Cells dynamically regulate their membrane surface area during a variety of processes critical to their survival. Recent studies with model membranes have pointed to a general mechanism for surface area regulation under tension in which cell membranes unfold or take up lipid to accommodate membrane strain. Yet we lack robust methods to simultaneously measure membrane tension and surface area changes in real time. Using lipid vesicles that contain two dyes isolated to spatially distinct parts of the membrane, we introduce a new method to monitor the processes of membrane stretching and lipid uptake in model membranes.
https://ift.tt/2PHeSSZ
Δευτέρα 27 Αυγούστου 2018
Visualizing tension and growth in model membranes using optical dyes
Intramolecular Diffusion in α-Synuclein: It Depends on How You Measure It.
Intramolecular protein diffusion, the motion of one part of the polypeptide chain relative to another part, is a fundamental aspect of protein folding and may modulate amyloidogenesis of disease-associated intrinsically disordered proteins. Much work has determined such diffusion coefficients using a variety of probes, but there has been an apparent discrepancy between measurements using long-range probes, such as FRET, and short range probes, such as Trp-Cys quenching. In this work, we make both such measurements on the same protein, α-synuclein, and confirm that such discrepancy exists.
https://ift.tt/2PHqSUD
An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin
Channelrhodopsins (ChRs) are microbial light-gated ion channels with a retinal chromophore, and are widely utilized in optogenetics to precisely control neuronal activity with light. Despite increasing understanding of their structures and photo-activation kinetics, the atomistic mechanism of light gating and ion conduction remains elusive. Here, we present an atomic structural model of a chimeric ChR in a precursor state of the channel opening determined by an accurate hybrid molecular simulation technique and a statistical theory of internal water distribution.
https://ift.tt/2MBOwnB
Water distribution within wild type NRas protein and Q61 mutants during unrestrained QM/MM dynamics
Point mutations in p21rasare associated with approximately 30% of human tumors by disrupting its GTP hydrolysis cycle, which is critical to its molecular switch function in cellular signalling pathways. In this work, we investigate the impact of Gln 61 substitutions in the structure of p21N-rasactive site and particularly focus on water reorganization around GTP, which appears to be crucial to evaluate favorable and unfavorable hydration sites for hydrolysis. The NRas-GTP complex is analyzed using hybrid quantum mechanics / molecular mechanics approach treating for the first time to our knowledge transient water molecules at the ab-initio level and leading to results that account for the electrostatic coupling between the protein complex and the solvent.
https://ift.tt/2LyHomu
Molecular determinants of small molecule affinity and enzyme activity of a cytochrome P450BM3 variant
Cytochrome P450BM3 catalyzes the hydroxylation and/or epoxidation of fatty acids, fatty amides, and alcohols. Protein engineering has produced P450BM3 variants capable of accepting drug molecules normally metabolized by human P450 enzymes. The enhanced substrate promiscuity has been attributed to the greater flexibility of the lid of the substrate channel. However, it is not well understood how structurally different and highly polar drug molecules can stably bind in the active site nor how the activity and coupling efficiency of the enzyme may be affected by the lack of enzyme-substrate complementarity.
https://ift.tt/2LyHpXA
The impacts of L1 promoter variation and L2 clavulanate susceptibility on ticarcillin-clavulanate susceptibility of Stenotrophomonas maltophilia [Mechanisms of Resistance]
Inducible expression of L1 and L2 β-lactamases is the principal mechanism responsible for β-lactam resistance in Stenotrophomonas maltophilia. Ticarcillin-clavulanate (TIM) is one of the few effective β-lactam for S. maltophilia treatment. Clavulanate (CA) is a β-lactamase inhibitor which specifically targets to Class A, C, and D β-lactamases. In view of the presence of class B L1 β-lactamase, it is of interest to elucidate why TIM is valid for S. maltophilia treatment. The L1, L2 allelic variation and TIM susceptibility from 22 clinical isolates were established. According to L1 and L2 protein sequences and TIM susceptibility, three L1-based phylogenetic clusters (L1-A, L1-B, and L1-C) and three L2-based phylogenetic clusters (L2-A, L2-B1, and L2-B2) were classified. The contribution of each L1- and L2-based phylogenetic cluster to ticarcillin (TIC) and TIM susceptibility was investigated. All L1s and L2s tested contributed to TIC resistance. L1s tested were inert to CA; nevertheless, the sensitivities of L2s toward CA were greatly different. In addition, the genetic organizations upstream of the L1 gene much varied in these isolates. At least three different L1 promoter structure (K279a-type, D457-type, and none) were found from the 22 isolates assayed. The difference in the L1 promoter structure made a great impact on the TIC-induced L1 β-lactamase activities. Collectively, the L1 promoter activity responding to TIC challenge and L2 susceptibility toward CA are critical factors determining TIM susceptibility in S. maltophilia.
https://ift.tt/2MUNvXa
ATTRIBUTABLE COST AND LENGTH OF STAY OF NOSOCOMIAL GRAM-NEGATIVE BACTERIA CULTURES [Epidemiology and Surveillance]
Introduction: Few studies have estimated the excess inpatient cost due to nosocomial Gram-negative bacteria (GNB) cultures and those that do are often subject to time-dependent bias. Our objective was to generate estimates of the attributable cost of the underlying infections associated with nosocomial cultures using a unique inpatient cost dataset from the US Department of Veterans Affairs that allowed us to reduce time-dependent bias.
Methods: Our study included data from inpatient admissions between 10/1/2007 and 11/30/2010. Nosocomial GNB positive cultures were defined as positive clinical cultures for Acinetobacter, Pseudomonas, or Enterobacteriaceae from 48 hours after admission to discharge. Positive cultures were further classified by site and their level of resistance. We conducted analyses using both a conventional approaches and an approach aimed at reducing the impact of time-dependent bias. In both instances, we used multivariable generalized linear models to compare the inpatient costs and LOS between patients with and without a nosocomial Gram-negative bacteria cultures.
Results: Of the 404,652 patients included in the conventional analysis, 12,356 had a nosocomial GNB positive culture. The excess cost of nosocomial GNB positive cultures was significant regardless of specific pathogen, site, or resistance level. Estimates generated using the conventional analysis approach were 32.0% - 131.2% higher in magnitude than those generated using an approach to reduce time-dependent bias.
Conclusion: These results are important because they underscore the high financial burden attributable to these infections and provide a baseline that can be used to assess the impact of improvements in infection control.
https://ift.tt/2PcFHxn
Genomic analysis of multi-resistant Staphylococcus capitis associated with neonatal sepsis [Epidemiology and Surveillance]
Coagulase-negative staphylococci (CoNS) such as Staphylococcus capitis, are major causes of bloodstream infections in neonatal intensive care units (NICUs). Recently a distinct clone of S. capitis (designated S. capitis NRCS-A) has emerged as an important pathogen in NICUs internationally. Here, 122 S. capitis isolates from New Zealand (NZ) underwent whole genome sequencing (WGS), and these data were supplemented with publicly available S. capitis sequence reads. Phylogenetic and comparative genomic analyses were performed, as were phenotypic assessments of antimicrobial resistance, biofilm formation and plasmid segregational stability on representative isolates. A distinct lineage of S. capitis was identified in NZ, associated with neonates and the NICU environment. Isolates from this lineage produced increased levels of biofilm, displayed higher levels of tolerance to chlorhexidine, and were multidrug-resistant. Although similar to globally circulating NICU-associated S. capitis at a core genome level, NZ NICU S. capitis isolates carried a novel, stably maintained multidrug-resistant plasmid that was not present in non-NICU isolates. Neonatal blood culture isolates were indistinguishable to environmental S. capitis isolates found on fomites such as stethoscopes and neonatal incubators, but were generally distinct from those isolates carried by NICU staff. This work implicates the NICU environment as a potential reservoir for neonatal sepsis caused by S. capitis, and highlights the capacity of genomics-based tracking and surveillance to inform future hospital infection control practices aimed at containing the spread of this important neonatal pathogen.
https://ift.tt/2PJb4AM
Alanine scanning mutagenesis of the MEDI4839 (Suvratoxumab) epitope reduces alpha toxin lytic activity in vitro and S. aureus fitness in infection models [Clinical Therapeutics]
Alpha toxin (AT) is a cytolytic pore-forming toxin that plays a key role in Staphylococcus aureus pathogenesis, consequently extensive research was undertaken to understand the AT mechanism of action and its utility as a target for novel prophylaxis and treatment strategies against S. aureus infections. MEDI4893 (Suvratoxumab) is a human anti-AT IgG1 monoclonal antibody (mAb), which targets AT and is currently in Phase 2 clinical development. As shown previously, the MEDI4893-binding epitope on AT is comprised of the highly conserved amino acid regions 177-200 and 261-271, suggesting these amino acids are important for AT function. To test this hypothesis, and gain insight into the effect mutations in the epitope on AT neutralization by MEDI4893, nine MEDI4893 contact residues in AT were individually mutated to alanine. Consistent with our hypothesis, 8 out of 9 mutants exhibited >2-fold loss in lytic activity resulting from a defect in cell binding and pore formation. MEDI4893 binding affinity was reduced >2-fold (2 – 27-fold) for 7 out of 9 mutants and no binding detected for W187A mutant. MEDI4893 effectively neutralized all the lytic mutants in vitro and in vivo. When the defective mutants were introduced into a S. aureus clinical isolate, the mutant-expressing strains exhibited less severe disease in mouse models and were effectively neutralized by MEDI4893. These results indicate the MEDI4893 epitope is highly conserved due, in part to its role in AT pore-formation and bacterial fitness, thus decreasing the likelihood for the emergence of mAb-resistant variants.
https://ift.tt/2LvhrUR
Argentilactone Molecular Targets in Paracoccidioides brasiliensis Identified by Chemoproteomics [Mechanisms of Action]
Paracoccidioidomycosis (PCM) is the cause of many deaths from systemic mycoses. The etiological agents of PCM belong to the Paracoccidioides genus, which is restricted to Latin America. The infection is acquired through the inhalation of conidia that primarily lodge in the lungs and may disseminate to other organs and tissues. The treatment for PCM is commonly performed via the administration of antifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungal toxicity and side effects, in addition to their long treatment times, have stimulated research for new bioactive compounds. Argentilactone is compound that was isolated from the Brazilian savanna plant Hyptis ovalifolia, and it has been suggested to be a potent antifungal, inhibiting the dimorphism of P. brasiliensis and the enzymatic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. This work was developed due to the importance of elucidating the putative mode of action of argentilactone. The chemoproteomics approach via affinity chromatography was the methodology used to explore the interactions between P. brasiliensis proteins and argentilactone. A total of 109 proteins were identified and classified functionally. The most representative functional categories were related to amino acid metabolism, energy, and detoxification. Argentilactone inhibited the enzymatic activity of malate dehydrogenase, citrate synthase, and pyruvate dehydrogenase. Furthermore, argentilactone induces the production of reactive oxygen species and inhibits the biosynthesis of cell wall polymers.
https://ift.tt/2MTbvd6
Reliable and easy-to-use Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) assay for quantification of Olorofim (F901318) - a novel antifungal drug - in human plasma and serum [Analytical Procedures]
Background A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, Olorofim (formerly F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated.
