Sonodynamic therapy‐assisted immunotherapy: A novel modality for cancer treatment

Cancer Science, EarlyView.


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VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival

Abstract

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

https://ift.tt/2FU0xwn

VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival

Abstract

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

https://ift.tt/2FU0xwn

Trunk, head and pelvis interactions in healthy children when performing seated daily arm tasks

Abstract

Development of trunk and head supportive devices for children with neuromuscular disorders requires detailed information about pelvis, trunk and head movement in interaction with upper extremity movement, as these are crucial for daily activities when seated in a wheelchair. Twenty-five healthy subjects (6–20 years old) were included to obtain insight in the physiological interactions between these segments and to assess maturation effects. Subjects performed a maximum range of trunk and head movement tasks and several daily tasks, including forward and lateral reaching. Movements of the arms, head, pelvis, and sub-sections of the trunk were recorded with an optical motion capture system. The range of motion of each segment was calculated. Contributions of individual trunk segments to the range of trunk motion varied with movement direction and therefore with the task performed. Movement of pelvis and all trunk segments in the sagittal plane increased significantly with reaching height, distance and object weight when reaching forward and lateral. Trunk movement in reaching decreased with age. Head movement was opposite to trunk movement in the sagittal (> 50% of the subjects) and transverse planes (> 75% of the subjects) and was variable in the frontal plane in most tasks. Both trunk and head movement onsets were earlier compared to arm movement onset. These results provide insight in the role of the upper body in arm tasks in young subjects and can be used for the design of trunk and head supportive devices for children with neuromuscular disorders.

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Cost-Effectiveness of Biological Asthma Treatments: A Systematic Review and Recommendations for Future Economic Evaluations

Abstract

Background

Recently developed asthma biological therapies have been shown to provide relief for severe asthma patients not controlled by inhaled treatment. Given the relatively high costs of biological therapies, cost-effectiveness analyses (CEAs) may be required as a prerequisite for coverage and reimbursement.

Objective

We aimed to systematically review published literature on the economic impact of biological asthma therapies and to identify key drivers that impact cost-effectiveness in order to provide recommendations for future economic evaluations.

Methods

We conducted a systematic literature search in PubMed and Google Scholar. We included studies that assessed the cost-effectiveness of asthma biologics and were published in English between 2000 and 2018. The Quality of Health Economic Studies (QHES) instrument was used to evaluate quality.

Results

Twenty asthma biological CEAs were identified. Nineteen studies analyzed the cost-effectiveness of omalizumab, and one study analyzed mepolizumab. Ten studies concluded that omalizumab was cost-effective in base-case scenarios, four studies concluded omalizumab was not cost-effective, and the remaining studies concluded omalizumab or mepolizumab was cost-effective only when targeted to specific severe subgroups or given considerable price discounts. Key drivers of cost-effectiveness included day-to-day health-related quality of life (HRQoL), asthma-related mortality, acquisition price of the biological therapy, and time horizon.

Conclusions

Most studies recommended carefully targeting biological therapy to specific populations such as responders or discounting acquisition price in order to further improve value. The quality of the studies was generally satisfactory, but improved evidence is needed linking HRQoL to utilities as well as understanding interventions' impact on asthma-related mortality. Key recommendations from this review may allow for greater comparability across future cost-effectiveness studies.

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Isavuconazole Concentration in Real-world Practice: Consistency with Results from Clinical Trials [PublishAheadOfPrint]

Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not evident from clinical trials of these drugs. In order to establish if this requirement also applies to isavuconazole, we examined the plasma concentrations of 283 samples receiving isavuconazole in clinical practice and compared the values to those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/mL in 90% of patients). These findings suggest that routine TDM may not be required for isavuconazole in most instances.

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A systematic approach to the selection of the appropriate avibactam concentration for use with ceftazidime in broth microdilution susceptibility testing [PublishAheadOfPrint]

Selection of the avibactam concentration to combine with ceftazidime in susceptibility testing was determined using Gram-negative isolates with characterized β-lactamases predefined as "susceptible" or "resistant" based on the known inhibition spectrum of avibactam. MIC values were determined by broth microdilution of ceftazidime with fixed concentrations and ratios of avibactam. A constant concentration of 4 μg/mL of avibactam was selected for susceptibility testing with ceftazidime because of its ability to correctly categorize susceptible and resistant isolates while minimizing categorical errors.

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Amphotericin B Deoxycholate in adults with Cryptococcal Meningitis; a Population Pharmacokinetic Model and Meta-Analysis of Outcomes [PublishAheadOfPrint]

There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis (CM). A PK study was conducted in n=42 patients receiving DAmB 1 mg/kg q24h. A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of CM patients treated with DAmB monotherapy and a meta-analysis was performed.

The PK parameter means (standard deviation) were: clearance, 0.03 (0.01) x weight + 0.95 (0.02) litres/hour; volume, 0.89 (0.90) x weight + 1.54 (1.13) litres; first-order rate constant from central to peripheral compartment, 7.12 (6.50) hours^-1; from peripheral to central compartment, 12.13 (12.50) hours^-1. The meta-analysis suggested that DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility, but not in mortality outcomes. Simulations of area under concentration-time curve (AUC_144-168) resulted in median (interquartile range) values 5.83 mg.h/litre (4.66-8.55), 10.16 (8.07-14.55) and 14.51 (11.48-20.42), with dosages of 0.4, 0.7 and 1.0 mg/kg q24h respectively.

DAmB PK is described adequately by a linear model that incorporates weight on clearance and volume. Inter-patient PK variability is modest and unlikely to be responsible for variability in clinical outcome. There is a discord between the impact that drug exposure has on CSF sterility and on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

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Protein Binding of First-Line Antituberculous Drugs [PublishAheadOfPrint]

Introduction: The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB). Its efficacy could be further improved by determining the free drug concentrations in plasma, knowing that only the unbound drug can freely penetrate to the tissues.

Methods: Using an ultrafiltration technique, we determined the protein binding (PB) extent and variability of the first-line anti-TB drugs when given simultaneously to TB patients, representing a real-life case scenario. We used clinical samples routinely received by our laboratory. Plasma proteins were also measured. A protein-free medium was used to determine the nonspecific binding.

Results: Plasma samples from 22 patients were included, of which plasma proteins were measured in 18 patients. The median PB was determined for rifampin (88%, range 72 – 91), isoniazid (14%, range 0 – 34), pyrazinamide (1%, range 0 – 7), and ethambutol (12%, range 4 – 24). Plasma proteins were not found to be significant predictors for the PB of first-line anti-TB drugs. Rifampin PB was positively correlated with its plasma concentration (p-value= 0.0051). Conversely, isoniazid PB was negatively correlated with its plasma concentration (p-value= 0.0417). Age was found to have a significant effect on isoniazid PB (p-value= 0.0376). No correlations were observed in pyrazinamide or ethambutol.

Conclusion: We have determined variable PB of rifampin, isoniazid, pyrazinamide, and ethambutol in patient plasma samples, with median values of 88, 14, 1, and 12%, respectively. In this small study, PB of rifampin and isoniazid are dependent on their plasma concentrations.

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Impact of Clofazimine Dosing on Treatment-Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis [PublishAheadOfPrint]

The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment-shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impact of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) six months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when co-administered with first-line drugs continuously throughout treatment, and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcome, an effect that was only evident after the first three months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the anti-tuberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow for the full evaluation of drugs administered in combination over long durations.

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Natamycin and Azithromycin are Synergistic in vitro against Ocular Pathogenic Aspergillus flavus species complex and Fusarium solani species complex Isolates [PublishAheadOfPrint]

The interaction of natamycin-azithromycin combination against 60 ocular fungal isolates was tested in vitro. The combination produced 100% synergistic interactions when natamycin added azithromycin at 20, 40, 50 μg/ml against Aspergillus flavus species complex (AFSC) isolates and added azithromycin at 50 μg/ml against Fusarium solani species complex isolates. The combination with 50 μg/ml azithromycin enhanced natamycin's effect against AFSC isolates by reducing natamycin MICs from MIC₉₀ 64μg/ml to MIC₉₀ 0.031μg/ml. No antagonism was observed.

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Germicidal Activity against Carbapenem/Colistin-Resistant Enterobacteriaceae Using a Quantitative Carrier Test Method [PublishAheadOfPrint]

Susceptibility to germicides for carbapenem/colistin-resistant Enterobacteriaceae is poorly described. We investigated the efficacy of multiple germicides against these emerging antibiotic-resistant pathogens using the disc-based quantitative carrier test method that can produce results more similar to those encountered in healthcare settings than a suspension test. Our study results demonstrated that germicides commonly used in healthcare facilities likely will be effective against carbapenem/colistin-resistant Enterobacteriaceae when used appropriately in healthcare facilities.

https://ift.tt/2HYTW9Z

The novel phage-derived antimicrobial agent HY-133 is active against livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) [PublishAheadOfPrint]

Livestock-associated, methicillin-resistant Staphylococcus aureus (LA-MRSA) are increasingly migrating from livestock into human and animal health care settings. Alternative substances are wanted to overcome the drawbacks of currently available drugs applied for MRSA eradication. The recombinant bacteriophage endolysin HY-133 has been proven as an active agent against S. aureus. Here, the in vitro activity of HY-133 was studied against a large collection of genetically diverse LA-MRSA revealing its high activity against mecA, mecB and mecC LA-MRSA.

