Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data

Abstract

Objective

We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy.

Methods

A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered.

Results

The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively.

Conclusions

This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

https://ift.tt/2RnIWmy

Cavitary Pulmonary Nodules in an Immunocompromised Patient With Urothelial Carcinoma of the Bladder

A 59-year-old Moroccan man with a history of metastatic urothelial cell carcinoma presented in May 2016 with fever, shortness of breath, and chest pain. Noninvasive urothelial carcinoma had been diagnosed in 2012 and treated with mitomycin. In 2014, the patient had received intravesicular Mycobacterium bovis BCG therapy, but invasive bladder carcinoma subsequently developed, requiring 4 cycles of chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. Nine months before the current admission, the patient underwent a radical cystoprostatectomy with creation of a neobladder. Nonetheless, brain metastases developed, for which he received dexamethasone (4 mg orally, twice daily), and underwent neurosurgical resection 3 months before presentation, followed by whole-brain irradiation. He continued receiving intermittent dexamethasone therapy until his admission to our hospital.

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In the Literature

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Clostridium difficile infection perceptions and practices: a multicenter qualitative study in South Africa

Clostridium difficile infection (CDI) is understudied in limited resource settings. In addition, provider awareness of CDI as a prevalent threat is unknown. An assessment of current facilitators and barriers to C...

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The effects on thermal lesion shape and size from bubble clouds produced by acoustic droplet vaporization

Bubbles formed by acoustic droplet vaporization (ADV) have proven to be an effective method for significant enlargement of the thermal lesions produced by high intensity focused ultrasound (HIFU). We investiga...

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Gene-Environment Interplay in Child Eating Behaviors: What the Role of “Nature” Means for the Effects of “Nurture”

Abstract

Purpose of Review

This narrative review describes the evidence for both genetic and environmental influences on child appetitive traits and suggests ways of thinking about how these interact and correlate to influence how a child eats.

Recent Findings

Emerging evidence from social network analysis, and from longitudinal studies questioning the direction of association between parent feeding behaviors and child obesity risk, suggest that children's genes may shape the environmental risk for obesity that they are exposed to.

Summary

There is strong evidence that child appetitive traits are both heritable and shaped by the environment. Instead of thinking about how genetic and environmental factors operate independently on each appetitive trait, research needs to expand the current paradigm to examine how genes and environments interact and shape each other.

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Genetics of anophthalmia and microphthalmia. Part 2: Syndromes associated with anophthalmia–microphthalmia

Abstract

As new genes for A/M are identified in the genomic era, the number of syndromes associated with A/M has greatly expanded. In this review, we provide a brief synopsis of the clinical presentation and molecular genetic etiology of previously characterized pathways involved in A/M, including the Sex-determining region Y-box 2 (SOX2), Orthodenticle Homeobox 2 (OTX2) and Paired box protein-6 (PAX6) genes, and the Stimulated by retinoic acid gene 6 homolog (STRA6), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and RA Receptor Beta (RARβ) genes that are involved in retinoic acid synthesis. Less common genetic causes of A/M, including genes involved in BMP signaling [Bone Morphogenetic Protein 4 (BMP4), Bone Morphogenetic Protein 7 (BMP7) and SPARC-related modular calcium-binding protein 1 (SMOC1)], genes involved in the mitochondrial respiratory chain complex [Holocytochrome c-type synthase (HCCS), Cytochrome C Oxidase Subunit 7B (COX7B), and NADH:Ubiquinone Oxidoreductase subunit B11 (NDUFB11)], the BCL-6 corepressor gene (BCOR), Yes-Associated Protein 1 (YAP1) and Transcription Factor AP-2 Alpha (TFAP2α), are more briefly discussed. We also review several recently described genes and pathways associated with A/M, including Smoothened (SMO) that is involved in Sonic hedgehog (SHH) signaling, Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) and Solute carrier family 25 member 24 (SLC25A24), emphasizing phenotype–genotype correlations and shared pathways where relevant.

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Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Audience: Consumer, Health Professional, Pharmacy October 26, 2018 -- Aurobindo Pharma Limited is voluntarily recalling 22 Batches of the drug substance Irbesartan due to the presence of an impurity, N-nitrosodiethylamine (NDEA). The impurity, which...