Methods Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. An isotope labeled analogue of F901318 was employed as internal standard. Chromatographic separation was achieved using a 50 mm x 2.1 mm, 1.9μm, polar Hypersil Gold C18 column and isocratic mobile phase consisting of 0.1 % formic acid/acetonitrile (60%/40%, v/v) at a flow rate of 330 μl/min. The analyte was detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI+) within a single runtime of t = 2.00 min.
Results The present LC-MS/MS-method was validated according to the international guidelines of the International Conference on Harmonisation (ICH) and the US Food and Drug Administration (FDA). Linearity of F901318 concentration ranges was verified by the Mandel-test. Calibration curve was tested linear across the range and fitted using least squares regression with a weighting factor of the reciprocal concentration. Limit of detection was: LOD = 0.0011 mg/l, lower limit of quantitation was: LLOQ = 0.0033 mg/l. Intra-day and inter-day precisions ranged from 1.17% to 3.23% for F901318, and intra-day and inter-day accuracies (%bias) ranged from 0.75% to 5.01%.
Conclusion The method was established for the rapid quantitation of F901318 concentrations in serum and plasma samples in patient trials, and optimizes TDM in applying an easy-to-use single method.
https://ift.tt/2Lx2Fgr
Diversity of high-level aminoglycoside resistance mechanisms among Gram-negative nosocomial pathogens in Brazil [Letters]
Studies on high-level aminoglycoside resistance (HLAR), especially pertaining to 16S ribosomal RNA methyltransferases (16S-RMTases), have mostly involved Enterobacteriales, whereas comparable data on glucose-non-fermenting Gram-negative bacilli (NFGNB) remain scarce (1, 2)....
https://ift.tt/2MTbohG
Implementation of Rapid Diagnostic Testing without Active Stewardship Team Notification for Gram-Positive Blood Cultures in a Community Teaching Hospital [Clinical Therapeutics]
In community hospitals, antimicrobial stewardship team notification of rapid diagnostic testing (RDT) results may not be feasible. A retrospective, quasi-experimental study was conducted evaluating 252 adult inpatients with blood cultures positive for Gram-positive cocci in clusters (pre-RDT n=143, post-RDT n=109). Median time to appropriate therapy was significantly shorter in the post-RDT group (15 vs. 0 hr, p <0.001), and mean length of stay for patients with Coagulase-negative staphylococcus was significantly shorter (10.5 vs. 7.7 days, p=0.015).
https://ift.tt/2LsQLEk
Antimicrobial Prophylaxis for Patients Undergoing Cardiac Surgery: Intraoperative Cefazolin Concentrations and Sternal Wound Infections [Pharmacology]
This study characterizes the pharmacodynamics of antimicrobial prophylaxis and sternal wound infections following cardiac surgery. Duration of surgery and cefazolin plasma concentration during wound closure were independently associated with surgical site infection at 30 days. Furthermore, duration of surgery >346 minutes and total cefazolin closure concentration <104 mg/L were significant thresholds for an increased risk of infection. This study provides new data that informs dosing strategies for effective AP in patients undergoing cardiac surgery with cardiopulmonary bypass.
https://ift.tt/2MTbh5K
Impact of efavirenz, ritonavir-boosted lopinavir and nevirapine based antiretroviral regimens on the pharmacokinetics of lumefantrine and safety of artemether-lumefantrine in falciparum-negative HIV-infected Malawian adults stabilized on antiretroviral therapy [Clinical Therapeutics]
There is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve (AUC0-14 days) of lumefantrine and safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV) infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n=6/group): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n=10-15/group): (i) antiretroviral-naïve, (ii) on efavirenz-based ART and (iii) on ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine's AUC0-14 days was 53% [95% CI: 0.27-0.82] lower in the efavirenz-based ART group than the ART-naïve group and was 2.4 [95% CI: 1.58-3.62] and 2.9 [95% CI: 1.75-4.72] times higher in the nevirapine and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine's AUC0-14 days was 1.9 [95% CI: 1.26-3.00] times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz- and ART-naïve groups (0.99 [95% CI: 0.63-1.57]). Frequent cases of haematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria co-infected adults.
https://ift.tt/2LxsQ6v
Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treating Plasmodium falciparum malaria patients using mathematical modelling [Analytical Procedures]
The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative co-administered with a longer acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine - DHA-PPQ-MQ), for use in South-East Asia, where DHA and PPQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at varying degrees of DHA and PPQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PPQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PPQ, the administration of three 6.7 mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by WHO guidelines. As a result, three 8.3 mg/kg doses of MQ, the current WHO recommended dosing regimen of MQ, combined with DHA-PPQ, has potential to produce high cure rates in the regions where resistance to DHA-PPQ has emerged.
https://ift.tt/2N0KWTy
Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis [Experimental Therapeutics]
We tested the ability of clavulanic acid to restore the efficacy of cefazolin against S. aureus TX0117, which exhibits the cefazolin inoculum effect (CzIE). In the rat infective endocarditis model, the co-administration of cefazolin plus clavulanic acid resulted in a significant reduction of bacterial counts (7.1 ± 0.5 log10 CFU/g) compared to cefazolin alone (2 ± 0.6 log10 CFU/g; p<0.0001). The addition of a β-lactamase inhibitor may be a viable strategy for overcoming the CzIE.
https://ift.tt/2PbJsTA
Single-day doxycycline therapy for Mediterranean spotted fever: a prospective cohort study [Clinical Therapeutics]
The objective of this study is to evaluate the results of single-day doxycycline therapy for Mediterranean spotted fever (MSF). This is a prospective cohort study of cases with confirmed MSF treated with the single-day doxycycline regimen in a teaching hospital from 1990 to 2015. Patients received two oral doses of 200 mg of doxycycline for one day. The outcomes evaluated were time interval between start of treatment and apyrexia, time interval between start of treatment and disappearance of other symptoms, adverse reactions to treatment and death. The study included 158 subjects, 18 of whom (11.4%) had a severe form of MSF and 31 (19.6%) were >65 years. The interval between onset of symptoms and start of treatment was 4.31±1.54 days. All patients recovered uneventfully. Fever disappeared 2.55±1.14 days after the start of treatment. The remaining symptoms (headache, arthromyalgia) disappeared 3.63±1.35 days after the start of treatment. Only one patient had a delay in reaching apyrexia (8 days). The fever disappeared somewhat later in severe cases (median, 3 [interquartile range {IQR}, 2-4] days) than in non-severe cases (median, 2 [IQR, 2-3] days). Likewise, the remaining symptoms disappeared later in severe cases (median, 5 [IQR, 4-6] days) than in non-severe cases (median, 3 [IQR, 3-4] days). The outcome was similar in the elderly and in the non-elderly patients. Eight patients had mild adverse effects possibly related to treatment. The results of the study confirm that single-day doxycycline therapy is an effective and well-tolerated treatment for MSF, including elderly patients and severe cases.
https://ift.tt/2LvVPb9
Simplified aztreonam dosing in patients with end stage renal disease: results of a Monte Carlo simulation [Clinical Therapeutics]
The manufacturer-labeled aztreonam dosing in patients with a creatinine clearance of <10 mL/min/1.73m2 is complex. It is unknown if simpler post-hemodialysis dosing administered once daily or thrice weekly can reliably achieve pharmacodynamic goals. We found that 1 or 2 grams once daily post-hemodialysis had a >90% probability of target attainment up to an MIC of 4 or 8mg/L, respectively. Thrice weekly dosing should generally be avoided except in non-severe infections where the MIC is ≤0.5mg/L.
https://ift.tt/2N0KGE4
In Vitro Antiviral Profile of Ruzasvir: A Potent and Pan-genotype Inhibitor of HCV NS5A [Antiviral Agents]
Inhibition of NS5A has emerged as an attractive strategy to intervene in HCV replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with EC50 values of 1-4 pM in Huh 7 or 7.5 cells bearing replicons for HCV genotypes 1-7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs) with the exception of M28G. De novo resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31 and 93 across genotypes. Substitutions at position 93 were more common in genotypes (GTs) 1-4 while changes at position 31 emerged frequently in GTs 5 and 6. With the exception of GT4, the reintroduction of selected RASs conferred a 100-fold or more potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with NS3/4A protease inhibitor (grazoprevir) and NS5B polymerase (uprifosbuvir) pro-drug was additive to synergistic with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.
https://ift.tt/2LxNiEC
Therapeutic drug monitoring of voriconazole in children: experience from a tertiary care center in China [Clinical Therapeutics]
Voriconazole is a broad-spectrum triazole antifungal and the first line treatment for invasive aspergillosis (IA). The aim of this research was to study the dose adjustments of voriconazole as well as the affecting factors influencing voriconazole trough concentrations in Asian children to optimize its daily administration. Clinical data were analyzed of inpatients aged 2-14 years who were subjected to voriconazole trough concentrations monitoring from June 1, 2015 to December 1, 2017. A total of 138 voriconazole trough concentrations from 42 paediatric patients were included. Voriconazole trough concentrations at steady state ranged from 0.02 to 9.35mg/liter with high inter- and intra-individual variability. Only 50.0% of children achieved the target range (1.0~5.5 mg/liter) at initial dosing, while 35.7% of children were subtherapeutic, and 14.3% of children were supratherapeutic at initial dosing. There was no correlation between initial trough concentrations and initial dosing. A total of 28.6% of children (12/42) adjusted the dose according to trough concentrations. Children aged <6,6~12 and >12 years old required median oral maintenance dose to achieve the target range of 11.1, 7.2 and 5.3 mg/kg twice daily respectively (P=0.043). The average doses required to achieved the target range were 7.7 mg/kg and 5.6 mg/kg, respectively, and were lower than the recommended dosage (P=0.033, 0.003). Affecting factors such as administration routes and co-administration with proton pump inhibitors (PPIs) explained 55.3% of variability in voriconazole exposure. Therapeutic drug monitoring (TDM) of voriconazole could help to individualize antifungal therapy for children and provide guidelines for TDM and dosing optimization in Asian children.
https://ift.tt/2P8Egjw
Immunosuppressed Adult Zebrafish Model of Mucormycosis [Letters]
Mucormycosis is a life threatening, rapidly progressing infection associated with high mortality....