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Self-Resistance During Muraymycin Biosynthesis: A Complementary Nucleotidyltransferase and Phosphotransferase with Identical Modification Sites and Distinct Temporal Order [PublishAheadOfPrint]

Muraymycins are antibacterial natural products from Streptomyces sp. that inhibit translocase I (MraY) involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5'-C-glycyluridine (GlyU) that is appended with a 5''-amino-5''-deoxyribose (ADR), forming a disaccharide core that is found in several peptidyl nucleoside inhibitors of MraY. For muraymycins the GlyU-ADR disaccharide is further modified with an aminopropyl-linked peptide to generate the simplest structures annotated as the muraymycin D series. Two enzymes encoded in the muraymycin biosynthetic gene cluster, Mur29 and Mur28, were functionally assigned in vitro as a Mg⋅ATP-dependent nucleotidyltransferase and a Mg⋅ATP-dependent phosphotransferase, respectively, that both modify the 3''-OH of the disaccharide. Biochemical characterization revealed that both enzymes can utilize several nucleotide donors as co-substrates and the acceptor substrate muraymycin also behaves as an inhibitor. Single-substrate kinetic analysis revealed Mur28 preferentially phosphorylates a synthetic GlyU-ADR disaccharide, a hypothetic biosynthetic precursor of muraymycins, while Mur29 preferentially adenylates the D series of muraymycins. The adenylated or phosphorylated products have significantly reduced MraY inhibitory activity (170- and 51-fold, respectively) and reduced antibacterial activity when compared with the respective unmodified muraymycin. The results are consistent with Mur29-catalyzed adenylation and Mur28-catalyzed phosphorylation serving as complementary self-resistance mechanisms with a distinct temporal order during muraymycin biosynthesis.

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Targocil-exposure of Staphylococcus aureus Blocks Translocation of the Major Autolysin Atl Across the Membrane Resulting in a Significant Decrease in Autolysis [PublishAheadOfPrint]

Peptidoglycan and wall teichoic acid (WTA) are the major staphylococcal cell wall components, and WTA biosynthesis has recently been explored for drug development. Targocil is a novel agent that targets the TarG subunit of the WTA translocase (TarGH) that transports WTA across the membrane to the wall. Previously we showed that targocil treatment of a methicillin-susceptible Staphylococcus aureus strain led to a rapid shut down of cellular autolysis. Targocil II, which targets the TarH subunit of TarGH, also resulted in a drastic decrease in autolysis. Here we address the mechanism of targocil-mediated decreased autolysis. The mechanism is WTA-dependent as targocil-treatment decreased autolysis in methicillin-resistant strains, but not in a WTA-deficient mutant. Similar to cellular autolysis, autolysin-retaining crude cell walls isolated from targocil-treated cells had vastly decreased autolytic activity compared to those from untreated cells. Purified cell walls from control and targocil-treated cells, which lack autolytic activity, were similarly susceptible to lysozyme and lysostaphin and had similar O-acetyl contents, indicating that targocil-treatment did not grossly alter PG structure and chemistry. Purified cell walls from targocil-treated cells were highly susceptible to autolysin extracts, supporting the notion that targocil-treatment led to decreased autolysin in the crude cell walls. Quantitative real-time PCR analysis revealed that the decrease in autolysis in the targocil-exposed cells was not due to transcriptional repression of the autolysin genes atl, lytM, lytN and sle1. Zymographic analysis of peptidoglycan hydrolase profiles showed a deficiency of cell surface autolysins in targocil-treated cells, but higher activity in cell membrane fractions. Here, we propose that the untranslocated WTA molecules in the targocil-exposed cells sequester Atl at the membrane, resulting in significantly decreased autolysis.

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Failure of daptomycin to kill Staphylococcus aureus: impact of bacterial membrane fatty acid composition [PublishAheadOfPrint]

Daptomycin is a last-resort membrane-targeting lipopeptide approved for the treatment of drug-resistant staphylococcal infections such as bacteraemia and implant-related infections. Although cases of resistance to this antibiotic are rare, increasing clinical, in vitro and animal studies report treatment failure, notably against Staphylococcus aureus. The aim of this study was to identify the features of daptomycin and its target bacteria that lead to daptomycin treatment failure. We show that daptomycin bactericidal activity against S. aureus to significantly varies with the growth state and strain according to membrane fatty acid composition. Daptomycin efficacy as an antibiotic relies on its ability to oligomerize within membranes and form pores that subsequently lead to cell death. Our findings ascertain that daptomycin interacts with tolerant bacteria and reaches its membrane target, regardless of its functionality. However, the final step of pore formation does not occur in cells that are daptomycin-tolerant, strongly suggesting its incapacity to oligomerize. Importantly, membrane fatty acid contents correlated with poor daptomycin bactericidal activity, which could be manipulated by fatty acid addition. In conclusion, daptomycin failure to treat S. aureus is not due to a lack of antibiotic-target interaction but is driven by its capacity to form pores, which depends on membrane composition. Manipulation of membrane fluidity to restore S. aureus daptomycin bactericidal activity in vivo could open the way to novel strategies of antibiotic treatment.

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Smoking Cessation: A Comparison of Two Model Structures

Abstract

Background

Most economic evaluations of smoking cessation interventions have used cohort state-transition models. Discrete event simulations (DESs) have been proposed as a superior approach.

Objective

We developed a state-transition model and a DES using the discretely integrated condition event (DICE) framework and compared the cost-effectiveness results. We performed scenario analysis using the DES to explore the impact of alternative assumptions.

Methods

The models estimated the costs and quality-adjusted life years (QALYs) for the intervention and comparator from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. The models considered five comorbidities: chronic obstructive pulmonary disease, myocardial infarction, coronary heart disease, stroke and lung cancer. The state-transition model used prevalence data, and the DES used incidence. The costs and utility inputs were the same between two models and consistent with those used in previous analyses for the National Institute for Health and Care Excellence.

Results

In the state-transition model, the intervention produced an additional 0.16 QALYs at a cost of £540, leading to an incremental cost-effectiveness ratio (ICER) of £3438. The comparable DES scenario produced an ICER of £5577. The ICER for the DES increased to £18,354 when long-term relapse was included.

Conclusions

The model structures themselves did not influence smoking cessation cost-effectiveness results, but long-term assumptions did. When there is variation in long-term predictions between interventions, economic models need a structure that can reflect this.

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Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 is evolutionarily conserved in model organisms. Here we conducted a natural history study and chemical-modifier screen on the Drosophila melanogaster NGLY1 homolog, Pngl. We generated a new fly model of NGLY1 Deficiency, engineered with a nonsense mutation in Pngl at codon 420 that results in a truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. We developed a 96-well-plate, image-based, quantitative assay of Drosophila larval size for use in a screen of the 2,650-member Microsource Spectrum compound library of FDA approved drugs, bioactive tool compounds, and natural products. We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also partially rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model, evidence of a defective proteasome "bounce-back" response that is also observed in nematode and cellular models of NGLY1 Deficiency. Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery and gene modifier screens.

https://ift.tt/2rqzp2Q

Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors

Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors

Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors, Published online: 08 May 2018; doi:10.1038/s41416-018-0044-7

Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors

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Psychological impact of providing women with personalised 10-year breast cancer risk estimates

Psychological impact of providing women with personalised 10-year breast cancer risk estimates

Psychological impact of providing women with personalised 10-year breast cancer risk estimates, Published online: 08 May 2018; doi:10.1038/s41416-018-0069-y

Psychological impact of providing women with personalised 10-year breast cancer risk estimates

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Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division

Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division

Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division, Published online: 08 May 2018; doi:10.1038/s41416-018-0081-2

Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division

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miRNA profiling of magnetic nanopore-isolated extracellular vesicles for the diagnosis of pancreatic cancer

Improved diagnostics for pancreatic ductal adenocarcinoma (PDAC) to detect the disease at earlier, curative stages and to guide treatments is crucial to progress against this disease. The development of a liquid biopsy for PDAC has proven challenging due to the sparsity and variable phenotypic expression of circulating biomarkers. Here we report methods we developed for isolating specific subsets of extracellular vesicles (EV) from plasma using a novel magnetic nanopore capture technique. In addition, we present a workflow for identifying EV miRNA biomarkers using RNA sequencing and machine-learning algorithms, which we used in combination to classify distinct cancer states. Applying this approach to a mouse model of PDAC, we identified a biomarker panel of 11 EV miRNAs that could distinguish mice with PDAC from either healthy mice or those with pre-cancerous lesions in a training set of N = 27 mice and a user-blinded validation set of N = 57 mice (88% accuracy in a three-way classification). These results provide strong proof-of-concept support for the feasibility of using EV miRNA profiling and machine learning for liquid biopsy.

https://ift.tt/2jGFl4o

Optimized dosing schedule based on circadian dynamics of mouse breast cancer stem cells improves the anti-tumor effects of aldehyde dehydrogenase

Although malignant phenotypes of triple-negative breast cancer (TNBC) are subject to circadian alterations, the role of cancer stem cells (CSC) in defining this circadian change remains unclear. CSC are often characterized by high aldehyde dehydrogenase (ALDH) activity, which is associated with the malignancy of cancer cells and used for identification and isolation of CSC. Here we show that the popultation of ALDH-positive cells in a mouse 4T1 breast tumor model exhibits pronounced circadian alterations. Alterations in the number of ALDH-positive cells was generated by time-dependent increases and decreases in the expression of Aldh3a1. Importantly, circadian clock genes were rhythmically expressed in ALDH-negative cells, but not in ALDH-positive cells. Circadian expression of Aldh3a1 in ALDH-positive cells was dependent on the time-dependent release of Wingless-type mmtv integration site family 10a (WNT10a) from ALDH-negative cells. Furthermore, anti-tumor and anti-metastatic effects of ALDH inhibitor N,N-diethylaminobenzaldehyde were enhanced by administration at the time of day when ALDH activity was increased in 4T1 tumor cells. Our findings reveal a new role for the circadian clock within the tumor microenvironment in regulating the circadian dynamics of CSC. These results should enable the development of novel therapeutic strategies for treatment of TNBC with ALDH inhibitors.