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Rhythmic auditory cues shape neural network recruitment in Parkinson's disease during repetitive motor behavior

European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.


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Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Audience: Consumer, Health Professional, Pharmacy October 26, 2018 -- Aurobindo Pharma Limited is voluntarily recalling 22 Batches of the drug substance Irbesartan due to the presence of an impurity, N-nitrosodiethylamine (NDEA). The impurity, which...

https://ift.tt/2SsXRNP

A case of Alemtuzumab-induced neutropenia in multiple sclerosis in association with the expansion of large granular lymphocytes

Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to β-interferon. It acts against CD52, leading primarily t...

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No polymorphisms in K13-propeller gene associated with artemisinin resistance in Plasmodium falciparum isolated from Brazzaville, Republic of Congo

In the Republic of Congo, artemisinin-based combinations have been recommended for the treatment of uncomplicated malaria since 2006. However, the emergence of resistant parasites again these combinations in S...

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Blood-borne and sexually transmitted infections: a cross-sectional study in a Swiss prison

Incarcerated people carry a high burden of infection, including blood-borne diseases (BBDs). It is also known that one million people contract a sexually transmitted infection (STI) every day worldwide, which ...

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Quality control implementation for universal characterization of DNA and RNA viruses in clinical respiratory samples using single metagenomic next-generation sequencing workflow

In recent years, metagenomic Next-Generation Sequencing (mNGS) has increasingly been used for an accurate assumption-free virological diagnosis. However, the systematic workflow evaluation on clinical respirat...

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Fomite-mediated transmission as a sufficient pathway: a comparative analysis across three viral pathogens

Fomite mediated transmission can be an important pathway causing significant disease transmission in number of settings such as schools, daycare centers, and long-term care facilities. The importance of these ...

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PPM1D Functions as Oncogene and is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma

Abstract

Mounting evidence has demonstrated that PPM1D participates in the development and progression of a wide variety of tumors. However, its precise roles in esophageal squamous cell carcinoma (ESCC) remain under investigation. Here, UALCAN, an interactive web-portal to perform the expression analyses of PPM1D using TCGA gene expression data, and PPM1D high expression was exhibited in primary esophageal cancer. Further investigation revealed that PPM1D expression was obviously higher in ESCC tissues than in normal tissues (P < 0.01), which was consistent with the results from real-time qPCR and Western blotting in ESCC tissues and paired normal esophageal tissues. Besides, PPM1D expression was closely correlated with TNM staging, tumor differentiation and lymph node metastasis (P < 0.01), but not related to the patients' gender and age (P > 0.05). Notably, PPM1D expression in metastatic ESCC patients was markedly higher than that in non-metastatic ESCC patients (P < 0.01), and the ESCC patients with high PPM1D expression predicted poor prognosis. Multivariate assay demonstrated that PPM1D and lymph node metastasis were considered as independent prognostic factors for the ESCC patients. These findings suggest PPM1D plays a pivotal important role in onset and progression of ESCC, and may be a new biomarker for metastasis and prognosis of the ESCC patients.

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A Mathematical Model of How People Solve Most Variants of the Number‐Line Task

Cognitive Science, EarlyView.


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Is Syntax Semantically Constrained? Evidence From a Grammaticality Judgment Study of Indonesian

Cognitive Science, EarlyView.


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Prognostic Significance of Anatomic Origin and Evaluation of Survival Statistics of Astrocytoma Patients—a Tertiary Experience