https://ift.tt/2MU1fBw
Randomized, Double-Blind, Placebo-Controlled Studies of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eravacycline [Pharmacology]
Eravacycline is a novel, fully-synthetic fluorocycline antibiotic with in vitro activity against aerobic and anaerobic Gram-positive and Gram-negative pathogens including multi-drug resistant (MDR) bacteria. The pharmacokinetics (PK), urinary excretion, and safety/tolerability of intravenous (IV) eravacycline were evaluated in single- and multiple ascending dose studies. Healthy subjects received single IV doses of 0.1 to 3 mg/kg or 10 days treatment with 0.5 or 1.5 mg/kg q24h over 30 minutes, 1.5 mg/kg q24h over 60 minutes, or 1 mg/kg q12h over 60 minutes. After single doses, total exposure (AUC) and peak plasma concentrations (Cmax) of eravacycline increased in an approximately dose-proportional manner. After multiple doses, steady-state was achieved within 5 to 7 days. Accumulation (AUC0-24) ranged between approximately 7% and 38% with the q24h dosing regimens and 45% with 1 mg/kg q12h. Eravacycline was generally well tolerated, with dose-related nausea, infusion site effects, and superficial phlebitis that were mild or moderate. These results provide support for the 1 mg/kg q12h regimen used in clinical studies of eravacycline.
https://ift.tt/2LuxSAJ
Mapping and Sequencing of a Significant Quantitative Trait Locus Affecting Resistance to Koi Herpesvirus in Common Carp
Cyprinids are the most highly produced group of fishes globally, with common carp being one of the most valuable species of the group. Koi herpesvirus (KHV) infections can result in high levels of mortality, causing major economic losses, and is listed as a notifiable disease by the World Organisation for Animal Health. Selective breeding for host resistance has the potential to reduce morbidity and losses due to KHV. Therefore, improving knowledge about host resistance and methods of incorporating genomic data into breeding for resistance may contribute to a decrease in economic losses in carp farming. In the current study, a population of 1,425 carp juveniles, originating from a factorial cross between 40 sires and 20 dams was challenged with KHV. Mortalities and survivors were recorded and sampled for genotyping by sequencing using Restriction Site-Associated DNA sequencing (RADseq). Genome-wide association analyses were performed to investigate the genetic architecture of resistance to KHV. A genome-wide significant QTL affecting resistance to KHV was identified on linkage group 44, explaining approximately 7 % of the additive genetic variance. Pooled whole genome resequencing of a subset of resistant (n = 60) and susceptible animals (n = 60) was performed to characterize QTL regions, including identification of putative candidate genes and functional annotation of associated polymorphisms. The TRIM25 gene was identified as a promising positional and functional candidate within the QTL region of LG 44, and a putative premature stop mutation in this gene was discovered.
https://ift.tt/2wizucj
Differentiation of atypical pancreatic neuroendocrine tumors from pancreatic ductal adenocarcinomas: Using whole‐tumor CT texture analysis as quantitative biomarkers
Cancer Medicine, EarlyView.
https://ift.tt/2PGCxD3
Transcultural adaptation and validation of the Persian version of the breast cancer awareness measure (BCAM) questionnaire
Cancer Medicine, EarlyView.
https://ift.tt/2Lxm5BF
Dose escalation of radiotherapy in unresectable extrahepatic cholangiocarcinoma
Cancer Medicine, EarlyView.
https://ift.tt/2whMxuw
Oral fluorouracil vs vinorelbine plus cisplatin as adjuvant chemotherapy for stage II‐IIIA non‐small cell lung cancer: Propensity score‐matched and instrumental variable analyses
Cancer Medicine, EarlyView.
https://ift.tt/2Nnxgi5
Two Ebola Patients Who Received Experimental Tx Have Recovered
MONDAY, Aug. 27, 2018 -- Two of the first 10 people to receive an experimental Ebola treatment have recovered from the highly dangerous disease, Congo's health ministry says. The patients received a treatment called mAb114, which was isolated from a...
https://ift.tt/2wrfZxi
Bigger Drop in Opioid Prescribing After CDC Guideline Release
MONDAY, Aug. 27, 2018 -- Release of the U.S. Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain in March 2016 corresponded to greater increases in several opioid prescribing patterns, according to a study...
https://ift.tt/2BZDALo
High LDL in Young, Healthy Adults Leaves Them Vulnerable to CVD
MONDAY, Aug. 27, 2018 -- Low-density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) ≥160 mg/dL are independently associated with increased relative risk of cardiovascular disease (CVD) mortality in a...
https://ift.tt/2ofLbMv
Pediatricians Advise Against Use of Marijuana in Pregnancy
MONDAY, Aug. 27, 2018 -- Due to the potential adverse effect of marijuana use during pregnancy and breastfeeding, pediatricians should recommend against marijuana use, according to a clinical report published online Aug. 27 in Pediatrics. Sheryl A....
https://ift.tt/2BTJfTi
Cardiac autonomic neuropathy in type 1 and type 2 diabetes patients
Cardiac autonomic neuropathy (CAN) in diabetes is among the strongest risk markers for future global and cardiovascular mortality. The aim of this study was to analyse CAN prevalence and to compare the associatio...
https://ift.tt/2odBMVz
Acute spontaneous intracerebral hemorrhage and traumatic brain injury are the most common causes of critical illness in the ICU and have high early mortality
Critical care covers multiple disciplines. However, the causes of critical illness in the ICU, particularly the most common causes, remain unclear. We aimed to investigate the incidence and the most common cau...
https://ift.tt/2BP1rgS
Early Gastric Cancer with Purely Enteroblastic Differentiation and No Conventional Adenocarcinoma Component
Gastric carcinoma with enteroblastic differentiation (GCED) is a rare variant of gastric carcinoma, and a part of GCED produces alpha-fetoprotein. GCED is characterized by cells with clear cytoplasm and a tubulopapillary and solid growth pattern resembling those in the primitive gut. GCED is typically overlaid by a conventional adenocarcinoma (CA) component, implying that CA in the mucosa differentiates into GCED during tumor invasion and proliferation. We present the case of a 73-year-old woman with a 10-mm superficial elevated lesion and a slight central depression at the anterior wall of the lower gastric body. Endoscopic submucosal dissection revealed tumor cells having clear cytoplasm and severely atypical nuclei characteristic of GCED. The growth pattern was predominantly solid and trabecular but included submucosal layer invasion and limited tubular growth. Atrophic pyloric mucosa without intestinal metaplasia surrounded the tumor. Immunohistochemically, the tumor cells were positive for AFP, GPC3, and SALL4. The present patient showed a purely enteroblastic differentiation without a CA component despite the presence of early cancer, indicating that few cases of GCED may arise de novo in the gastric mucosa. GCED is more aggressive compared with CA; therefore, pathologists should be aware that GCED without CA can appear in biopsy specimens of early cancer while making an accurate diagnosis.
https://ift.tt/2BTrZh4
Memorial Hermann-Texas Medical Center Ranked Among the Top 20 Nationally in Adult ENT Care by US News & World Report
Memorial Hermann-Texas Medical Center's Otorhinolaryngology Service holds the 19th spot in the nation among hospitals that provide adult ENT care,...
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Toddler Enjoys Sound of Success
A new cochlear implant is helping 3-year-old Bellemere Hernandez hear for the first time. The toddler faces several disorders caused...
https://ift.tt/2PG7BCW
UTHealth Sponsors 2018 ORL Frontiers
More than 70 physicians and other health care professionals attended 2018 ORL Frontiers, an annual CME event that highlights emerging...
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Congratulations to Our Graduating Residents
Uma Ramaswamy, MD, and Matthew A. Tyler, MD, have completed their residencies in otorhinolaryngology at McGovern Medical School at UTHealth. ...
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MiR-139-5p regulates VEGFR and downstream signaling pathways to inhibit the development of esophageal cancer
MiR-139-5p plays a significant role in tumorigenesis, metastasis and recurrence, suggesting that it may potentially be used as a promising biomarker for esophageal cancer diagnosis, prognosis and therapy. This study aimed to investigate the role and the mechanism of miRNA-139-5p in esophageal cancer.
https://ift.tt/2BRGeTt
Monitoring the Rapidly Changing Landscape of E-Cigarettes
In their Annals article, Mirbolouk and colleagues report data on e-cigarette use among U.S. adults from the 2016 Behavioral Risk Factor Surveillance System survey. The editorialist discusses the findings and the need to monitor the complex and rapidly evolving landscape of alternative tobacco products.
https://ift.tt/2ofpbkE
https://ift.tt/2ofpbkE
Opioid Prescribing in the United States Before and After the Centers for Disease Control and Prevention's 2016 Opioid Guideline
Background:
In response to adverse outcomes from prescription opioids, the Centers for Disease Control and Prevention (CDC) released the Guideline for Prescribing Opioids for Chronic Pain in March 2016. Objective:
To test the hypothesis that the CDC guideline release corresponded to declines in specific opioid prescribing practices. Design:
Interrupted time series analysis of monthly prescribing measures from the IQVIA transactional data warehouse and Real-World Data Longitudinal Prescriptions population-level estimates based on retail pharmacy data. Population size was determined by U.S. Census monthly estimates. Setting:
United States, 2012 to 2017. Patients:
Persons prescribed opioid analgesics. Measurements:
Outcomes included opioid dosage, days supplied, overlapping benzodiazepine prescriptions, and the overall rate of prescribing. Results:
The rate of high-dosage prescriptions (≥90 morphine equivalent milligrams per day) was 683 per 100 000 persons in January 2012 and declined by 3.56 (95% CI, −3.79 to −3.32) per month before March 2016 and by 8.00 (CI, −8.69 to −7.31) afterward. Likewise, the percentage of patients with overlapping opioid and benzodiazepine prescriptions was 21.04% in January 2012 and declined by 0.02% (CI, −0.04% to −0.01%) per month before the CDC guideline release and by 0.08% (CI, −0.08% to −0.07%) per month afterward. The overall opioid prescribing rate was 6577 per 100 000 persons in January 2012 and declined by 23.48 (CI, −26.18 to −20.78) each month before the guideline release and by 56.74 (CI, −65.96 to −47.53) per month afterward. Limitation:
No control population; inability to determine the appropriateness of opioid prescribing. Conclusion:
Several opioid prescribing practices were decreasing before the CDC guideline, but the time of its release was associated with a greater decline. Guidelines may be effective in changing prescribing practices. Primary Funding Source:
CDC.https://ift.tt/2PeMird
Prevalence and Distribution of E-Cigarette Use Among U.S. Adults: Behavioral Risk Factor Surveillance System, 2016
Background:
Contemporary data on the prevalence of e-cigarette use in the United States are limited. Objective:
To report the prevalence and distribution of current e-cigarette use among U.S. adults in 2016. Design:
Cross-sectional. Setting:
Behavioral Risk Factor Surveillance System, 2016. Participants:
Adults aged 18 years and older. Measurements:
Prevalence of current e-cigarette use by sociodemographic groups, comorbid medical conditions, and states of residence. Results:
Of participants with information on e-cigarette use (n = 466 842), 15 240 were current e-cigarette users, representing a prevalence of 4.5%, which corresponds to 10.8 million adult e-cigarette users in the United States. Of the e-cigarette users, 15% were never–cigarette smokers. The prevalence of current e-cigarette use was highest among persons aged 18 to 24 years (9.2% [95% CI, 8.6% to 9.8%]), translating to approximately 2.8 million users in this age range. More than half the current e-cigarette users (51.2%) were younger than 35 years. In addition, the age-standardized prevalence of e-cigarette use was high among men; lesbian, gay, bisexual, and transgender (LGBT) persons; current combustible cigarette smokers; and those with chronic health conditions. The prevalence of e-cigarette use varied widely among states, with estimates ranging from 3.1% (CI, 2.3% to 4.1%) in South Dakota to 7.0% (CI, 6.0% to 8.2%) in Oklahoma. Limitation:
Data were self-reported, and no biochemical confirmation of tobacco use was available. Conclusion:
E-cigarette use is common, especially in younger adults, LGBT persons, current cigarette smokers, and persons with comorbid conditions. The prevalence of use differs across states. These contemporary estimates may inform researchers, health care policymakers, and tobacco regulators about demographic and geographic distributions of e-cigarette use. Primary Funding Source:
American Heart Association Tobacco Regulation and Addiction Center, which is funded by the U.S. Food and Drug Administration and National Heart, Lung, and Blood Institute.https://ift.tt/2PdLy5H
Medical Education and the Public Service Loan Forgiveness Program: Unnecessary Uncertainties
Intended to encourage employment in a wide range of typically low-paying public service positions, the federal Public Service Loan Forgiveness (PSLF) program is now popular to help medical school graduates alleviate growing educational debt burdens. The PSLF program requires medical school graduates to make 10 years of loan repayments while working at nonprofit or governmental institutions, after which any remaining debt is forgiven. In this commentary, the authors discuss how PSLF affects the affordability of medical school and the distribution of the physician workforce and consider the possible effect of proposed changes, including its elimination.