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HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL=1.31, 95% CI=1.06-1.60; OR MZL=1.45, 95% CI=1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL=2.10, 95% CI=1.24-3.55; OR MZL= 2.10, 95% CI=0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (p-trend<0.0001, FDR=0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.

https://ift.tt/2jGUUZZ

Novel Richter's syndrome xenograft models to study genetic architecture, biology and therapy responses

Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed over-activation of the B cell receptor, NF-kB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of RS represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.

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MicroRNA 339 promotes development of Stem Cell Leukemia/Lymphoma syndrome via downregulation of the BCL2L11 and BAX pro-apoptotic genes

Development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of activated FGFR1 kinase on gene transcription, including dysregulation of microRNAs. In a screen for miRNAs that are directly regulated by FGFR1 and that stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhanced cell survival, wherease inhibition of its function reduced cell viability. miR-339-5p overexpression also protected cells from the effects of FGFR1 inactivation, promoting cell cycle progression and reducing apoptosis. BCR-FGFR1 fusion directly regulated miR-339-5p expression in cells lines; this correlation between miR-339-5p and FGFR1 expression was also observed in primary human B cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the pro-apoptotic genes BCL2L11 and BAX. In vivo, SCLL cells forced to overexpress miR-339-5p exhibited a more rapid onset of disease and poorer survival compared with cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL showed significantly higher expression of miR339-5p compared with two cohorts of CLL patient samples, suggesting direct roles for miR339-5p in disease progression and supporting the evidence generated in mouse models of SCLL.

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Mechanistic distinctions between CHK1 and WEE1 inhibition guide the scheduling of triple therapy with gemcitabine

Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesised that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modelling and single-cell assays distinguished the synergy kinetics of WEE1i from CHK1i by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine. These divergent properties collectively supported a triple-agent strategy, whereby a pulse of gemcitabine and CHK1i followed by WEE1i durably suppressed tumour cell growth. In xenografts, CHK1i exaggerated replication stress without mitotic CDK hyperactivation, enriching a geminin-positive subpopulation and intratumoral gemcitabine metabolite. Without overt toxicity, addition of WEE1i to low-dose gemcitabine and CHK1i was most effective in tumour control compared to single and double agents. Overall, our work provides quantitative insights into the mechanisms of DDRi chemosensitisation, leading to the rational development of a tolerable multitherapeutic regimen.

https://ift.tt/2wlQvot

TNFRSF19 inhibits TGF{beta} signaling through interaction with TGF{beta} receptor type I to promote tumorigenesis

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of TNF receptors, TNFRSF19 was not involved in NF-κB activation or associated with TRAF proteins. We identified TGFβ receptor type-I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in NPC patients. Our data reveal that gain-of-function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ.

https://ift.tt/2rsy64h

Epigenetic regulation of CXCL12 plays a critical role in mediating tumor progression and the immune response in osteosarcoma

The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8+ T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma.

https://ift.tt/2wkHGel

Long noncoding RNA AB074169 inhibits cell proliferation via modulation of KHSRP-mediated p21 expression in papillary thyroid carcinoma

Long noncoding RNAs (lncRNAs) are emerging as a novel class of regulators in gene expression associated with tumorigenesis. However, the role of lncRNAs in papillary thyroid carcinoma (PTC) is poorly understood. Here we conducted global lncRNA profiling and identified lncRNA AB074169 (lncAB) as significantly downregulated in PTC. Decreased expression of lncAB in PTC was caused by CpG hypermethylation within its gene promoter. Functional studies showed that lncAB overexpression led to cell cycle arrest and tumor growth inhibition in vitro and in vivo, whereas lncAB knockdown promoted cell proliferation. Mechanistic analyses revealed that lncAB bound KH-type splicing regulatory protein (KHSRP) and also decreased expression of KHSRP, thus increasing CDKN1a (p21) expression and decreasing CDK2 expression to repress cell proliferation. Taken together, these findings demonstrate that lncAB functions as a tumor suppressor during PTC tumorigenesis.

https://ift.tt/2jDUenW

Nuclear IGF-1R interacts with regulatory regions of chromatin to promote RNA polymerase II recruitment and gene expression associated with advanced tumor stage

Internalization of ligand-activated type 1 IGF receptor (IGF-1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF-1R reportedly associates with clinical response to IGF-1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here we investigated the significance of nuclear IGF-1R in clinical cancers and cell line models. In prostate cancers, IGF-1R was predominantly membrane-localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF-1R, and nuclear IGF-1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF-1R binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF-1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF-1 also enriched RNAPol2 on promoters containing IGF-1R binding sites. These functions were inhibited by IGF-1/2 neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected nuclear IGF-1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF-1R, with evidence of correlation between nuclear IGF-1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.

https://ift.tt/2wlKp7l

Loss of MED12 induces tumor dormancy in human epithelial ovarian cancer via downregulation of EGFR

A high rate of disease relapse makes epithelial ovarian cancer (EOC) the leading cause of death among all gynecological malignancies. These relapses are often due to tumor dormancy. Here we identify the RNA polymerase II transcriptional Mediator subunit 12 (MED12) as an important molecular regulator of tumor dormancy. MED12 knockout (KO) induced dormancy of EOC cells in vitro and in vivo, and microarray analysis showed that MED12 KO decreased expression of EGFR. Restoration of EGFR expression in MED12 KO cells restored proliferation. Additionally, MED12 bound to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with EGFR expression in EOC patient samples. Clinical data demonstrated that chemotherapy-resistant patients expressed lower levels of MED12 compared to responsive patients. Overall, our data show that MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.

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RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis

Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS–mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. RASSF1A deficiency profoundly enhanced the development of K-RAS–driven lung tumors in vivo. Analysis of these tumors showed loss of RASSF1A-uncoupled RAS from the proapoptotic Hippo pathway as expected. We also observed an upregulation of AKT and RALGEF signaling in the RASSF1A− tumors. Heterozygosity of RASSF1A alone mimicked many of the effects of RAS activation on mitogenic signaling in lung tissue, yet no tumors developed, indicating that nonstandard Ras signaling pathways may be playing a key role in tumor formation in vivo. In addition, we observed a marked increase in inflammation and IL6 production in RASSF1A-deficient tumors. Thus, RASSF1A loss profoundly affects RAS-driven lung tumorigenesis and mitogenic signaling in vivo. Deregulation of inflammatory pathways due to loss of RASSF1A may be essential for RAS-mediated tumorigenesis. These results may have considerable ramifications for future targeted therapy against RAS+/RASSF1A− tumors.Significance: A transgenic mouse model shows that suppression of RASSF1A dramatically enhances Ras-driven tumorigenesis and alters Ras signaling pathway activity. Cancer Res; 78(10); 1–10. ©2018 AACR. F1

https://ift.tt/2wnrc59

PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent

Aberrant DNA methylation plays a critical role in the development and progression of cancer. Failure to demethylate and to consequently reactivate methylation-silenced genes in cancer contributes to chemotherapeutic resistance, yet the regulatory mechanisms of DNA demethylation in response to chemotherapeutic agents remain unclear. Here, we show that promyelocytic leukemia (PML) recruits ten–eleven translocation dioxygenase 2 (TET2) to regulate DNA modification and cell proliferation in response to chemotherapeutic agents. TET2 was required by multiple chemotherapeutic agents (such as doxorubicin) to promote 5-hydroxymethylcytosine (5hmC) formation. Stable isotope labeling with amino acids in cell culture, followed by immunoprecipitation–mass spectrometry, identified potential binding partners of TET2, of which PML mostly enhanced 5hmC formation. PML physically bound to TET2 via the PML C-terminal domain and recruited TET2 to PML-positive nuclear bodies. This interaction was disrupted by the PML-RARA t(15;17) mutation, which stems from chromosomal translocation between DNA encoding the C-terminal domain of PML and the retinoic acid receptor alpha (RARA) gene. In response to chemotherapeutic drugs, PML recruited TET2, regulated DNA modification, reactivated methylation-silenced genes, and impaired cell proliferation. Knockout of PML abolished doxorubicin-promoted DNA modification. In addition, PML and TET2 levels positively correlated with improved overall survival in patients with head and neck cancer. These findings shed insight into the regulatory mechanisms of DNA modification in response to chemotherapeutic agents.Significance: Promyeloctic leukemia protein recruits TET2, regulating DNA modification and cell proliferation in response to chemotherapeutic agents. Cancer Res; 78(10); 1–15. ©2018 AACR.

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Mild TBI Linked to Increased Dementia Risk in Veterans

MONDAY, May 7, 2018 -- Even mild traumatic brain injury (TBI) without loss of consciousness (LOC) is associated with increased risk of dementia among veterans, according to a study published online May 7 in JAMA Neurology. Deborah E. Barnes, Ph.D.,...

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Folic Acid May Cut Stroke Risk in High-Risk Hypertensive Patients

MONDAY, May 7, 2018 -- Hypertensive patients may lower their stroke risk with folic acid supplements, according to a study published in the May 15 issue of the Journal of the American College of Cardiology. Xiangyi Kong, M.D., from Peking University...

https://ift.tt/2I1TE2c

Cancer Incidences and Burden Expected to Shift in HIV-Positive

MONDAY, May 7, 2018 -- The cancer burden among persons living with HIV (PLWH) is projected to shift by 2030, according to a study published online May 8 in the Annals of Internal Medicine. Meredith S. Shiels, Ph.D., from the National Cancer...