Abstract

Astrocytoma constitutes the most noted malignancies of the central nervous system with worse clinical outcomes in grade IV astrocytoma or glioblastoma multiforme. Owing to poor clinical outcomes with existing therapeutic regime, there is a need to revisit the initial course of treatment. Statistical information of clinicopathological parameters could be used to understand the spread of disease and, in turn, to formulate updated treatment management. In the present study, we have seen anatomic distribution of astrocytoma subtypes in a group of 479 patients and correlated it with survival outcomes. Anatomic location was confirmed by MRI (magnetic resonance imaging) images. A registry of patients was maintained with clinicopathological details as tumor type, location, age/sex, and survival after surgery. We have observed overall survival particulars in patients diagnosed with astrocytoma. Our findings highlight that in total cases, tumor location was anatomically dominated by frontal and temporal lobes. Survival analysis in high-grade (grade III, p = 0.03; grade IV, p = 0.01) astrocytic tumors confirms poor outcomes with temporal, parietal, and occipital location as compared to frontal lobe. Overall survival study demonstrates glioblastoma multiforme (GBM) was associated with worse prognosis as compared to astrocytoma subtypes (p < 0.0001). In high-grade astrocytomas, anaplastic astrocytoma was found with 34 months of median survival age while 14 months in the case of patients with glioblastoma multiforme. In conclusion, we report dismal prognosis in parietal, temporal, and occipital lobes in grade II, grade III, and grade IV astrocytoma patients. Among astrocytoma subtypes, patients with glioblastoma multiforme were associated with worse survival outcomes. We uniquely feature the survival of astrocytoma patients for the first time and observe GBM patients have slightly longer survival.

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Predominance of triple wild-type and IGF2R mutations in mucosal melanomas

Abstract

Background

Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.

Methods

Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.

Results

Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).

Conclusions

These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

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Phenomic Selection Is a Low-Cost and High-Throughput Method Based on Indirect Predictions: Proof of Concept on Wheat and Poplar

Genomic selection - the prediction of breeding values using DNA polymorphisms - is a disruptive method that has widely been adopted by animal and plant breeders to increase productivity. It was recently shown that other sources of molecular variations such as those resulting from transcripts or metabolites could be used to accurately predict complex traits. These endophenotypes have the advantage of capturing the expressed genotypes and consequently the complex regulatory networks that occur in the different layers between the genome and the phenotype. However, obtaining such omics data at very large scales, such as those typically experienced in breeding, remains challenging. As an alternative, we proposed using near-infrared spectroscopy (NIRS) as a high-throughput, low cost and non-destructive tool to indirectly capture endophenotypic variants and compute relationship matrices for predicting complex traits, and coined this new approach "phenomic selection" (PS). We tested PS on two species of economic interest (Triticum aestivum L. and Populus nigra L.) using NIRS on various tissues (grains, leaves, wood). We showed that one could reach predictions as accurate as with molecular markers, for developmental, tolerance and productivity traits, even in environments radically different from the one in which NIRS were collected. Our work constitutes a proof of concept and provides new perspectives for the breeding community, as PS is theoretically applicable to any organism at low cost and does not require any molecular information.

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Training Population Optimization for Prediction of Cassava Brown Streak Disease Resistance in West African Clones

Cassava production in the central, southern and eastern parts of Africa is under threat by cassava brown streak virus (CBSV). Yield losses of up to 100% occur in cases of severe infections of edible roots. Easy illegal movement of planting materials across African countries, and long-range movement of the virus vector (Bemisia tabaci) may facilitate spread of CBSV to West Africa. Thus, effort to pre-emptively breed for CBSD resistance in W. Africa is critical. Genomic selection (GS) has become the main approach for cassava breeding, as costs of genotyping per sample have declined. Using phenotypic and genotypic data (genotyping-by-sequencing), followed by imputation to whole genome sequence (WGS) for 922 clones from National Crops Resources Research Institute, Namulonge, Uganda as a training population (TP), we predicted CBSD symptoms for 35 genotyped W. African clones, evaluated in Uganda. The highest prediction accuracy (r = 0.44) was observed for cassava brown streak disease severity scored at three months (CBSD3s) in the W. African clones using WGS-imputed markers. Optimized TPs gave higher prediction accuracies for CBSD3s and CBSD6s than random TPs of the same size. Inclusion of CBSD QTL chromosome markers as kernels, increased prediction accuracies for CBSD3s and CBSD6s. Similarly, WGS imputation of markers increased prediction accuracies for CBSD3s and for cassava brown streak disease root severity (CBSDRs), but not for CBSD6s. Based on these results we recommend TP optimization, inclusion of CBSD QTL markers in genomic prediction models, and the use of high-density (WGS-imputed) markers for CBSD predictions across population.

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Albumin infusion in spontaneous bacterial peritonitis: another brick off the wall?