https://ift.tt/2om4q7b
https://ift.tt/2om4q7b
Disappearance of the National Guideline Clearinghouse: A Huge Loss for Evidence-Based Health Care
Evidence-based guidelines play a pivotal role in optimizing quality of care and improving clinical outcomes for patients. In recognition of this important role, the National Guideline Clearinghouse (NGC) was created in 1998. In July 2018, the NGC went dark because of the federal government's budgetary cuts. This commentary discusses the potential negative consequences of this action.
https://ift.tt/2NltrKj
https://ift.tt/2NltrKj
The MCAT's Restrictive Effect on the Minority Physician Pipeline: A Legal Perspective
Since 1991, federal law has required that an employment practice be discarded if a plaintiff can show that the practice has a disparate impact based on race and the employer is unable to demonstrate that the practice is job-related and consistent with business necessity. The authors of this article explain why the principle behind this law implies that we should stop using MCAT scores to decide who enters medical school.
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https://ift.tt/2ogx75i
Timing of Lymphedema Following Treatment for Breast Cancer: When Are Patients Most At-Risk?
Breast cancer treatment-associated lymphedema is a potentially devastating complication but the time-course for developing lymphedema is unknown. We conducted a prospective study of 2,171 women to determine when patients are at greatest risk for lymphedema in the context of modern surgical and radiation techniques. We observed that the time-course of lymphedema development depends on therapy received: with early-onset lymphedema associated with axillary lymph node dissection and late-onset lymphedema more associated with regional lymph node radiation.
https://ift.tt/2wgyxkA
Patterns of Local-Regional Failure after Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy with Concurrent Chemotherapy for Non-Small Cell Lung Cancer
We compared differences in patterns of local-regional failure, and the influence of adaptive planning on those patterns, for 212 patients given passively scattered proton therapy (PSPT) or intensity-modulated radiation therapy (IMRT), both with concurrent chemotheapy, for non-small cell lung cancer. No differences in patterns of local, marginal, or regional failure were found between treatment groups, and use of adaptive planning (or not) did not influence failure patterns.
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Characteristics and predictors for secondary leukemia and myelodysplastic syndrome in Ewing and osteosarcoma survivors
Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS).
https://ift.tt/2LuSbhv
What Is the Diagnostic Accuracy of Cardiac Biomarkers for the Prediction of Adverse Cardiac Events in Patients Presenting With Acute Syncope?
The initial search identified 1,595 articles, and 104 met the inclusion criteria and underwent a full test review. Eleven studies met the inclusion criteria for analysis and were included in the review. Four of the included studies used contemporary troponins, 4 used brain-type natriuretic peptides, and 3 used high-sensitivity troponins. The majority of included studies (9) enrolled emergency department (ED) patients, but 2 included hospitalized patients who were admitted from the ED. According to the Quality Assessment of Diagnostic Accuracy Studies instrument, the included studies were at low to moderate risk of bias.
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Prescription Drug Monitoring Program May Not Cut Opioid Use
MONDAY, Aug. 27, 2018 -- Implementation of a mandatory prescription drug monitoring program (PDMP) does not necessarily reduce the overall rate of opioid prescribing or the mean number of pills prescribed for patients undergoing general surgical...
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Care Coordination Strategies Aid in Multiple Chronic Diseases
MONDAY, Aug. 27, 2018 -- Care coordination strategies can be beneficial for older patients with multiple chronic diseases, according to a review published in the Aug. 27 issue of CMAJ, the journal of the Canadian Medical Association. Monika Kastner,...
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Sensor Array May Detect De Novo Parkinson's Disease in Breath
MONDAY, Aug. 27, 2018 -- A sensor array has the potential to identify de novo Parkinson's disease (PD) patients with high sensitivity, specificity, and accuracy values, according to a research letter published online July 10 in ACS Chemical...
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Doctors Have Difficulty Finding Practices Offering Deliveries
MONDAY, Aug. 27, 2018 -- Finding a practice that provides opportunities to do deliveries is a considerable barrier to performing obstetric deliveries, according to a study published in the May-June issue the Journal of the American Board of Family...
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Experiencing Parental Cancer As Child Has Lasting Impact
MONDAY, Aug. 27, 2018 -- Individuals who experience parental cancer as children or adolescents have a higher risk of low educational attainment and attenuated income at age 30 years, according to a study published online Aug. 20 in the Journal of...
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Computer-Aided Colonoscopy Reliably Identifies Small Polyps
MONDAY, Aug. 27, 2018 -- Computer-aided colonoscopy can reliably diagnose small polyps that do not need to be removed, according to a study published online Aug. 14 in the Annals of Internal Medicine. Yuichi Mori, M.D., Ph.D., from the Showa...
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Emergency Department Visits After Abortion Extremely Rare
MONDAY, Aug. 27, 2018 -- Abortion-related visits to the emergency department comprise a very small proportion of reproductive-aged women's visits, according to a study published June 14 in BMC Medicine. Ushma D. Upadhyay, from the University of...
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Smartphone App Can Help Improve Outcomes With HIV
MONDAY, Aug. 27, 2018 -- A smartphone app designed for people living with HIV increases users' consistency in doctor visits and improves their health outcomes, according to a study recently published in AIDS Patient Care and STDs. Rebecca...
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Odds of Marijuana Use Up With Nausea, Vomiting in Pregnancy
MONDAY, Aug. 27, 2018 -- Women with nausea and vomiting in pregnancy (NVP) have increased odds of marijuana use, according to a research letter published online Aug. 20 in JAMA Internal Medicine. Kelly C. Young-Wolff, Ph.D., M.P.H., from Kaiser...
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Cover
Clinical Oral Implants Research, Volume 29, Issue 8, Page i-i, August 2018.
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5 critical thinking skills crucial to EMS professional development
Continuous skills development is the key for emergency responders staying current in a changing world
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Occupational radiation exposure and risk of cataract incidence in a cohort of US radiologic technologists
Abstract
It has long been known that relatively high-dose ionising radiation exposure (> 1 Gy) can induce cataract, but there has been no evidence that this occurs at low doses (< 100 mGy). To assess low-dose risk, participants from the US Radiologic Technologists Study, a large, prospective cohort, were followed from date of mailed questionnaire survey completed during 1994–1998 to the earliest of self-reported diagnosis of cataract/cataract surgery, cancer other than non-melanoma skin, or date of last survey (up to end 2014). Cox proportional hazards models with age as timescale were used, adjusted for a priori selected cataract risk factors (diabetes, body mass index, smoking history, race, sex, birth year, cumulative UVB radiant exposure). 12,336 out of 67,246 eligible technologists reported a history of diagnosis of cataract during 832,479 person years of follow-up, and 5509 from 67,709 eligible technologists reported undergoing cataract surgery with 888,420 person years of follow-up. The mean cumulative estimated 5-year lagged eye-lens absorbed dose from occupational radiation exposures was 55.7 mGy (interquartile range 23.6–69.0 mGy). Five-year lagged occupational radiation exposure was strongly associated with self-reported cataract, with an excess hazard ratio/mGy of 0.69 × 10−3 (95% CI 0.27 × 10−3 to 1.16 × 10−3, p < 0.001). Cataract risk remained statistically significant (p = 0.030) when analysis was restricted to < 100 mGy cumulative occupational radiation exposure to the eye lens. A non-significantly increased excess hazard ratio/mGy of 0.34 × 10−3 (95% CI − 0.19 × 10−3 to 0.97 × 10−3, p = 0.221) was observed for cataract surgery. Our results suggest that there is excess risk for cataract associated with radiation exposure from low-dose and low dose-rate occupational exposures.
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Rainer W. Guillery and the genetic analysis of brain development
European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.
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Suppression of somatosensory stimuli during motor planning may explain levels of balance and mobility after stroke
European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.
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Enhanced motivation of cognitive control in Parkinson's disease
European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.
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Issue Information
European Journal of Neuroscience, Volume 48, Issue 4, Page i-iii, August 2018.
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Issue Information
European Journal of Neuroscience, Volume 48, Issue 3, Page i-iii, August 2018.