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Adverse Outcomes Up for Vaginal Birth After Previous C-Section

MONDAY, May 7, 2018 -- The rates of severe maternal and neonatal morbidity and mortality are elevated with attempted vaginal delivery after single prior cesarean delivery, according to a study published in the May 7 issue of CMAJ, the journal of the...

https://ift.tt/2HXdHhV

FDA Approves Drug Combo for Aggressive Thyroid Cancer

MONDAY, May 7, 2018 -- Two anti-cancer drugs administered together have been approved by the U.S. Food and Drug Administration to treat BRAF-positive anaplastic thyroid cancer. Tafinlar (dabrafenib) and Mekinist (trametinib) combined have been...

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A response to: “Sleep and Circadian Rhythms in Severely Brain-Injured Patients – A Comment”

We can only agree with all methodological criticisms raised by Schabus et al. (2018) in their brief Letter-to-the-Editor. We conducted our study (Rossi Sebastiano et al., 2018) taking into account many limitations, including the brevity of recordings, the inclusion of nocturnal sleep only, the objective limits in sleep staging and the possibility of subjective interpretations, due to the modifications of the standard AASM criteria we applied (American Academy of Sleep Medicine & Iber et al., 2007).

https://ift.tt/2rqNCh7

Migraine and temporomadibular disorders

https://ift.tt/2IoEe7e

Amitriptyline and intraoral devices for migraine prevention: a randomized comparative trial

ABSTRACT Objectives: Nonpharmacological treatments, such as the Nociceptive Trigeminal Inhibition Tension Suppression System (NTI-tss), are approved for migraine prophylaxis. We aimed at evaluating the effectiveness of the NTI-tss and to compare its efficacy with amitriptyline and with a sham intraoral device in the preventive treatment of migraine. Methods: Consecutive patients with migraine were randomized to receive 25 mg of amitriptyline/day (n = 34), NTI-tss (n = 33) and a non-occlusal splint (n = 30). The headache frequency was evaluated at six and 12 weeks. Results: The amitriptyline group showed, respectively, 60% and 64% reduction in attack frequency at six and 12 weeks (P = 0.000). In the NTI-tss and non-occlusal splint groups, reduction was 39% and 30%, respectively, at six weeks and 48% for both groups at 12 weeks. Conclusions: Amitriptyline proved superior to the NTI-tss and the non-occlusal splint. Despite its approval by the United States Food and Drug Administration, the NTI-tss was not superior to a sham device.

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RESUMO Objetivo: Tratamentos não farmacológicos como o Nociceptive Trigeminal Inhibition Tension Suppression System (NTI-tss), são aprovados para a prevenção da migrânea. Avaliamos a eficácia do NTI-tss no tratamento preventivo da migrânea e comparamos sua eficácia com a de um medicamento tradicional (amitriptilina) e com um dispositivo intraoral que não interfere com a oclusão (placa palatina). Métodos: Pacientes consecutivos com migrânea foram randomizados e receberam 25mg de amitriptilina/dia (n = 34), NTI-tss (n = 33) ou placa palatina não oclusal (n = 30). A frequência da cefaleia foi comparada após seis e 12 semanas. Resultados: No grupo da amitriptilina houve redução de 60% em seis semanas e de 64% em 12 semanas (P = 0.000). Nos grupos do NTI-tss e da placa não oclusal a redução foi respectivamente de 39% e 30% após seis semanas, e de 48% para ambos em 12 semanas. Conclusões: Amitriptilina foi superior ao NTI-tss e à placa palatina no tratamento da migrânea sem aura. O NTI-tss obteve resultados similares aos da placa não oclusal.

https://ift.tt/2K448KN

Investigation of the cardiovascular risk profile in a south Brazilian city: surveys from 2012 to 2016

ABSTRACT The aim of this study was to investigate the cardiovascular risk profile of the participants recruited from stroke awareness campaigns in Santa Maria RS, Brazil, from 2012 to 2016, using the simplified version of the Framingham Risk Score (FRS). Questionnaires were used to evaluate 1,061 participants from 20 to 74 years old. Data on cardiovascular risk factors were obtained. The prevalence of risk factors and mean FRS for men and women were estimated. The FRS for women was 11.8% (moderate risk) and 24.7% for men (high risk). The vascular age for women was 61.6 years, whereas the vascular age for men was 66 years. Two percent of women had hypertension and diabetes, while both these risk factors were present in 5% of men. Based on the data, the prevalence of stroke risk factors is worrisome, as are the numbers of individuals with moderate and high cardiovascular risk in Santa Maria.

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RESUMO O objetivo desse estudo foi investigar o perfil de risco cardiovascular dos participantes de campanhas sobre acidente vascular cerebral (AVC) em Santa Maria-RS, dos anos de 2012 a 2016, por meio do Escore de Risco de Framingham (ERF) simplificado. Foram utilizados questionários para avaliação de 1061 indivíduos de 20 a 74 anos. Informações sobre fatores de risco cardiovascular foram obtidas. O ERF médio para as mulheres foi de 11,8% (risco moderado) e para os homens, 24,7% (risco alto). A idade vascular média no sexo feminino foi de 61,6 anos, sendo 66 anos o valor encontrado para o sexo masculino. 2% das mulheres eram hipertensas e tabagistas; nos homens, a concomitância desses fatores de risco foi de 5%. Assim, as prevalências de fatores de risco para AVC e de indivíduos com moderado e alto risco cardiovascular são alarmantes em Santa Maria.

https://ift.tt/2IozoXN

Association between cognitive function and parameters of echocardiography and coronary artery angiography

ABSTRACT We aimed to determine whether there is an association between cognition and the results of echocardiography and angiography, based on neuropsychological assessments. Methods: We assessed the cognition of 85 patients who had recently undergone coronary artery angiography. We calculated the Gensini score for the coronary artery disease index. We also performed echocardiography to find indices of cardiac functioning. Results: The lower left ventricular ejection fraction correlated with lower scores on visuospatial, executive function, processing speed/attention and verbal memory capacities (p ≤ 0.05). A higher Gensini score and left atrial size correlated with lower executive function and processing speed/attention (p ≤ 0.05). In the group of patients with an impaired cognitive state, higher Gensini scores correlated with decreased processing speed/attention (p = 0.01) and the e' index was associated with lower capacity of executive function (p = 0.05). Conclusion: Decreased processing speed/attention and executive function may correlate with cardiac dysfunction and coronary artery disease. The Color Trail Test may be considered for simple screening for cognitive problems in elderly patients with coronary artery disease or diastolic dysfunction.

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RESUMO O objetivo deste estudo é encontrar associação entre cognição e resultados de exames ecocardiográficos e angiográficos, com base em avaliações neuropsicológicas. Método: Foi avaliada a cognição de 85 pacientes que foram submetidos a angiografia coronária. O escore de Gensini foi calculado para o índice de doença arterial coronariana (DAC). Foi realizado também, o exame ecocardiográfico a fim de descobrir os índices de funcionamento cardíaco. Resultados: A fração de ejeção do ventrículo inferior esquerdo está correlacionada com a baixa pontuação na capacidade visual e espacial, função executiva, velocidade de processamento/atenção e memória verbal (p ≤ 0,05). Alto escore de Gensini e tamanho do átrio esquerdo correlacionados com baixa função executiva, velocidade de processamento/atenção (p ≤ 0,05). No grupo de pacientes com estado cognitivo prejudicado, alto escore de Gensini correlacionado com diminuição da velocidade de processamento/atenção (p = 0,01) e índice e' associado a baixa capacidade da função executiva (p = 0,05). Conclusão: Diminuição da velocidade de processamento/atenção e da função executiva pode estar correlacionado a disfunção cardíaca e DAC. O Color Trail Test pode ser considerado para uma triagem simples de problemas cognitivos em pacientes idosos com DAC ou disfunção diastólica.

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Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI): neuropsychological evolution profile after one-year follow up

ABSTRACT The Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI) study is a longitudinal prospective cohort of 50 participants at a single institution in Buenos Aires, Argentina. Longitudinal assessments on a neuropsychological test battery were performed on 15 controls, 24 mild cognitive impairment (MCI) patients and 12 Alzheimer's disease (AD) dementia patients. In our study population, there was a high prevalence of positive AD biomarkers in the AD group, 92.3% (12/13); and a low prevalence in the normal controls, 20%; almost half (48%) of the patients diagnosed with MCI had positive amyloid detection. After a one year, the significant differences found at baseline on neuropsychological testing were similar at the follow-up assessment even though the AD group had significantly altered its functional performance (FAQ and CDR). The exception was semantic fluency, which showed greater impairment between the AD group and MCI and normal controls respectively. For these tests, the addition of AD biomarkers as a variable did not significantly alter the variations previously found for the established clinical group's model. Finally, the one-year conversion rate to dementia was 20% in the MCI cohort.

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RESUMO El estudio de Argentina-Alzheimer's Disease Neuroimaging Initiative (Arg-ADNI) es una cohorte prospectiva de 50 pacientes seguidos en una misma institución. Fueron evaluados cognitivamente 15 controles normales (CN), 24 sujetos con deterioro cognitivo leve (DCL) y 12 con demencia tipo Alzheimer (DTA) leve. En los DTA, 92,3% tuvieron biomarcadores positivos para Alzheimer y 20% en los CN. Casi la mitad de los DCL presentaron biomarcadores positivos. Después de un año de seguimiento, la diferencias significativas halladas en la visita de inicio en las pruebas cognitivas fueron similares al año aunque los DTA tuvieron empeoramiento funcional medido en el FAQ y CDR. La excepción fue la fluencia semántica, la cual mostró mayor declinación entre DTA y los demás grupos. La incorporación de los biomarcadores como variable no alteró significativamente los hallazgos de grupo. La tasa de conversión a demencia anual fue del 20%.

https://ift.tt/2IpAYsA

OxLDL plasma levels in patients with Alzheimer's disease

ABSTRACT Objective: The objective of this study was to characterize the conventional lipid profile, oxLDL levels and ApoE polymorphism in patients with Alzheimer's disease (AD) and in elderly individuals without cognitive impairment. Methods: Eighty elderly individuals were selected and the levels of oxLDL were determined using the ELISA kit, and ApoE gene polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism. Results: Significantly reduced levels of oxLDL were observed in patients with AD compared to the control group. A higher frequency of the ApoE ε4 allele was observed in patients with AD compared to controls. No difference was observed for total cholesterol, HDL-C, and LDL-C levels between the two groups, while triglyceride levels were higher in controls compared with patients with AD. Conclusion: The data analyzed together did not reveal significant differences in lipid profiles, including oxLDL levels. However, the importance of lipid changes in the genesis of the disease cannot be ruled out. Nevertheless, the ApoE ε4 allele was significantly more frequent in patients with Alzheimer's dementia in agreement with previous findings in the literature, but this genetic component did not change the levels of oxLDL.