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Hemodynamic support in the early phase of septic shock: a review of challenges and unanswered questions

Improving sepsis support is one of the three pillars of a 2017 resolution according to the World Health Organization (WHO). Septic shock is indeed a burden issue in the intensive care units. Hemodynamic stabil...

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Practical approach to diastolic dysfunction in light of the new guidelines and clinical applications in the operating room and in the intensive care

There is growing evidence both in the perioperative period and in the field of intensive care (ICU) on the association between left ventricular diastolic dysfunction (LVDD) and worse outcomes in patients. The ...

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Fluoroscopy-guided simultaneous distal perfusion as a preventive strategy of limb ischemia in patients undergoing extracorporeal membrane oxygenation

Limited data are available regarding prevention of limb ischemia in femorally cannulated patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO). We investigated the association between strategy...

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Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients

Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients

Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients, Published online: 30 October 2018; doi:10.1038/s41416-018-0320-6

Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients

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WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer

WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer

WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer, Published online: 30 October 2018; doi:10.1038/s41416-018-0317-1

WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer

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Successfull treatment of Saksenaea sp. osteomyelitis by conservative surgery and intra-diaphysal incorporation of amphotericin B cement beads. [Clinical Therapeutics]

Osteoarticular mucormycosis are quite rare and challenging infections mostly due to direct inoculation during traumatic injury in immunocompetent patients. Their classical management includes a combination of aggressive surgical debridement that may lead to amputation and long-term systemic liposomal amphotericin B therapy. This article describes successful treatment of a Saksenaea sp. osteomyelitis in a patient with diabetes mellitus with a combination of systemic antifungal agents and a conservative surgery with insertion of amphotericin-impregnated cement beads.

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Vaginal gel component hydroxyethyl cellulose significantly enhances the infectivity of Chlamydia trachomatis serovars D and E [Mechanisms of Action]

The transmission of the urogenital serovars of Chlamydia trachomatis can be significantly influenced by vaginal gels. Hydroxyethyl cellulose is a commonly used gelling agent which can be found in vaginal gels. Hydroxyethyl cellulose showed a concentration dependent growth enhancing effect on Chlamydia trachomatis serovars D and E with a 26.1 fold maximal increase in vitro and a 2.57 fold increase in vivo.

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Ceftobiprole Activity against Gram-Positive and -Negative Pathogens Collected from the United States Across a Decade: 2006 and 2016 [Susceptibility]

Ceftobiprole is an advanced cephalosporin with potent activity against Gram-positive and Gram-negative bacteria that is approved in many European and non-European countries to treat community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). This study reports on the activity of ceftobiprole against a large set of clinical isolates from hospitalized patients in the United States in 2016 that caused serious infections including pneumonia, bacteremia, and skin and skin structure infections. To assess any potential temporal changes in ceftobiprole activity, the 2016 results were compared to corresponding MIC data from a 2006 U.S. survey that included key target pathogens. Ceftobiprole exhibited potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus isolates that were 99.3% susceptible), coagulase-negative staphylococci (100% susceptible), Enterococcus faecalis (100% susceptible), Streptococcus pneumoniae (99.7% susceptible), and other tested streptococci. Similarly, ceftobiprole was highly active against Enterobacteriaceae isolates that did not exhibit an ESBL phenotype, including Escherichia coli (99.8% susceptible) and Klebsiella pneumoniae (99.6% susceptible). Against Haemophilus influenzae and Moraxella catarrhalis, 99.6% of all isolates were inhibited at ≤1 mg/L of ceftobiprole, and 72.7% of the Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. With the exception of decreased cephalosporin susceptibility among the Enterobacteriaceae, which correlates with an increased prevalence of ESBL-producing isolates, ceftobiprole had similar activity against the isolate sets collected in 2006 and 2016. Therefore, ceftobiprole remains highly active when tested in vitro against a large number of current Gram-positive and Gram-negative pathogens that cause serious infections.