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APTA National Student Conclave and Go Baby Go
Join us at NSC 2018 where Go Baby Go will build adaptive toys for young kids who experience limited mobility.
https://www.youtube.com/watch?v=8LmcTtRRAvs
Detection of Solitary Axillary Lymph Node Metastases from Hürthle Cell Carcinoma of the Thyroid on 18 F-FDG PET/CT
Abstract
Thyroid carcinoma is the most common neoplasm of endocrine malignancies. Differentiated thyroid carcinoma (DTC) constitutes 90% of the thyroid carcinomas, rest being medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). Distant metastases occur in up to 10% of patients with DTC. Metastases to axillary lymph nodes (ALN) are very rare. As per literature, only 25 cases have been reported. We report an unusual case of 47-year-old male with Hürthle cell carcinoma of the thyroid presenting with a solitary axillary lymph node metastasis 17 years after thyroidectomy, along with review of literature.
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Use of erbium laser in the treatment of persistent post-radiotherapy laryngeal edema: a case report and review of the literature
Abstract
Background
Post-radiotherapy laryngeal edema may affect the patients' quality of life, leading to repeated treatment attempts, which include massage/physical therapy, inhalations, and/or tracheostomy.
Case presentation
We report the surgical treatment approach of a 69-year-old patient with severe persistent post-radiotherapy laryngeal edema. After multiple inpatient admissions and failed conservative therapy, we used the erbium laser to treat the arytenoid edema. After repeated procedures, no complications were observed. The patient remained free of symptoms after 30 months of follow-up.
Conclusions
The authors provide an easy-to-perform, safe, and quick surgical technique without non-severe or severe complications. Using this technique repeatedly, complications from excessive thermal damage with CO2 laser or unpleasant solutions such as tracheostomy can be avoided.
https://ift.tt/2MWkDh5
Surgical management and outcome of synovial sarcoma in the spine
Abstract
Background
Synovial sarcoma (SS) is a soft tissue sarcoma that rarely occurs in the spine, and a minimal number of cases have been reported in the literature. Spinal SS is challenging in diagnosis and treatment and has a poor prognosis. The aim of this study was to summarize and analyse the clinical features and outcomes of patients with spinal SS.
Methods
A total of 16 cases of patients with spinal SS admitted to our institution were reviewed retrospectively. General information, radiological findings and treatment strategies were collected. These patients were followed up regarding their continuing treatment, local or distant recurrence and survival.
Results
Spinal SS patients in this series ranged in age from 12 to 68 years (median, 33). Four en bloc resections and 12 piecemeal resections were performed. Improved Frankel (P = 0.002), visual analogue scale (P = 0.002) and Karnofsky Performance Status (P = 0.002) scores were seen postoperatively. The mean follow-up period was 35.9 ± 23.5 (median 31.5, range 4–87) months, with four local recurrences and three distant metastases detected. Eight patients (50.0%) died of disease by the last follow-up. The 1-, 3- and 5-year overall survival rates were 87.5%, 61.4% and 40.9%, respectively. Preoperative chemotherapy was used in three patients to facilitate surgical resection, and adjuvant chemotherapy and radiotherapy were used in six patients.
Conclusions
Spinal SS has a relatively high risk of local recurrence and distant metastasis. Surgical intervention can improve the neurological function and relieve pain in these patients. En bloc excision is an effective treatment strategy to improve survival and prevent local recurrence. Management of spinal SS should be under the instruction of a multidisciplinary team.
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Integrated analysis of lncRNA associated‐competing endogenous RNAs as prognostic biomarkers in clear cell renal carcinoma
Cancer Science, Volume 0, Issue ja, -Not available-.
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Searching for a Stable High‐Performance Magnetorheological Suspension
Advanced Materials, EarlyView.
https://ift.tt/2PFj59L
Corrugated Heterojunction Metal‐Oxide Thin‐Film Transistors with High Electron Mobility via Vertical Interface Manipulation
Advanced Materials, EarlyView.
https://ift.tt/2wpyQcf
Designing Liquid‐Infused Surfaces for Medical Applications: A Review
Advanced Materials, EarlyView.
https://ift.tt/2PHe4gT
Thrombocytopenia-associated multiple-organ failure (TAMOF): recognition and management
Thrombocytopenia-associated multiple-organ failure (TAMOF) is an increasingly fatal phenomenon that may be associated with sepsis. TAMOF results from immune dysregulation and impaired activity of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13. Early recognition of this premorbid condition and specific management results in a significantly improved outcome. Herein, we report the presentation and management of a 2-year-old child with TAMOF who was successfully treated with plasma exchange and recovered without long-term sequelae.
https://ift.tt/2wghoYo
Corneal epithelial toxicity with intravitreal methotrexate in a case of B-cell lymphoma with ocular involvement
A 49-year-old woman, known case of diffuse large B-cell lymphoma, presented with complaints of floater in both eyes since 3 days. On examination, visual acuity was 0.18 logMAR in both eyes. Indirect ophthalmoscopy revealed presence of vitreous clumps. Vitreous biopsy was done and the histopathological report suggested a diagnosis of ocular lymphoma. The patient was treated with weekly injections of intravitreal methotrexate in both eyes. The patient developed severe photophobia, watering, redness and diminution of vision in the both eyes 2 days following the fifth dose of intravitreal methotrexate. Severe limbitis with annular corneal epitheliopathy and corneal haze was noted on slit-lamp examination. The patient was started on topical lubricants, antibiotic, ciclosporin, loteprednol, folinic acid and oral folic acid. Complete resolution was noted at 2-week follow-up. The patient, however, refused further injections and was kept on close follow-up to look for recurrence of the disease.
https://ift.tt/2P6dOXE
Paraneoplastic cerebellar degeneration as a manifestation of metastatic recurrent carcinoma breast: rare scenario
Carcinoma breast presenting with paraneoplastic cerebellar degeneration is a rare scenario. We report a case of a 52-year-old woman, which is a follow-up case of completely treated carcinoma breast presenting with paraneoplastic cerebellar degeneration which, on investigation, revealed metastatic disease with recurrence at previous scar site and metastasis to contralateral axilla. The patient was given pulse methyl prednisolone therapy and underwent wide local excision of nodule and right axillary lymph node dissection with 14 cycles of trastuzumab and paclitaxel as adjuvant therapy. However, there was no detectable change in neurological symptoms at 6-month follow-up postoperatively. This case report highlights the need for clinicians to be aware of all possible presentations of carcinoma breast and its recurrence, including rare manifestations as in this case.
https://ift.tt/2wijeIh
'Stony shoulder: an exuberant case of glenohumeral synovial chondromatosis with extra-articular extension
Description
A 27-year-old man presented with a history of 4-year duration of mechanical pain in the left shoulder and a progressive reduction in the range of movements. In the physical examination stands out a swelling of stony consistency on the posterior aspect of the left arm, pain with all active and passive movements of the left shoulder associated with limitation of active and passive abduction above 90°.
The blood tests were normal. The X-ray of the left shoulder showed multiple calcified intra-articular and extra-articular loose bodies (figure 1).
Figure 1
Conventional left shoulder radiography: multiple calcified intra-articular and extra-articular bodies.
A shoulder MRI was ordered demonstrating exuberant expansion of all joint spaces and recesses from the glenohumeral interface to the subcoracoid and subscapularis recess and along the tendon sheath of the long portion of the biceps, which suggested cartilaginous nature with...
https://ift.tt/2Nq3n0S
Recurrent chikungunya retinitis
Chikungunya is a systemic viral disease transmitted to humans by infected mosquitoes in endemic areas of Africa, Asia and more recently in the Americas. Chikungunya infection produces a sudden onset of fever, joint pains and erythematous skin eruption. A plethora of ocular manifestations have been described ranging from a non-specific conjunctivitis to exudative retinal detachment. Ocular chikungunya seems to respond well to corticosteroid therapy, and outcomes are usually better if treated early. Our patient acquired this infection on a travel to Mexico jungle. This was confirmed by ReverseTranscriptase-PCR test once she returned to the UK. The peculiarity of the case is the inordinate delay of almost a year in the onset of eye symptoms, from acquiring the viral infection. The ocular inflammation responded to systemic corticosteroid therapy with a favourable visual outcome. She developed a recurrence many months later which again responded well to a course of oral steroids.
https://ift.tt/2wicjyv
Red, white and blues: Darier disease and mood disorder
Description
A middle-aged woman presented with a progressively worsening rash for 25 years. The rash was foul smelling and tender, occurring symmetrically in the folds of her abdomen and lower legs. Her medical history was significant for major depressive disorder. She had been receiving care from multiple psychiatrists over the last 10 years, and she has been hospitalised in inpatient psychiatric facilities for acute psychotic episodes. She admitted to having two of five siblings with similar skin problems, both additionally having been diagnosed with mood disorders including bipolar disorder and major depressive disorder. The patient stated the other three siblings were healthy. On examination, the patient had plaques of confluent papules and foul-smelling, weeping patches which were distributed over the folds of her chest and abdomen, as well as the flexure surfaces of her bilateral lower extremities (figure 1). Examination of her nails revealed red and white...
https://ift.tt/2Pcv91n
Amyloidosis: a unifying diagnosis for nephrotic syndrome and congestive cardiac failure
Diagnosing patients simply with heart failure or nephrotic syndrome is insufficient, and clinicians should always search for the underlying causes of these syndromes. Amyloidosis represents a rare group of diseases in which abnormal protein, namely amyloid fibrils, build up in various organs. Presentation depends on which organ systems are involved, and symptoms could include breathlessness associated with fluid overload suggestive of cardiac and/or renal involvement and diarrhoea and weight loss, suggestive of gastrointestinal involvement. The authors present a case of congestive cardiac failure and nephrotic range proteinuria in a patient with persistent fluid overload secondary toamyloid light-chain (AL) amyloidosis.
https://ift.tt/2wiS6sG
Unusual case of dasatinib-associated acute bilateral hyphemas leading to blindness in a patient with chronic myeloid leukaemia
Chronic myeloid leukaemia (CML) is a myeloproliferative disorder with an incidence of 1–2 cases per 100 000 adults per year.1 Since the International Randomized Study of Interferon and STI571 trial (IRIS trial) in 2003, treatment with tyrosine kinase inhibitors (TKIs) has become the standard of care for patients with newly diagnosed CML in the chronic phase.2 Dasatinib is a second-generation TKI and is generally well tolerated, with cytopenias, gastrointestinal (GI) symptoms and fluid retention being the most commonly observed side effects.3–5 Bleeding complications, although unusual, have been reported with dasatinib, with an incidence ranging from 8% to 24%.3–6 The most commonly reported site of bleeding is the GI tract.3 5 We report an unusual case of dasatinib-associated bleeding presenting with acute bilateral hyphemas, which, to our knowledge, is the first report of its kind.
https://ift.tt/2PcuWeB
Resolution of bulbar and spinal symptoms postcranial dural arteriovenous fistula embolisation
Dural arteriovenous fistulas (DAVF) are uncommon lesions. Multiple classification systems have been proposed to attempt to describe these lesions. We describe the case of a patient with a dorsal epidural DAVF that, while cerebral in origin, presented with classic spinal DAVF symptoms. Following embolisation, the patient had complete radiographic and symptomatic resolution. Classification of these DAVFs by embryological development allows for potential stratification of DAVFs with a different biological aetiology and diverse characteristics to more fully understand disease mechanisms.