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RESUMO Objetivo: O objetivo deste estudo foi caracterizar o perfil lipídico convencional, os níveis de LDL-ox e o polimorfismo da ApoE em pacientes com doença de Alzheimer (DA) e em indivíduos idosos sem comprometimento cognitivo. Métodos: Foram selecionados oitenta indivíduos idosos. Os níveis de LDL-ox foram determinados usando o kit ELISA e a investigação do polimorfismo do gene da ApoE por PCR-RFLP. Resultados: Níveis significativamente reduzidos de LDL-ox foram observados em pacientes com DA comparado ao grupo controle. Uma maior frequência do alelo ε4 da ApoE foi observada nos pacientes com DA em relação aos controles. Nenhuma diferença foi observada para os níveis de colesterol total, HDL-C e LDL-C entre os dois grupos, enquanto níveis de triglicérides foram mais altos em controles comparados aos pacientes com DA. Conclusão: Os dados analisados em conjunto não revelaram diferenças significativas no perfil lipídico, incluindo os níveis de LDL-ox. No entanto, não se pode excluir a importância de alterações lipídicas na gênese da doença. Não obstante, o alelo ε4 da ApoE foi signicativamente mais frequente nos pacientes com demência de Alzheimer em concordância com achados prévios da literatura, mas esse componente genético não interferiu nos níveis de LDL-ox.

https://ift.tt/2K091EE

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

ABSTRACT Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

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RESUMO A doença de Pompe é uma doença hereditária causada pela deficiência da enzima alfa-glicosidase ácida (GAA). Estudo observacional foi realizado, em um único centro, para determinar a prevalência da doença de Pompe de início tardio (LOPD) em uma população brasileira de alto risco, usando teste em gota seca (DBS) como ferramenta principal de triagem para detectar a deficiência da GAA. DBS foi coletado para avaliar a atividade da GAA em 24 pacientes com fraqueza muscular de cinturas "não explicada" sem miopatia vacuolar na biópsia muscular. As amostras com atividade enzimática reduzida foram também submetidas a análise de mutações no gene GAA. Dos 24 pacientes com DBS, baixa atividade da enzima GAA (NaG/AaGIA: 40.42; %INH: 87.22%) foi encontrada em um paciente (4.2%). Nessa paciente, a análise genética confirmou duas mutações em heterozigose composta no gene GAA (c.-32-13T > G/p.Arg854Ter). Nossos resultados confirmam que LOPD deve ser investigada quando a manifestação clínica é uma fraqueza muscular de cinturas "não explicada", mesmo na ausência de miopatia vacuolar na biópsia muscular.

https://ift.tt/2rr0ljN

Propentofylline decreases hypothalamic astrogliosis induced by hypercaloric diet in the rat

ABSTRACT Obesity is associated with a chronic and low-grade inflammatory response in the hypothalamus, where astrogliosis occurs with the upregulation of the astrocyte structural protein GFAP. As propentofylline (PPF) has inhibitory effects on astrocyte and microglial activation during inflammation, this study aimed to investigate if this xanthine derivative could decrease the astrocyte reaction induced by a hypercaloric diet (HD). Male Wistar rats were divided into four groups: NDS – rats receiving a normocaloric diet (ND) and daily saline solution; NDP – rats receiving ND and daily PPF (12.5 mg/kg/day, intraperitoneal route); HDS – rats receiving HD and saline solution, HDP – rats receiving HD and PPF. On the 21st day, rats were anesthetized, and perfused, and brains were collected for GFAP immunohistochemical study in the hypothalamus. Results showed that HD induced increased weight gain and hypothalamic astrogliosis. Propentofylline decreased the expression of GFAP in the HDP group, although it did not affect the weight gain induced by this diet.

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RESUMO A obesidade está associada com uma resposta inflamatória crônica e de baixo grau no hipotálamo, onde ocorre astrogliose com a superexpressão da proteína astrocitária GFAP. Como a propentofilina (PPF) possui efeitos inibitórios sobre a ativação astrocitária e microglial durante a inflamação, este estudo visou a investigar se esta xantina podia diminuir a reação astrocitária induzida pela dieta hipercalórica (HD). Ratos Wistar machos foram divididos em 4 grupos: NDS- ratos recebendo dieta normocalórica (ND) e solução salina diária; NDP- ratos recebendo ND e PPF diária (12.5 mg/kg/dia, via intraperitoneal); HDS- ratos recebendo HD e solução salina, HDP- ratos recebendo HD e PPF. No 21° dia, os ratos foram perfundidos e os encéfalos, coletados para estudo imuno-histoquímico para a GFAP no hipotálamo. Os resultados mostram que a HD induziu aumento do ganho de peso e astrogliose no hipotálamo. A PPF diminuiu a expressão de GFAP no grupo HD, embora não tenha afetado o ganho de peso induzido por esta dieta.

https://ift.tt/2K1DAKl

Analysis of direct costs of decompressive craniectomy in victims of traumatic brain injury

ABSTRACT Background: Decompressive craniectomy is a procedure required in some cases of traumatic brain injury (TBI). This manuscript evaluates the direct costs and outcomes of decompressive craniectomy for TBI in a developing country and describes the epidemiological profile. Methods: A retrospective study was performed using a five-year neurosurgical database, taking a sample of patients with TBI who underwent decompressive craniectomy. Several variables were considered and a formula was developed for calculating the total cost. Results: Most patients had multiple brain lesions and the majority (69.0%) developed an infectious complication. The general mortality index was 68.8%. The total cost was R$ 2,116,960.22 (US$ 661,550.06) and the mean patient cost was R$ 66,155.00 (US$ 20,673.44). Conclusions: Decompressive craniectomy for TBI is an expensive procedure that is also associated with high morbidity and mortality. This was the first study performed in a developing country that aimed to evaluate the direct costs. Prevention measures should be a priority.

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RESUMO Introdução: A craniectomia descompressiva (CD) é procedimento necessário em alguns casos de trauma cranioencefálico (TCE). Este manuscrito objetiva avaliar os custos diretos e desfechos da CD no TCE em um país em desenvolvimento e descrever o perfil epidemiológico. Métodos: Estudo retrospectivo foi realizado usando banco de dados neurocirúrgico de cinco anos, considerando amostra de pacientes com TCE que realizaram CD. Algumas variáveis foram analisadas e foi desenvolvida uma fórmula para cálculo do custo total. Resultados: A maioria dos pacientes teve múltiplas lesões intracranianas, sendo que 69.0% evoluíram com algum tipo de complicação infecciosa. A taxa de mortalidade foi de 68,8%. O custo total foi R$ 2.116.960,22 (US$ 653,216.00) e o custo médio por paciente foi R$ 66.155,00 (US$ 20,415.00). Conclusões: CD no TCE é um procedimento caro e associado á alta morbidade e mortalidade. Este foi o primeiro estudo realizado em um país em desenvolvimento com o objetivo de avaliar os custos diretos. Medidas de prevenção devem ser priorizadas.

https://ift.tt/2Im5W4E

Therapeutic advances in 5q-linked spinal muscular atrophy

ABSTRACT Spinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector. These therapeutic perspectives open a new era in the natural history of the disease. In this review, we intend to discuss the most recent and promising therapeutic strategies, with special consideration to the pathogenesis of the disease and the mechanisms of action of such therapies.

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RESUMO A atrofia muscular espinhal (AME) é uma grave doença dos neurônios motores, de grande variabilidade clínica e causada na maioria dos casos por mutação em homozigose no gene SMN1. Pelo menos quatro fenótipos clínicos distintos são reconhecidos com base na idade de início e no grau de envolvimento motor. Tal variabilidade clínica é em parte relacionada com o número de cópias do gene SMN2. Até recentemente, apenas terapias de suporte estavam disponíveis. Atualmente, terapias especificas estão sendo desenvolvidas com base em diferentes mecanismos para aumentar o nível de proteína SMN; em particular oligonucleotídeos antissenso por via intratecal e inserção de cópia do gene SMN1, via endovenosa, usando vetor viral. Nesta revisão, objetivamos discutir as mais recentes e promissoras estratégias terapêuticas, com consideração especial aos aspectos patogênicos da doença e aos mecanismos de ação de tais terapias.

https://ift.tt/2K43XPD

Pain in Charcot-Marie-Tooth disease: an update

ABSTRACT Charcot-Marie-Tooth (CMT) disease, the most common inherited peripheral neuropathy, has pain as one of its clinical features, yet it remains underdiagnosed and undertreated. This literature review assessed data related to pain from CMT to determine its prevalence, type and importance as a symptom, which, unlike other symptoms, is likely to be treated. The research encompassed 2007 to 2017 and included five articles that addressed pain from CMT. All of the papers concurred that pain is frequently present in CMT patients, yet its classification remains undefined as there has been no consensus in the literature about the mechanisms that cause it.