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In Vitro Activity of Plazomicin against Gram-negative and Gram-positive Bacterial Pathogens Isolated from Patients in Canadian Hospitals from 2013 to 2017: CANWARD Surveillance Study [Susceptibility]

The Clinical and Laboratory Standards Institute (CLSI) broth microdilution method was used to evaluate the in vitro activities of plazomicin and comparator antimicrobial agents against 7,712 Gram-negative and 4,481 Gram-positive bacterial pathogens obtained from patients in Canadian hospitals (CANWARD, 2013 to 2017). Plazomicin demonstrated potent in vitro activity against Enterobacteriaceae (MIC₉₀ ≤1 µg/ml for all species tested except Proteus mirabilis and Morganella morganii), including aminoglycoside non-susceptible, extended-spectrum β-lactamase (ESBL)-positive, and multidrug-resistant (MDR) isolates. Plazomicin was equally active against methicillin-susceptible and methicillin-resistant isolates of Staphylococcus aureus.

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In Vivo Efficacy of Humanized WCK 5222 (Cefepime-Zidebactam) Exposures Against Carbapenem-Resistant Acinetobacter baumannii in the Neutropenic Thigh Model [Experimental Therapeutics]

Herein we describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against carbapenem-resistant Acinetobacter baumannii in a neutropenic murine thigh infection model. Five of six isolates examined expressed OXA-23 or OXA-24. WCK 5222, despite showing MICs 16 – 64 mg/L, produced remarkable in vivo activity; human-simulated exposure showed a decline in bacterial burden for all isolates [mean reduction -2.09 ± 1.01 log₁₀ CFU/thigh], while lack of activity was observed with cefepime and zidebactam monotherapies.

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Applying Rapid Whole Genome Sequencing to Predict Phenotypic Antimicrobial Susceptibility Testing Results Among Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates [Mechanisms of Resistance]

Objective: Standard antimicrobial susceptibility testing (AST) approaches lead to delays in the selection of optimal antimicrobial therapy. We sought to determine the accuracy of antimicrobial resistance (AMR) determinants identified by Nanopore whole genome sequencing in predicting AST results.

Methods: Using a cohort of 40 clinical isolates (21 carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae, 10 non-carbapenemase-producing carbapenem resistant K. pneumoniae, and 9 carbapenem-susceptible K. pneumoniae), three separate sequencing and analysis pipelines were performed: (1) a real-time Nanopore analysis approach identifying acquired AMR genes, (2) an assembly-based Nanopore approach identifying acquired AMR genes and chromosomal mutations, and (3) an approach using short read correction of Nanopore assemblies. The short read correction of Nanopore assemblies served as the reference standard to determine the accuracy of Nanopore sequencing results.

Results: With the real-time analysis approach, full annotation of acquired AMR genes occurred within 8 hours of subcultured isolates. Assemblies sufficient for full resistance gene and single nucleotide polymorphism annotation were available within 14 hours from subcultured isolates. The overall agreement of genotypic results and anticipated AST results for the 40 K. pneumoniae isolates was 77% (range 30-100%) and 92% (range 80-100%) for the real-time approach and the assembly approach, respectively. Evaluating the patients contributing the 40 isolates, the real-time approach and assembly approach could shorten the median time to effective antibiotic therapy by 20 hours and 26 hours, respectively, compared to standard AST.

Conclusions: Nanopore sequencing offers a rapid approach to both accurately identify resistance mechanisms as well as predict AST results for K. pneumoniae isolates. Bioinformatics improvements enabling real-time alignment coupled with rapid extraction and library preparation will further enhance the accuracy and workflow of the Nanopore real-time approach.

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Single-dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers [Pharmacology]

Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial Type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double strand cleavages in bacteria. We report results from two Phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin, and the absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed with a T_max between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg, and less than dose proportionally between 800 and 4000 mg. Urinary excretion of unchanged zoliflodacin was >5.0% of the total dose. In the fed state, absorption was delayed (T_max 4 h), accompanied by an increase in the AUC at 1500 and 3000 mg doses. In the ADME study (3000 mg PO), the PK profile of zoliflodacin had similar exposure (AUC and C_max) to the ascending dose study and a median T_max of 2.5 hours. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon the safety, PK, and the PK/PD targets, a dosage regimen was selected for evaluation in a Phase 2 study in urogenital gonorrhea.