https://ift.tt/2wh90aQ
Chronic thromboembolic pulmonary hypertension: an enigma
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary arterial hypertension (PAH) in which the pulmonary thrombus fails to resolve, resulting in occlusion and remodelling of pulmonary arteries.1 Timely diagnosis is critical since it is potentially curable by pulmonary thromboendarterectomy. Twenty five per cent of cases do not have a history of thromboembolic event. The diagnosis should be considered in the diagnostic work-up of PAH despite lack of history of episodes of thromboembolism. Here we are reporting a case of CTEPH with multiple systemic to pulmonary collaterals delineated by angiogram and CT.
https://ift.tt/2Pbhes7
Additional distal femoral osteotomy for insufficient correction after high tibial osteotomy
A 70-year-old man who was treated with a closed-wedge high tibial osteotomy (HTO) had recurrent right medial knee pain 12 years after the initial osteotomy. We planned a recorrection osteotomy because the patient led an active lifestyle, had well-preserved range of motion and the lateral compartment was still intact. According to preoperative deformity analysis, which indicated a tibia in slight valgus and a femur in moderate varus, recorrection of the distal femur was chosen. Seven degrees of biplanar distal femoral osteotomy (DFO) was performed using a contralateral version of the TomoFix Medial Distal Femur. At 1 year follow-up, the femorotibial angle had improved from 178° to 170°, and the Japanese Orthopaedic Association score had improved from 75 to 95 points. Additional DFO could be a viable alternative for total knee arthroplasty or recorrection HTO when the centre of the deformity is located at the distal femur.
https://ift.tt/2whMy1l
Challenging case of an intramedullary tibial abscess in the setting of chronic osteomyelitis
Description
This is the case of a 43-year-old wheelchair-user man with a history of hepatitis C, cirrhosis, intravenous drug abuse and a 2-year history of chronic right lower extremity ulcers who presented to the emergency department with 4 days of worsening right leg pain. On physical exam, there was a new area of fluctuance on the anterior tibial surface. Labs included a white cell count of 9.3 K/µL, C reactive protein of 129 mg/L and erythrocyte sedimentation rate of 90 mm/hour. A CT scan demonstrated proximal tibia osteomyelitis with an intramedullary abscess, surrounding soft tissue abscesses and septic arthritis of the knee joint (figure 1).
Figure 1
(A) Permeative appearance of the proximal tibial metaphysis and diaphysis with areas of cortical lucency and endosteal scalloping, suspicious for osteomyelitis. (B) Intramedullary fluid collection within the proximal tibial metaphysis/epiphysis, containing hyperattenuating contents with two punctate foci of air measuring approximately 6.7x4.7x16.6 cm,...
https://ift.tt/2Nolq7u
Tubular adenomas of the breast: a rare diagnosis
Tubular adenomas of the breast are rare benign tumours and few cases have been reported. Most often, the tumours are described as palpable, well-circumscribed masses in women of childbearing age and are commonly diagnosed as fibroadenomas both clinically and radiographically. Surgical excision is required for diagnosis and to prevent continuing growth. Here, we present two cases of these rare tumours, both with unusual presentations. The first case describes a very large specimen (10 cm x 9.5 cm x 4 cm mass) with tubular adenoma pathology, which is one of the largest reported in medical literature. The second case illustrates another rare specimen, a mixture of both tubular adenoma and fibroadenoma pathology. We elected to document these cases to assist in the management of these rare lesions. Our hope is that this will allow future physicians to better identify and treat the pathology with improved outcomes for these patients.
https://ift.tt/2whui8m
Weeping Leg'
Description
A 37-year-old daily wager from Uttar Pradesh in Northern India presented with multiple painless small nodules and granules discharging sinuses over the left leg. The lesions were uniformly distributed below the knee up to the ankle crease (figure 1). The skin was puckered and tethered to the underlying tissues. However, the foot and thigh of the involved limb and rest of the other limbs were absolutely symptom free. Radiographs showed erosion of the entire tibia and fibula with mixed sclerotic and osteolytic areas (figure 2, black arrows) along with sub tissue swelling and periosteal reactions (figure 2, white arrows). The culture of the grains in Modified Sabouraud Agar media supplemented with 0.5% yeast extract revealed Madurella mycetomatis from its characteristic colony of fruiting bodies.
Figure 1
Clinical photograph of the left leg of the patient showing multiple discharging sinuses with...
https://ift.tt/2Nj3KKq
Documented vancomycin-induced severe immune-mediated thrombocytopaenia
A 69-year-old man developed Propionibacterium acnes left knee hardware infection after suffering from an infected ingrown toenail. The hardware was removed and he was treated with intravenous vancomycin. Ten days after initiation of vancomycin, he developed severe thrombocytopaenia, epistaxis and petechiae. Vancomycin was discontinued, and platelets rapidly recovered. Serum vancomycin IgG were positive. Patient completed a 6-week course of ceftriaxone with no further complications.
https://ift.tt/2wcPTPp
Opioid toxicity with underlying tumour lysis syndrome in a patient with CMML: a diagnostic and therapeutic challenge
Use of strong opioids like morphine as analgesics for painful conditions in haematological malignancies is a challenging task. We report a unique case of chronic myelomonocytic leukaemia presenting with opioid toxicity overlapping with tumour lysis syndrome. The patient was on hydroxyurea-based chemotherapy for the primary disease. She was receiving oral morphine for abdominal pain due to splenomegaly. She was brought to the emergency in unresponsive state with pinpoint pupils. Opioid overdose leading to unconsciousness was suspected as the first diagnosis. Further workup revealed a final diagnosis of tumour lysis syndrome overlapping with opioid overdose. The patient was ventilated and started on naloxone infusion, and supportive measures for managing tumour lysis were added. The patient gradually improved and was extubated on the fifth day of ventilation. This case presents several learning points for the treating physician. Haematological malignancies have a dynamic course of disease with waxing and waning tumour burden during the course of chemotherapy. This fact should be kept in mind when prescribing strong opioids like morphine on outpatient basis to these patients. Massive tumour cell lysis during the course of chemotherapy may precipitate tumour lysis syndrome and may lead to renal dysfunction which makes the patient susceptible to morphine-related adverse effects. Pain physician should keep a watch for therapy-related adverse effects to avoid diagnostic and therapeutic dilemma associated with coexisting features of these two fatal conditions.
https://ift.tt/2P9Nj3z
Novel microguidewire-assist (MGA) manoeuver for coil embolisation of an unruptured middle cerebral artery aneurysm
We describe here a novel yet very simple technique, called microguidewire-assist (MGA) manoeuvre, for coil embolisation of unruptured intracranial aneurysms. A 79-year-old woman with a small, broad-necked middle cerebral artery (MCA) bifurcation aneurysm that incorporated the orifice of the acute-angled M2 superior trunk underwent coil embolisation. Since the balloon assist technique was not feasible, we inserted and retained only the microguidewire through M1 to the M2 superior trunk; subsequently, with appropriate use of the microguidewire, coil embolisation was completed. The MGA manoeuvre resulted in slight vessel straightening and subsequent changes in the angulation of the aneurysmal neck, with which stable placement of the platinum coil was successfully accomplished. For coil embolisation of small, broad-necked MCA aneurysms that partially straddle the M2 trunk, this manoeuvre might provide an effective therapeutic alternative if other techniques are not feasible.
https://ift.tt/2wjzPv9
Short stature and growth hormone deficiency: unexpected manifestations of McCune-Albright syndrome
McCune-Albright syndrome (MAS) is a rare disease characterised by triad of monostotic or polyostotic fibrous dysplasia, café au-lait skin spots and a variety of endocrine disorders; precocious puberty (PP) being the most common presenting symptom in female patients. Hyperfunction endocrinopathies including hyperthyroidism, growth hormone excess and cortisol excess are typical presentations in MAS. We present a case of 21-year-old woman with clinical and radiological characteristics of MAS triad; she presented with short stature which was attributed to both growth hormone deficiency and PP. Growth hormone deficiency in MAS has not been reported in English medical literature.
https://ift.tt/2P89CXC
Cobb syndrome (cutaneomeningospinal angiomatosis)
Description
A 62-year-old woman was referred to the orthopaedic oncology service for evaluation of a bleeding and enlarging soft tissue mass along the right anterior abdominal wall. She had a lifelong history of a cutaneous and subcutaneous vascular malformation, affecting the right lateral chest and right abdomen and extending proximally to involve the mid-thoracic spine. Her medical history was significant for a prior aborted attempted surgical resection of the vascular malformation in 1980 due to intraoperative bleeding. Her history also included L4–L5 laminectomy without fusion for lower extremity weakness without radicular symptoms in 1989 and coil embolisation of a T9 epidural fistula in 2011 to prevent any abnormal vascular flow. Examination of the bilateral lower extremity showed marked steppage gait with bilateral external rotation deformities and bilateral foot drop. Motor examination of the lower extremities revealed muscle power grading of 1/5 extensor hallucis longus bilaterally, 2/5 tibialis anterior...
https://ift.tt/2whue8C
Anti-AMPA receptor encephalitis associated with Medullary thyroid cancer
AMPA receptor (AMPAR) antibodies are a group of recently discovered antibodies which target the neuronal synaptic proteins causing B-cell (immune) mediated neuronal damage, resulting in various neurologic syndromes depending on the area of central nervous system involvement. These syndromes are mostly reversible if treated early. Tumour association has been reported in up to 60% of cases in the most recent case series with lung, breast, ovarian cancers and thymomas being the most commonly associated malignancies with these antibodies. We present here the first case of AMPAR encephalitis associated with medullary thyroid cancer. Our patient presented with cognitive dysfunction and behavioural changes over a period of 3 weeks, with a full recovery after starting immunotherapy, once the diagnosis of AMPAR limbic encephalitis was established. This case highlights the importance of early diagnosis and management of AMPAR encephalitis as these patients respond well to immunotherapy and can have an almost complete recovery.
https://ift.tt/2P8gnsc
Improvement on prescribing appropriateness after implementing an interdisciplinary pharmacotherapy quality programme in a long-term care hospital
Objectives
To determine the prevalence of inappropriate prescribing in elderly patients with polypharmacy admitted to a long-term care hospital (LTCH) and to evaluate the impact of an interdisciplinary pharmacotherapy quality programme on improvement of prescribing appropriateness.