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RESUMO A doença de Charcot-Marie-Tooth (CMT), a neuropatia periférica hereditária mais comum, tem a dor como uma de suas características clínicas, a qual permanece subdiagnosticada e subtratada. Essa revisão de literatura avaliou os dados relacionados à dor em CMT com objetivo de observar sua prevalência, tipo e importância como sintoma que, em detrimento de outros, é possível ser tratado. O intervalo da pesquisa foi entre 2007 e 2017, através de cinco artigos abordando a dor em CMT. Todos os artigos concordam que a dor é frequente nos pacientes com a doença de CMT e a sua classificação permanece indefinida por não haver consenso na literatura sobre os mecanismos da dor.

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Phrenology and the Rwandan Genocide

ABSTRACT Belgian colonizers used phrenology to create an irreducible division between the two major groups living for centuries in Rwanda-Urundi. This formed the basis for the implementation of systematic efforts to subdue the large Hutu population. Both the Hutus and the smaller, and initially privileged, Tutsi group soon incorporated the racist discourse, which was pivotal to the gradual increase in violence before and after Rwandan independence in 1962. The Rwandan genocide in 1994 culminated in the horrible pinnacle of this process, involving recurrent episodes of slaughtering. Doctors should not underestimate the racist potential of pseudoscientific misconceptions.

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RESUMO Os colonizadores belgas usaram a frenologia para criar uma divisão irredutível entre os dois maiores grupos populacionais vivendo há séculos em Ruanda-Urundi. Isso criou as bases para a implementação de esforços sistemáticos para subjugar a grande população Hutu. Tanto os Hutu quanto o grupo menor e inicialmente privilegiado dos Tutsi logo incorporaram o discurso racista, que foi crucial no aumento gradual da violência antes e após a independência de Ruanda em 1962. O genocídio de 1994 constituiu o terrível ápice deste processo envolvendo massacres repetidos. Os médicos não devem subestimar o potencial racista e discriminatório de falsas concepções pseudocientíficas.

https://ift.tt/2K1DwKB

Typical clinical and neuroimaging features in Sjögren-Larsson syndrome

ABSTRACT Belgian colonizers used phrenology to create an irreducible division between the two major groups living for centuries in Rwanda-Urundi. This formed the basis for the implementation of systematic efforts to subdue the large Hutu population. Both the Hutus and the smaller, and initially privileged, Tutsi group soon incorporated the racist discourse, which was pivotal to the gradual increase in violence before and after Rwandan independence in 1962. The Rwandan genocide in 1994 culminated in the horrible pinnacle of this process, involving recurrent episodes of slaughtering. Doctors should not underestimate the racist potential of pseudoscientific misconceptions.

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RESUMO Os colonizadores belgas usaram a frenologia para criar uma divisão irredutível entre os dois maiores grupos populacionais vivendo há séculos em Ruanda-Urundi. Isso criou as bases para a implementação de esforços sistemáticos para subjugar a grande população Hutu. Tanto os Hutu quanto o grupo menor e inicialmente privilegiado dos Tutsi logo incorporaram o discurso racista, que foi crucial no aumento gradual da violência antes e após a independência de Ruanda em 1962. O genocídio de 1994 constituiu o terrível ápice deste processo envolvendo massacres repetidos. Os médicos não devem subestimar o potencial racista e discriminatório de falsas concepções pseudocientíficas.

https://ift.tt/2Iozlv5

Psychological impact of providing women with personalised 10-year breast cancer risk estimates

https://ift.tt/2wlrBFv

Effects of high-intensity interval training on fatigue and quality of life in testicular cancer survivors

https://ift.tt/2rpsUy6

Addition of ultrasound to mammography in the case of dense breast tissue: systematic review and meta-analysis

https://ift.tt/2wlUHV2

Mps1 inhibitors synergise with low doses of taxanes in promoting tumour cell death by enhancement of errors in cell division

https://ift.tt/2rqHVjk

Projected Cancer Incidence Rates and Burden of Incident Cancer Cases in HIV-Infected Adults in the United States Through 2030

Background:

Persons living with HIV (PLWH) have an elevated risk for certain types of cancer. With modern antiretroviral therapy, PLWH are aging and cancer rates are changing.

Objective:

To project cancer incidence rates and burden (number of new cancer diagnoses) among adult PLWH in the United States through 2030.

Design:

Descriptive.

Setting:

HIV/AIDS Cancer Match Study to project cancer rates and HIV Optimization and Prevention Economics model to project HIV prevalence.

Participants:

HIV-infected adults.

Measurements:

Projected cancer rates and burden among HIV-infected adults in the United States by age during 2006 to 2030 for AIDS-defining cancer (ADC)—that is, Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer—and certain types of non–AIDS-defining cancer (NADC). All other cancer types were combined.

Results:

The proportion of adult PLWH in the United States aged 65 years or older is projected to increase from 8.5% in 2010 to 21.4% in 2030. Age-specific rates are projected to decrease through 2030 across age groups for Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer, lung cancer, Hodgkin lymphoma, and other cancer types combined, and among those aged 65 years or older for colon cancer. Prostate cancer rates are projected to increase. The estimated total cancer burden in PLWH will decrease from 8150 cases in 2010 (2730 of ADC and 5420 of NADC) to 6690 cases in 2030 (720 of ADC and 5980 of NADC). In 2030, prostate cancer (n = 1590) and lung cancer (n = 1030) are projected to be the most common cancer types.

Limitation:

Projections assume that current trends in cancer incidence rates, HIV transmission, and survival will continue.

Conclusion:

The cancer burden among PLWH is projected to shift, with prostate and lung cancer expected to emerge as the most common types by 2030. Cancer will remain an important comorbid condition, and expanded access to HIV therapies and cancer prevention, screening, and treatment is needed.

Primary Funding Source:

National Cancer Institute.

https://ift.tt/2HZ2sFW

Firearms and Dementia: Clinical Considerations

Many persons in the United States support limiting firearm access for those whose mental illness would place them or others at heightened risk, but less attention has been paid to progressive cognitive impairment and firearm access. For persons with dementia, their family members, and their health care providers, discussions about firearm access strongly parallel discussions about driving. This commentary discusses when persons with dementia need to "give up the keys," be they to a gun safe or a car, and how to do so.

https://ift.tt/2I0BdXy

Prescription Drug Monitoring Programs: Promising Practices in Need of Refinement

All 50 states and the District of Columbia have prescription drug monitoring programs (PDMPs), but their implementation varies and research assessing their effect on opioid misuse, diversion, and overdose is sparse. Thus, the systematic review by Fink and colleagues is a welcome contribution. The editorialists discuss the review, the challenge of assessing PDMP effectiveness, and the reason PDMPs should be viewed as 1 component of a complex strategy to address the opioid crisis.

https://ift.tt/2HWQxs7

Physician Burnout in the Electronic Health Record Era: Are We Ignoring the Real Cause?

The widespread adoption of electronic health records (EHRs) has been perceived as driving physician dissatisfaction and burnout. The authors of this essay present data comparing EHR use in other countries with that in the United States and offer a possible explanation of, and solutions to, a root cause of dissatisfaction with the EHR.

https://ift.tt/2wnZSDS

Transfusion-Transmitted Plasmodium falciparum in a Patient With Sickle Cell Hemoglobinopathy

https://ift.tt/2IpgWOH

Association Between Prescription Drug Monitoring Programs and Nonfatal and Fatal Drug Overdoses A Systematic Review

Background:

Prescription drug monitoring programs (PDMPs) are a key component of the president's Prescription Drug Abuse Prevention Plan to prevent opioid overdoses in the United States.

Purpose:

To examine whether PDMP implementation is associated with changes in nonfatal and fatal overdoses; identify features of programs differentially associated with those outcomes; and investigate any potential unintended consequences of the programs.

Data Sources:

Eligible publications from MEDLINE, Current Contents Connect (Clarivate Analytics), Science Citation Index (Clarivate Analytics), Social Sciences Citation Index (Clarivate Analytics), and ProQuest Dissertations indexed through 27 December 2017 and additional studies from reference lists.

Study Selection:

Observational studies (published in English) from U.S. states that examined an association between PDMP implementation and nonfatal or fatal overdoses.

Data Extraction:

2 investigators independently extracted data from and rated the risk of bias (ROB) of studies by using established criteria. Consensus determinations involving all investigators were used to grade strength of evidence for each intervention.

Data Synthesis:

Of 2661 records, 17 articles met the inclusion criteria. These articles examined PDMP implementation only (n = 8), program features only (n = 2), PDMP implementation and program features (n = 5), PDMP implementation with mandated provider review combined with pain clinic laws (n = 1), and PDMP robustness (n = 1). Evidence from 3 studies was insufficient to draw conclusions regarding an association between PDMP implementation and nonfatal overdoses. Low-strength evidence from 10 studies suggested a reduction in fatal overdoses with PDMP implementation. Program features associated with a decrease in overdose deaths included mandatory provider review, provider authorization to access PDMP data, frequency of reports, and monitoring of nonscheduled drugs. Three of 6 studies found an increase in heroin overdoses after PDMP implementation.

Limitation:

Few studies, high ROB, and heterogeneous analytic methods and outcome measurement.

Conclusion:

Evidence that PDMP implementation either increases or decreases nonfatal or fatal overdoses is largely insufficient, as is evidence regarding positive associations between specific administrative features and successful programs. Some evidence showed unintended consequences. Research is needed to identify a set of "best practices" and complementary initiatives to address these consequences.

