) at a current density of 0.2 A g(-1), respectively, and their discharge capacities after 50 cycles were 433 and 141 mA h g(-1), respectively. The yolk-shell-structured MoSe₂ microspheres also exhibited outstanding high rate capabilities. The hierarchical yolk-shell structure comprised of wrinkled nanosheets facilitated fast Na-ion and electron kinetics, and buffered the large volume changes encountered during cycling.
The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon ...18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility.
VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes.
A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib.
ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.
•This study comprehensively documents the landscape of KIT and PDGFRA mutations in metastatic, imatinib-resistant GIST.•Selective pressure exerted with prior lines promotes a shift toward increased resistant subpopulations in the KIT A-loop.•Individual mutations in KIT/PDGFRA determine TKI sensitivity and resistance in metastatic GIST.•ctDNA-detected KIT/PDGFRA mutations in imatinib-resistant GIST prognosticate third- or fourth-line TKI treatment outcomes.
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