MethodsAn interventional, longitudinal, prospective study was conducted in a Spanish LTCH (October 2013 to July 2014) including 162 elderly (≥70 years) patients with polypharmacy (≥5 medications). Pharmacists conducted the pharmacotherapy follow-up of patients with medication reconciliation, pharmacotherapeutic optimisation and educational interviews from admission to discharge. Reconciliation errors, potentially inappropriate medications (PIMs), potentially prescribing omissions (PPOs) and significant drug interactions rates were calculated. The impact of the programme was evaluated considering the difference between the inappropriateness score per patient (total number of reconciliation errors, PIMs, PPOs and significant drug interactions) before and after implementing pharmacotherapy recommendations.
ResultsAt admission, 163 reconciliation errors (median(range), 1(1-6)) in 92 (56.8%) patients (65.6% drug omissions), 335 PIMs (2(1-6)) in 147 (90.7%) patients (39.3% use ≥2 anticholinergic drugs), 43 PPOs (1(1-3)) in 32 (19.8%) patients (48.5% statin omission) and 594 significant drug interactions (4(1-19)) in 130 (80.2%) patients were detected. After implementing pharmacotherapy recommendations, statistically significant reductions in admission reconciliation errors (8.3% to 0.1%), PIMs (17.0% to 12.2%), PPOs (2.2% to 0.7%) and significant drug interactions (30.2% to 26.8%) rates were found. The programme achieved a 31% improvement in prescribing appropriateness, with a statistically significant reduction in the inappropriateness score (6(IQR:4–9) to 4(IQR:2–7)).
ConclusionReconciliation errors, PIMs and drug interactions are highly prevalent in elderly patients with polypharmacy admitted to an LTCH. This interdisciplinary pharmacotherapy quality programme seems to be a useful approach in the improvement of prescribing appropriateness in a high-risk older population.
https://ift.tt/2PFzeft
EAHP European Statements Survey 2017, focusing on sections 2 (Selection, Procurement and Distribution), 5 (Patient Safety and Quality Assurance) and 6 (Education and Research)
Objectives
The 2017 EAHP European Statements Survey focussed on sections 2, 5 and 6 of the European Statements of Hospital Pharmacy. Statistical data on the level of implementation and on the main barriers to implementation of the Statements were collected. A further aim was to identify barriers in general, such as lack of awareness.
MethodsAn online questionnaire was sent to all hospital pharmacies in European Association of Hospital Pharmacists (EAHP) member countries. Data were analysed at Keele University School of Pharmacy, UK by and the EAHP Survey Group.
ResultsThere were 783 complete responses (response rate 17.4%). Some 42% of responders worked in teaching hospitals, 76% of hospital pharmacies had 10 or less pharmacists, and 46% of hospital pharmacies served over 500 beds.
Five questions revealing the lowest implementation levels were further analysed in greater detail. Only 30% of respondents reported that their hospital pharmacists routinely publish hospital pharmacy practice research, and only 50% are involved in the development of local or national guidelines. 45% of respondents reported that computerised decision support was used to reduce the risk of medication errors in their hospitals, 69% stated that they had contingency plans for medicines shortages and 60% answered that they had had reason to contact their medicines authority because of drug shortages. 63% reported that the transcription step had been eliminated from the medicines administration process.
ConclusionsThe survey has provided the EAHP with an overview of the implementation level as well as the barriers to and drivers of implementation of sections 2, 5 and 6. This is important for informing the plans of EAHP and its members so that implementation can be fully supported.
https://ift.tt/2NnovVj
Implementation of a new health information technology for the management of cancer chemotherapies
Background
Cancer chemotherapy drugs are classified as high-risk molecules. Safety of the cancer chemotherapy process is often achieved with the implementation of a health information technology to each step or to the entire process. However, computerisation could lead to the emergence of new unintended medication errors. The aim of the study was to evaluate the impact of new software designed for the management of anticancer chemotherapies.
MethodThe cartography of the process and the failure modes, effects and criticality analysis were performed by a multidisciplinary team. Criticality indexes were calculated considering or not the implementation of the commercial software (CytoWeb). Quality and satisfactory indicators were measured before the implementation and during the use of the software.
ResultsOur results demonstrated the complexity of the cancer chemotherapy process in the hospital. Risk analysis highlighted the positive impact of CytoWeb on the process safety but pointed out some steps that were not positively influenced by the software. Although a decrease of 38.6% of error rate was observed with the electronic system, new unintended medication errors emerged. These errors were due to inadequate use of the software (encoding of the wrong drug, the wrong dose, the wrong patient parameters or lab results and lack of prescriber adherence). Our satisfaction survey showed that the hospital pharmacists and doctors were less satisfied by the software than the nurses, mostly in terms of task achievement and time saving. Survey's results highlighted some weaknesses in the user training and in the collaboration between the medical staff.
ConclusionsOur work showed the emergence of unintended medication errors linked to computerisation that were due to an inadequate use of the software. Other issues were highlighted such as the lack of collaboration between the medical staff, the lack of prescriber implication and weaknesses in the user training or in the information related to CytoWeb.
https://ift.tt/2PIiNPu
Electronic medication reconciliation in hospitals: a systematic review and meta-analysis
Objective
Medication reconciliation (MedRec) is recognised as a multiprofessional process for the prevention of medication discrepancies. The goal of this study is to evaluate the available electronic medication reconciliation (eMedRec) tools and their effect on unintended discrepancies that occur in hospital institutions.
MethodPubMed, EMBASE, the Cochrane Library, Web of Science, the ClinicalTrials.gov website and four other Chinese databases were searched for relevant studies starting from their inception through October 2017. Methodological quality was assessed using the nine standard criteria of Cochrane Effective Practice and Organisation of Care Review Group (EPOC) and meta-analysis was performed using RevMan5.3 software.
ResultsA total of 13 studies (three randomised controlled trials and 10 non-randomised controlled trials) were identified. Meta-analysis results demonstrated a reduced number of medications with unintended discrepancies (relative risk (RR)=1.85, 95% confidence interval (CI) 1.55 to 2.21), while no statistically significant differences were observed in the number of patients with unintended medication discrepancies (RR=2.74, 95% CI 0.59 to 12.73). Common discrepancies included medication omission, dose discrepancy, and frequency discrepancy. We found that the clinical impact of medication discrepancy was mild. A total of 12 electronic tools were reported and were mostly integrated into the hospital's information system. However, the usability, user adherence, and user satisfaction were found to lack sufficient evidence.
ConclusioneMedRec was shown to reduce the incidence of medication with unintended discrepancies and improve medication safety. However, the electronic tools are diversified and the effects on other outcomes still require a comprehensive evaluation.
Systematic review registrationPROSPERO CRD42017067528.
https://ift.tt/2wA0a7N
A complexity scale for clinical trials from the perspective of a pharmacy service
Objective
To establish a method for evaluating the complexity of clinical trials (CTs) from the perspective of a pharmacy service (PS) and to analyse the complexity of CTs carried out in a tertiary level hospital.
MethodsAn observational, prevalence and retrospective study was carried out in a Spanish tertiary level hospital during the period 2008–2013. A scale of complexity was developed, whose internal consistency was determined by Cronbach's alpha. The study involved five steps: an analysis of the activities involved, score allocation to the activities, identification of CTs started in the study period, data collection and assessment of the complexity. Three complexity levels were determined: low, medium and high. The variables calculated were mean overall complexity, mean complexity per medical specialty, per pathology, per phase of CT, per initiation year and percentage of CTs by complexity level.
ResultsCronbach's alpha of the scale of complexity was 0.738. The two most influential items were dose preparation and number of professionals involved. 55.0% of CTs were in the medium level of complexity and 12.1% of CTs were in the high level. The mean complexity of CTs studied was 13.3±4.7 (median 12, range 6–32). Statistically significant differences were found in the complexity values between CTs of different medical specialties, pathologies, phase and dose preparation in the PS (p<0.001).
ConclusionsThe scale designed to evaluate the complexity of CTs had internal consistency. More than half of the CTs are in the medium level if complexity. The largest number of CTs with a high level of complexity were in rheumatology and oncology.
https://ift.tt/2wqLpUr
Impact of a pharmaceutical care programme for patients with chronic disease initiated at the emergency department on drug-related negative outcomes: a randomised controlled trial
Background
The resolution of potential drug-related problems is a priority of pharmaceutical care programmes.
ObjectivesTo assess the clinical impact on drug-related negative outcomes of a pharmaceutical care programme focusing on the resolution of potential drug-related problems, initiated in the emergency department for patients with heart failure (HF) and/or chronic obstructive pulmonary disease (COPD).
MethodsControlled trials, in which older adults (≥65 years) receiving four or more medications admitted to the emergency department for ≥12 hours for worsening of HF and/or COPD were randomised (1:1) to either a pharmaceutical care programme focusing on resolving potential drug-related problems initiated at the emergency department (intervention group (IG)) or standard care (control group). Comparisons between the groups were made for the proportion of patients with drug-related negative outcomes, number of drug-related negative outcomes per patient, mean stay, patients readmitted within 180 days and 180-day mortality.
Results118 patients were included, 59 in each group. Fewer patients in the IG had drug-related negative outcomes (37 (62.7%) vs 47 (79.7%) in the control group (p=0.042)). Fewer drug-related negative outcomes per patient occurred in the IG (56 (0.95 per patient) vs 85 (1.44 per patient) in the control group (p=0.01)). The mean stay was similar between groups (194.7 hours in the IG vs 242.5 hours in the control group (p=0.186)). No difference in revisits within 180 days was found (32 (54.24%) in the IG vs 22 (37.3%) in the control group (p=0.065)). 180-Day mortality was detected in 11 (18.6%) patients in the IG compared with 13 (22%) in the control group (p=0.647).
ConclusionA pharmaceutical care programme focusing on resolving potential drug-related problems initiated at the emergency department has a favourable clinical impact, as it reduces the number and prevalence of drug-related negative outcomes. No difference was found in other outcome variables.
Trial registration number NCT02368548.
https://ift.tt/2PHUIs3
Junior doctors communication with hospital pharmacists about prescribing: findings from a qualitative interview study
Objectives
To explore factors affecting communication between Foundation Year (FY) 1 doctors and hospital pharmacists about prescribing from the junior doctors' perspective.
MethodsTrained interviewers (n=4) conducted semistructured interviews with FY1 doctors who were purposively sampled from three hospitals in England. FY1 doctors were asked about their experiences of communication with hospital pharmacists about their prescribing; instances where they disagreed with or did not implement a hospital pharmacist's recommendation; and their preferences for communicating with hospital pharmacists about prescribing. Interviews were audiorecorded, transcribed verbatim and analysed thematically.