Primary Funding Source:

National Institute on Drug Abuse and Bureau of Justice Assistance.

https://ift.tt/2wpWR6c

Pulmonary Screening in Subjects after the Fontan Procedure

To review the pulmonary findings of the first 51 patients who presented to our interdisciplinary single-ventricle clinic after undergoing the Fontan procedure.

https://ift.tt/2jFNmql

Prevalence of Functional Gastrointestinal Disorders in Children and Adolescents: Comparison Between Rome III and Rome IV Criteria

To assess the prevalence of functional gastrointestinal disorders (FGIDs) in children using Rome IV criteria and to compare the prevalence of FGIDs using Rome IV with Rome III criteria.

https://ift.tt/2FW0NLy

Early oral nutrition in patients with acute pancreatitis: risk assessment for children and adolescents

Ellery et al determined the advantage of early oral nutrition in children with mild acute pancreatitis.1 The authors recognized that early patient-directed oral nutrition in mild acute pancreatitis showed decreased length of time nil per os status and hospitalization without obvious complications, by setting treatment team-directed nutrition as a control. I would like to comment about their study.

https://ift.tt/2FTpqsb

Timing and Stability of Fellowship Choices during Pediatric Residency: A Longitudinal Survey

To determine, among pediatric residents, the timing and stability of decisions to pursue fellowship training and select a specific subspecialty, which can be used to inform strategies to better match the distribution of pediatric subspecialist with the needs of children.

https://ift.tt/2jE785q

Tinea Imbricata

An 8-year-old aboriginal boy living in Gua Musang, Malaysia, presented with a 2-year history of a round, concentric, and scaly rash on his trunk. The rash was itchy and progressively spread to involve approximately 80% of the body surface area. His 32-year-old mother and 1-year-old sister had similar lesions. His history was otherwise unremarkable. Dermatologic examination revealed generalized concentric, annular, scaly, lamellar plaques with an overlapping-ring appearance over his trunk (Figure 1), limbs, and palmoplantar surfaces.

https://ift.tt/2jE7fOo

eCore Software Inc. to attend 2018 ZOLL Summit

Brought to you by eCore Software The 21st ZOLL Summit, put on by ZOLL Medical Corporation will take place from May 8th to the 10th at the Sheraton Denver Downtown Hotel in Denver, Colorado. This is an annual conference hosted by ZOLL each year for customers and individuals alike who are looking to learn more about the latest technology for data management within the EMS industry. Since being founded ...

https://ift.tt/2FTh4Rd

ePro Scheduler- New location-based time clock software

Now Available For Clients With Timekeeping : Location-Based Timeclocks with Geofencing! eCore's new Location-Based Timeclocks for mobile provide an easy solution for managing your field employees that are always on the go. The new Location-Based Timeclocks are equipped with geofencing that keeps you in control even from miles away. How it Works With the new Location-Based Timeclocks, employees ...

https://ift.tt/2FSkjsl

Incorporate 3 C’s of Mobile Communication into your EMS scheduling processes

Brought to you by eCore Software Communicating effectively is a key skill in all professions, but in the EMS industry, it can be the difference between life and death. Effective communication encompasses much more than simply being able to talk to someone. Learning to be an active listener and picking up on non-verbal cues are great skills to have in the field, but when it comes to getting a message ...

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How do EMS agencies increase productivity with automated certification tracking?

Brought to you by eCore Software Each year more requirements are put on the EMS industry to fulfill the need for higher quality EMS professionals. As the U.S. population grows, it becomes more critical for emergency medical services and agencies to keep track of required licenses and certifications and ensure that all documentation is up to date and valid every time employees are on a shift. Usually ...

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Top 6 reasons air medical agencies need EMS employee scheduling software

Brought to you by eCore Software Efficiency and time saving are key in all air medical agencies. The need to create complex schedules and communicate that schedule out to the team in a timely manner is a critical process, which requires the most reliable software and workflows to be in place. Fortunately, with the advancements in technology, the majority of air transport organizations have transitioned ...

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Exploring the Clinical Relevance of Providing Increased Removal of Large Middle Molecules

Dialysis technologies have continued to advance over recent decades; however, these advancements have not always been met with improved patient outcomes. In part, the high morbidity and mortality associated with dialysis have been attributed to a group of uremic toxins, which are described as "difficult to remove." With a new generation of hemodialysis membranes now making meaningful clearance of these molecules possible, it is an apt time to review the clinical relevance of these middle molecules. Our review describes the developments in membrane technology that enable the removal of large middle molecules (molecular mass >15 kD) that is limited with high-flux dialysis membranes. Of the known 58 middle molecules, a literature search identified 27 that have molecular mass >15 kD. This group contains cytokines, adipokines, hormones, and other proteins. These molecules are implicated in chronic inflammation, atherosclerosis, structural heart disease, and secondary immunodeficiency in the literature. Single-center safety and efficacy studies have identified that use of these membranes in maintenance dialysis populations is associated with limited loss of albumin and increased clearance of large middle molecules. Larger, robustly conducted, multicenter studies are now evaluating these findings. After completion of these safety and efficacy studies, the perceived clinical benefits of providing clearance of large middle molecules must be assessed in rigorously conducted, randomized clinical studies.

https://ift.tt/2wuj9nt

Chronic Kidney Disease in India: A Clarion Call for Change

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Glucocorticoids in the Treatment of Glomerular Diseases: Pitfalls and Pearls

Glucocorticoids exert anti-inflammatory and immunosuppressive activities by genomic and nongenomic effects. The classic genomic effects are mediated by cytosolic glucocorticoid receptors that can upregulate the expression of anti-inflammatory proteins in the nucleus (transactivation) or repress the translocation of proinflammatory transcription factors from the cytosol into the nucleus (transrepression). The nongenomic effects are probably mediated by membrane glucocorticoid receptors. Glucocorticoid receptors are expressed also in podocytes and experimental data suggest that glucocorticoids may protect from podocyte injury. Glucocorticoids have a low therapeutic index and may exert a number of time-dependent and dose-dependent side effects. Measures to prevent or attenuate side effects include single-morning administration of short-acting glucocorticoids, dietetic counseling, increasing physical activity, frequent monitoring, and adapting the doses to the clinical conditions of the patient. Synthetic glucocorticoids, either given alone or in combination with other immunosuppressive drugs, are still the cornerstone therapy in multiple glomerular disorders. However, glucocorticoids are of little benefit in C3 glomerulopathy and may be potentially deleterious in patients with maladaptive focal glomerulosclerosis. Their efficacy depends not only on the type and severity of glomerular disease, but also on the timeliness of administration, the dosage, and the duration of treatment. Whereas an excessive use of glucocorticoids can be responsible for severe toxicity, too low a dosage and too short duration of glucocorticoid treatment can result in false steroid resistance.

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Chimeric Antigen Receptor T Cell Therapy and the Kidney: What the Nephrologist Needs to Know

https://ift.tt/2jE9iC4

Treatment Choices for Hepatitis C in Patients with Kidney Disease

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Immunoglobulin G-Degrading Enzyme of Streptococcus pyogenes (IdeS), Desensitization, and the Kidney Allocation System: Complementary Approaches to Increase Transplantation in Highly HLA Sensitized Patients

https://ift.tt/2jD4EEp

Management of Severe Hyponatremia with Continuous Renal Replacement Therapies

https://ift.tt/2I4hk1I

Management of Membranous Nephropathy in the PLA2R Era

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Protecting Donors and Safeguarding Altruism in the United States: The Living Donor Protection Act

https://ift.tt/2wlzri5

Awareness of Racial Disparities in Kidney Transplantation among Health Care Providers in Dialysis Facilities

Background and objectives

Despite the important role that health care providers at dialysis facilities have in reducing racial disparities in access to kidney transplantation in the United States, little is known about provider awareness of these disparities. We aimed to evaluate health care providers' awareness of racial disparities in kidney transplant waitlisting and identify factors associated with awareness.

Design, setting, participants, & measurements

We conducted a cross-sectional analysis of a survey of providers from low-waitlisting dialysis facilities (n=655) across all 18 ESRD networks administered in 2016 in the United States merged with 2014 US Renal Data System and 2014 US Census data. Awareness of national racial disparity in waitlisting was defined as responding "yes" to the question: "Nationally, do you think that African Americans currently have lower waitlisting rates than white patients on average?" The secondary outcome was providers' perceptions of racial difference in waitlisting at their own facilities.

Results

Among 655 providers surveyed, 19% were aware of the national racial disparity in waitlisting: 50% (57 of 113) of medical directors, 11% (35 of 327) of nurse managers, and 16% (35 of 215) of other providers. In analyses adjusted for provider and facility characteristics, nurse managers (versus medical directors; odds ratio, 7.33; 95% confidence interval, 3.35 to 16.0) and white providers (versus black providers; odds ratio, 2.64; 95% confidence interval, 1.39 to 5.02) were more likely to be unaware of a national racial disparity in waitlisting. Facilities in the South (versus the Northeast; odds ratio, 3.05; 95% confidence interval, 1.04 to 8.94) and facilities with a low percentage of blacks (versus a high percentage of blacks; odds ratio, 1.86; 95% confidence interval, 1.02 to 3.39) were more likely to be unaware. One quarter of facilities had >5% racial difference in waitlisting within their own facilities, but only 5% were aware of the disparity.

Conclusions

Among a limited sample of dialysis facilities with low waitlisting, provider awareness of racial disparities in kidney transplant waitlisting was low, particularly among staff who may have more routine contact with patients.

https://ift.tt/2jCTP54

HLA-DQ Mismatching and Kidney Transplant Outcomes

Background and objectives

Recent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined.

Design, setting, participants, & measurements

Using the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection.

Results

A total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P<0.01), but not in deceased kidney donor recipients (HR, 1.05; 95% CI, 0.98 to 1.12; P=0.18) (P value for interaction <0.01). When taking cold ischemic time into account, HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P=0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P=0.49) (P value for interaction <0.01). Recipients with one or two HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P<0.01) in deceased donor and 1.14 (95% CI, 1.03 to 1.27; P=0.02) in living donor kidney transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not.

Conclusions

HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.

https://ift.tt/2I4DUHF

The Effect of Learning Styles on Adverse Events in Home Hemodialysis Patients

https://ift.tt/2rslDNW

Add-On Antihypertensive Medications to Angiotensin-Aldosterone System Blockers in Diabetes: A Comparative Effectiveness Study

Background and objectives

In individuals with diabetes, the comparative effectiveness of add-on antihypertensive medications added to an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on the risk of significant kidney events is unknown.

Design, setting participants, & measurements

We used an observational, multicenter cohort of 21,897 individuals with diabetes to compare individuals who added β-blockers, dihydropyridine calcium channel blockers, loop diuretics, or thiazide diuretics to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. We examined the hazard of significant kidney events, cardiovascular events, and death using Cox proportional hazard models with propensity score weighting. The composite significant kidney event end point was defined as the first occurrence of a ≥30% decline in eGFR to an eGFR<60 ml/min per 1.73 m², initiation of dialysis, or kidney transplant. The composite cardiovascular event end point was defined as the first occurrence of hospitalization for acute myocardial infarction, acute coronary syndrome, stroke, or congestive heart failure; coronary artery bypass grafting; or percutaneous coronary intervention, and it was only examined in those free of cardiovascular disease at baseline.

Results

Over a maximum of 5 years, there were 4707 significant kidney events, 1498 deaths, and 818 cardiovascular events. Compared with thiazide diuretics, hazard ratios for significant kidney events for β-blockers, calcium channel blockers, and loop diuretics were 0.81 (95% confidence interval, 0.74 to 0.89), 0.67 (95% confidence interval, 0.58 to 0.78), and 1.19 (95% confidence interval, 1.00 to 1.41), respectively. Compared with thiazide diuretics, hazard ratios of mortality for β-blockers, calcium channel blockers, and loop diuretics were 1.19 (95% confidence interval, 0.97 to 1.44), 0.73 (95% confidence interval, 0.52 to 1.03), and 1.67 (95% confidence interval, 1.31 to 2.13), respectively. Compared with thiazide diuretics, hazard ratios of cardiovascular events for β-blockers, calcium channel blockers, and loop diuretics compared with thiazide diuretics were 1.65 (95% confidence interval, 1.39 to 1.96), 1.05 (95% confidence interval, 0.80 to 1.39), and 1.55 (95% confidence interval, 1.05 to 2.27), respectively.

Conclusions

Compared with thiazide diuretics, calcium channel blockers were associated with a lower risk of significant kidney events and a similar risk of cardiovascular events.

https://ift.tt/2wlJyUj

Secular Trends in Infection-Related Mortality after Kidney Transplantation

Background and objectives

Infections are the most common noncardiovascular causes of death after kidney transplantation. We analyzed the current infection-related mortality among kidney transplant recipients in a nationwide cohort in Finland.

Design, setting, participants, & measurements

Altogether, 3249 adult recipients of a first kidney transplant from 1990 to 2012 were included. Infectious causes of death were analyzed, and the mortality rates for infections were compared between two eras (1990–1999 and 2000–2012). Risk factors for infectious deaths were analyzed with Cox regression and competing risk analyses.

Results

Altogether, 953 patients (29%) died during the follow-up, with 204 infection-related deaths. Mortality rate (per 1000 patient-years) due to infections was lower in the more recent cohort (4.6; 95% confidence interval, 3.5 to 6.1) compared with the older cohort (9.1; 95% confidence interval, 7.6 to 10.7); the incidence rate ratio of infectious mortality was 0.51 (95% confidence interval, 0.30 to 0.68). The main causes of infectious deaths were common bacterial infections: septicemia in 38% and pulmonary infections in 45%. Viral and fungal infections caused only 2% and 3% of infectious deaths, respectively (such as individual patients with Cytomegalovirus pneumonia, Herpes simplex virus meningoencephalitis, Varicella zoster virus encephalitis, and Pneumocystis jirovecii infection). Similarly, opportunistic bacterial infections rarely caused death; only one death was caused by Listeria monocytogenes, and two were caused by Mycobacterium tuberculosis. Only 23 (11%) of infection-related deaths occurred during the first post-transplant year. Older recipient age, higher plasma creatinine concentration at the end of the first post-transplant year, diabetes as a cause of ESKD, longer pretransplant dialysis duration, acute rejection, low albumin level, and earlier era of transplantation were associated with increased risk of infectious death in multivariable analysis.

Conclusions

The risk of death due to infectious causes after kidney transplantation in Finland dropped by one half since the 1990s. Common bacterial infections remained the most frequent cause of infection-related mortality, whereas opportunistic viral, fungal, or unconventional bacterial infections rarely caused deaths after kidney transplantation.

https://ift.tt/2jDb6Lx

Hydroxychloroquine Use and Risk of CKD in Patients with Rheumatoid Arthritis

Background and objectives

Hydroxychloroquine is widely used in patients with rheumatoid arthritis. However, large-scale studies examining the long-term effects of hydroxychloroquine on the development of kidney disease in patients with rheumatoid arthritis are lacking. We aimed to assess the long-term association of hydroxychloroquine use with the risk of developing CKD in this population.

Design, setting, participants, & measurements

We conducted an observational cohort study for patients with newly diagnosed rheumatoid arthritis who were enrolled prospectively in Taiwan's National Health Insurance Research Database between January 1, 2000 and December 31, 2013. We used multivariable Cox proportional hazard regression to analyze the association of hydroxychloroquine use with incident CKD.

Results

A total of 2619 patients, including 1212 hydroxychloroquine users and 1407 hydroxychloroquine nonusers, were analyzed. Incident CKD was reported in 48 of 1212 hydroxychloroquine users and 121 of 1407 hydroxychloroquine nonusers. The incidence rate of CKD was lower in hydroxychloroquine users than in hydroxychloroquine nonusers (10.3 versus 13.8 per 1000 person-years). After multivariable adjustment, hydroxychloroquine users still had a lower risk of incident CKD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.90; P=0.01) than hydroxychloroquine nonusers. The lower risk of subsequent CKD development was dose dependent and consistent across subgroup analyses.

Conclusions

Hydroxychloroquine use in patients with newly diagnosed rheumatoid arthritis is associated with a significantly lower risk of incident CKD compared with in nonusers.

https://ift.tt/2wnlsZn

Survey of Kidney Biopsy Clinical Practice and Training in the United States

Background and Objectives

Practicing clinical nephrologists are performing fewer diagnostic kidney biopsies. Requiring biopsy procedural competence for graduating nephrology fellows is controversial.

Design, Setting, Participants, & Measurements

An anonymous, on-line survey of all Walter Reed training program graduates (n=82; 1985–2017) and all United States nephrology program directors (n=149; August to October of 2017), regarding kidney biopsy practice and training, was undertaken.

Results

Walter Reed graduates' response and completion rates were 71% and 98%, respectively. The majority felt adequately trained in native kidney biopsy (83%), transplant biopsy (82%), and tissue interpretation (78%), with no difference for ≤10 versus >10 practice years. Thirty-five percent continued to perform biopsies (13% did ≥10 native biopsies/year); 93% referred at least some biopsies. The most common barriers to performing biopsy were logistics (81%) and time (74%). Program director response and completion rates were 60% and 77%. Seventy-two percent cited ≥1 barrier to fellow competence. The most common barriers were logistics (45%), time (45%), and likelihood that biopsy would not be performed postgraduation (41%). Fifty-one percent indicated that fellows should not be required to demonstrate minimal procedural competence in biopsy, although 97% agreed that fellows should demonstrate competence in knowing/managing indications, contraindications, and complications. Program directors citing ≥1 barrier or whose fellows did <50 native biopsies/year in total were more likely to think that procedural competence should not be required versus those citing no barriers (P=0.02), or whose fellows performed ≥50 biopsies (P<0.01).

Conclusions

Almost two-thirds of graduate respondents from a single military training program no longer perform biopsy, and 51% of responding nephrology program directors indicated that biopsy procedural competence should not be required. These findings should inform discussion of kidney biopsy curriculum requirements.

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Performance on the Nephrology In-Training Examination and ABIM Nephrology Certification Examination Outcomes

Background and objectives

Medical specialty and subspecialty fellowship programs administer subject-specific in-training examinations to provide feedback about level of medical knowledge to fellows preparing for subsequent board certification. This study evaluated the association between the American Society of Nephrology In-Training Examination and the American Board of Internal Medicine Nephrology Certification Examination in terms of scores and passing status.

Design, setting, participants, & measurements

The study included 1684 nephrology fellows who completed the American Society of Nephrology In-Training Examination in their second year of fellowship training between 2009 and 2014. Regression analysis examined the association between In-Training Examination and first-time Nephrology Certification Examination scores as well as passing status relative to other standardized assessments.

Results

This cohort included primarily men (62%) and international medical school graduates (62%), and fellows had an average age of 32 years old at the time of first completing the Nephrology Certification Examination. An overwhelming majority (89%) passed the Nephrology Certification on their first attempt. In-Training Examination scores showed the strongest association with first-time Nephrology Certification Examination scores, accounting for approximately 50% of the total explained variance in the model. Each SD increase in In-Training Examination scores was associated with a difference of 30 U (95% confidence interval, 27 to 33) in certification performance. In-Training Examination scores also were significantly associated with passing status on the Nephrology Certification Examination on the first attempt (odds ratio, 3.46 per SD difference in the In-Training Examination; 95% confidence interval, 2.68 to 4.54). An In-Training Examination threshold of 375, approximately 1 SD below the mean, yielded a positive predictive value of 0.92 and a negative predictive value of 0.50.

Conclusions

American Society of Nephrology In-Training Examination performance is significantly associated with American Board of Internal Medicine Nephrology Certification Examination score and passing status.

https://ift.tt/2wjpnq7