ResultsA total of 27 FY1 doctors were interviewed. Findings were categorised into four main themes: (1) nature and context of communication; (2) FY1 doctors' perceptions of communication with hospital pharmacists; (3) factors influencing FY1 doctors' decision whether to act on pharmacists' prescribing recommendations; and (4) suggestions to improve communication with pharmacists. FY1 doctors and hospital pharmacists generally communicated well. FY1 doctors appreciated and frequently acted on pharmacists' advice yet there was deference to senior medical staff when advice differed. Joint ward rounds, pharmacist-led teaching sessions and a standardised approach to communication were all suggested as ways to improve communication and may increase the likelihood of pharmacists' recommendations being acted on.
ConclusionsFY1 doctors and hospital pharmacists communicated frequently about medication prescribing. Issues occurred when there were differences in professional judgement between senior medical staff and pharmacists but these were usually resolved satisfactorily for the FY1 doctor. Further interventions to improve communication and safe prescribing could involve a multidisciplinary and systems approach.
https://ift.tt/2wt4l55
Drug information center: challenges of the research process to answer enquiries in hospital pharmaceutical practices
Objective
To characterise information requests (IRs) from hospitals received by a drug information center (DIC-RS) according to the resolution of the inquiries.
MethodThe sample consisted of all requestors and their respective IRs registered in the DIC-RS database from January 2012 to December 2016. Request without information in the consulted literature (RWI) were categorised according to the institution of origin. IRs from hospitals were classified by the information source, topic and subtopic of the questions, and the number of drugs and the pharmacological or therapeutic group.
ResultsA total of 2,500 IRs were analysed. Of those, 25% did not exhibit conclusive information in the consulted sources. RWI from hospitals represented 51% of all RWI, followed by those from community pharmacies (13%) and health centres (9%). Tertiary literature was the most commonly used source (73%) for IRs from hospitals. The greatest difficulties in finding information were related to off-label drug administration and indication issues (52% of RWI). The most common type of off-label use was related to changes in the original pharmaceutical form of the drug. Furthermore, 61% of RWI were directed at a specific drug, mostly systemic anti-infectives.
ConclusionWe found that a quarter of the answers did not exhibit conclusive information in the consulted sources. Answers to IRs from the hospital environment exhibited the greatest extent of limited information, and off-label use was responsible for most cases.
https://ift.tt/2wsqYGT
Good vibrations: itch induction by whole body vibration exercise without the need of a pruritogen
Experimental Dermatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2PEl6D0
Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer-types
Abstract
Background
We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer-types. Patients and Methods
RNASeqv2 data from 10,078 tumor samples representing 34 different cancer-types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in-silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer-types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results
In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer-type was variable (0-84%). Strikingly, the PD1-high proportions across cancer-types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer-type were identified in our in-house 773-tumor dataset as compared to TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low=8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs were not found associated with response. Conclusions
Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.https://ift.tt/2PHt1PV
PD-L1 Expression, Tumor Mutational Burden, and Response to Immunotherapy in Patients with MET exon 14 Altered Lung Cancers
Abstract
BackgroundMET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized.Patients and Methods Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was performed and TMB was calculated by estimation from targeted next-generation sequencing panels.Results We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1-49%, and ≥50% was 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers were lower than that of unselected non-small cell lung cancers (NSCLCs) in both independently-evaluated cohorts: 3.8 vs 5.7 mutations/megabase (p < 0.001, n = 78 vs 1,769, Cohort A), and 7.3 vs 11.8 mutations/megabase (p < 0.001, n = 62 vs 1,100, Cohort B). There was no association between PD-L1 expression and TMB (Spearman rho = 0.18, P = 0.069). In response-evaluable patients (n = 24), the objective response rate was 17% (95% CI 6-36%) and the median progression free survival was 1.9 months (95% CI 1.7 – 2.7). Responses were not enriched in tumors with PD-L1 expression ≥ 50% nor high TMB.Conclusion A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.https://ift.tt/2NnEnXM
Associations between RAD51D germline mutations and breast cancer risk and survival in BRCA1/2-negative breast cancers
Abstract
Background
RAD51D is involved in DNA double-strand break repair by homologous recombination and plays an important role in the maintenance of genomic stability. The associations between RAD51D germline mutations and breast cancer risk and survival are not fully elucidated. Patients and methods
RAD51D germline mutations were determined using a multi-gene panel in 7657 unselected breast cancer patients who were negative for BRCA1/2 germline mutations. The RAD51D recurrent mutation p.K91fs was screened in 7947 healthy controls by Sanger sequencing. Results
A total of 29 cases (0.38%) carried deleterious RAD51D germline mutations among this cohort of 7657 unselected breast cancer patients. The RAD51D recurrent mutation p.K91fs was identified in 18 cases (0.24%) of these 7657 patients. In contrast, the p.K91fs mutation was found in 8 of 7947 healthy controls with a frequency of 0.10%. The RAD51D p.K91fs mutation was significantly associated with increased breast cancer risk in unselected breast cancer [odds ratio=2.34, 95% confidence interval (CI) 1.02-5.38; P=0.040]. RAD51D mutation carriers were diagnosed at a younger age (P=0.006) and were more likely to be triple-negative breast cancer (P=0.003), estrogen receptor negative (P=0.005) and high-grade cancers (P=0.023) than non-carriers. Furthermore, RAD51D mutation carriers had a significantly worse recurrence-free survival [unadjusted hazard ratio (HR)=3.00, 95% CI 1.56-5.80; P=0.001] and distant recurrence-free survival (unadjusted HR = 2.54, 95% CI 1.14-5.67; P=0.023) than non-carriers. Conclusion
The RAD51D recurrent mutation, p.K91fs, confers a moderately increased breast cancer risk, and RAD51D mutation carriers have an unfavorable survival compared with non-carriers.https://ift.tt/2PFafZz
Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer
Abstract
Background
We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and Methods
ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing (NGS) and FISH analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were performed to exclude confounders. Results
Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients median PFS and OS was significantly lower compared to TP53 wildtype patients (PFS 3.9 months [95% CI: 2.4-5.6] vs. 10.3 months [95% CI: 8.6-12.0], p<0.001; OS 15.0 months [95% CI: 5.0-24.9] vs. 50.0 months [95% CI: 22.9-77.1], p=0.002). This difference was confirmed in all treatment-related subgroups including chemotherapy only (PFS first line chemotherapy 2.6 months [95% CI: 1.3-4.1] vs. 6.2 months [95% CI: 1.8-10.5], p=0.021; OS 2.0 months [95% CI: 0.0-4.6] vs. 9.0 months [95% CI: 6.1-11.9], p=0.035), crizotinib plus chemotherapy (PFS crizotinib 5.0 months [95% CI: 2.9-7.2] vs. 14.0 months [95% CI: 8.0-20.1], p<0.001; OS 17.0 months [95% CI: 6.7-27.3] versus not reached, p=0.049) and crizotinib followed by next-generation ALK-inhibitor (PFS next-generation inhibitor 5.4 months [95% CI: 0.1-10.7] vs. 9.9 months [95% CI: 6.4-13.5], p=0.039; OS 7.0 months vs. 50.0 months [95% CI: not reached] (p=0.001). Conclusions
In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.https://ift.tt/2PDLzkp
Granulysin, a novel marker for extranodal NK/T cell lymphoma, nasal type
Abstract
Granulysin is a cytolytic protein expressed in cytotoxic T and natural killer (NK) cells. Abnormal serum levels of granulysin in lymphomas with NK and cytotoxic phenotype have been shown to correlate with tumour progression. In this study, we investigated the expression pattern of granulysin in routine sections of normal and reactive lymphoid tissues as well as in a large series of lymphomas. In normal tissues, granulysin labelled a small population of cells that double immunostaining revealed to belong to the pool of cytotoxic T/NK cells. Among lymphoid neoplasms, the highest expression of granulysin (71%) was found in extranodal NK/T cell lymphomas of nasal type (ENKTL). To note is that 29% of ENKTLs, which were negative for one or more of classical cytotoxic markers strongly expressed granulysin. Furthermore, expression of granulysin was observed in rare cases of T cell lymphomas with a cytotoxic phenotype (i.e. ALK-negative anaplastic large cell lymphoma (26%), enteropathy-associated T cell lymphoma (12%) and peripheral T cell lymphoma, NOS (4%)). None of the investigated non-Hodgkin B cell lymphomas, Hodgkin lymphoma and plasma cell myeloma were granulysin positive. The results suggest granulysin as a novel marker for a subset of cytotoxic NK cell derived malignancies and its usefulness is highlighted in those ENKTLs that lack expression of other cytotoxic markers but retain granulysin expression.
https://ift.tt/2PcgUcV
PulmCrit- The hidden fragility of meta-analyses: case study of the IOTA trial
Meta-analyses are widely assumed to be robust, without any attempt to test their fragility. This post describes two techniques to evaluate the fragility of a meta-analysis
EMCrit Project by Josh Farkas.
https://ift.tt/2BPXCbp
Adjuvant Therapy Using Mistletoe Containing Drugs Boosts the T-Cell-Mediated Killing of Glioma Cells and Prolongs the Survival of Glioma Bearing Mice
Viscum album L. extracts (VE) are applied as complementary cancer therapeutics for more than one century. Extracts contain several compounds like mistletoe lectins (ML) 1-3 and viscotoxins, but also several minor ingredients. Since ML-1 has been described as one of the main active components harboring antitumor activity, purified native or recombinant ML-1 has been also used in clinical trials in the last years. The present study examined and compared the immunoboosting effects of three ML-1 containing drugs (the extract ISCADOR Qu, the recombinant ML-1 Aviscumine, and purified native ML-1) in the context of the T-cell mediated killing of glioma cells. Additionally we examined the possible underlying T-cell stimulating mechanisms. Using cocultures of immune and glioma cells, a PCR-based microarray, quantitative RT-PCR, and an antibody-based array to measure cytokines in blood serum, immunosupporting effects were determined. A highly aggressive, orthotopic, immunocompetent syngeneic mouse glioma model was used to determine the survival of mice treated with ISCADOR Qu alone or in combination with tumor irradiation and temozolomide (TMZ). Treatment of glioblastoma (GBM) cells with ISCADOR Qu that contains a high ML concentration, but also viscotoxins and other compounds, as well as with Aviscumine or native ML-1, enhanced the expansion of cancer cell-specific T-cells as well as T-cell-mediated tumor cell lysis, but to a different degree. In GBM cells all three ML-1-containing preparations modulated the expression of immune response associated genes. In vivo, subcutaneous ISCADOR Qu injections at increasing concentration induced cytokine release in immunocompetent VM/Dk-mice. Finally, ISCADOR Qu, if applied in combination with tumor irradiation and TMZ, further prolonged the survival of glioma mice. Our findings indicate that ML-1 containing drugs enhance anti-GBM immune responses and work in synergy with radiochemotherapy. Therefore, adjuvant mistletoe therapy should be considered as an auspicious treatment option for glioma patients.
https://ift.tt/2LvzyKn
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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