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Zidovudine-mediated autophagy inhibition enhances mitochondrial toxicity in muscle cells [Antiviral Agents]

Nucleoside reverse transcriptase inhibitors (NRTI) such as zidovudine (AZT) are constituents of HIV-1 therapy and prevention of mother to child transmission. Prolonged thymidine analogues exposure has been associated with mitochondrial toxicities to heart, liver, and skeletal muscle. We hypothesized that the thymidine analogue AZT might interfere with autophagy in myocytes, a lysosomal degradation pathway implicated in regulation of mitochondrial recycling, cell survival and the pathogenesis of myodegenerative diseases. The impact of AZT and lamivudine (3TC) on C2C12 myocyte autophagy was studied using various methods based on LC3-GFP overexpression or LC3 staining in combination with western blotting, flow cytometry and confocal and electron microscopy. Lysosomal and mitochondrial functions were studied using appropriate staining for lysosomal mass, acidity, cathepsin activity as well as mitochondrial mass and membrane potential in combination with flow cytometry and confocal microscopy. AZT, but not 3TC, exerted a significant dose and time-dependent inhibitory effect on late stages of autophagosome maturation, which was reversible upon mTOR inhibition. Inhibition of late autophagy at therapeutic drug concentrations led to dysfunctional mitochondria accumulation with membrane hyperpolarization and increased ROS generation, and ultimately compromised cell viability. These AZT effects could be readily replicated by pharmacological and genetic inhibition of myocyte autophagy and most importantly rescued by pharmacological stimulation of autophago-lysosomal biogenesis. Our data suggest that the thymidine analogue AZT inhibits autophagy in myocytes, which in turn leads to accumulation of dysfunctional mitochondria with increased ROS generation and compromised cell viability. This novel mechanism could contribute to our understanding of the long-term side effects of antiviral agents.

https://ift.tt/2qe8KWW

Azidothymidine produces synergistic activity in combination with colistin against antibiotic-resistant Enterobacteriaceae [Experimental Therapeutics]

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae is prevalent and extremely difficult to treat. Reusing existing drugs and rejuvenating the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here we investigated in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae including extended-spectrum beta-lactamase (ESBL), New Delhi metallo-beta-lactamase 1 (NDM) or the mobilized colistin resistance (mcr-1) producing strains. Minimum inhibitory concentration was determined using the broth microdilution method. The combinatory effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. Fractional inhibitory concentration index from checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae, respectively, 100% of NDM-1-producing strains and 92% of mcr-1 producing E. coli. Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In the murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. AZT and colistin combination poses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.

https://ift.tt/2CMgpDj

Inhibition of Cytomegalovirus Replication with Extended Half-Life Synthetic Ozonides [Antiviral Agents]

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication in vitro, but therapeutic success in humans has been variable. We hypothesized that the short in vivo half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV in vitro and mouse CMV (MCMV) in vivo. Screening of four ozonides against HCMV Towne pp28-luciferase recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting 50% viral growth (EC₅₀) was 9.8±0.2 µM, and cytotoxicity in non-infected human fibroblasts (CC₅₀) was 128.1±8.0 µM. In plaque reduction assays, OZ418 inhibited HCMV TB40 in a concentration-dependent manner as well as a ganciclovir (GCV)-resistant HCMV. The combination of OZ418 and ganciclovir (GCV) was synergistic in HCMV inhibition in vitro. Virus inhibition by OZ418 occurred at early stage and was dependent on cell density at the time of infection. OZ418 treatment reversed HCMV-mediated cell cycle progression and correlated with reduction of HCMV-induced expression of pRb, E2F1 and CDKs 1, 2, 4, and 6. In a MCMV model, once daily oral administration of OZ418 had significantly improved efficacy against MCMV as compared to twice daily oral AS. A parallel pharmacokinetic study with a single oral dose of OZ418 or AS showed a prolonged plasma half-life and higher unbound concentrations of OZ418 compared to AS. In summary, ozonides are proposed as potential therapeutics, alone or in combination with GCV, for HCMV infection in humans.

https://ift.tt/2qe8Gqa

Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus [Antiviral Agents]

NVR 3-778 is the first Capsid Assembly Modulator (CAM) that has demonstrated antiviral activity in HBV infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA containing virus particles with a mean antiviral EC₅₀ of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pgRNA encapsidation, viral replication and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC₅₀ values of 0.81 µM against HBV DNA and between 3.7 to 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achievable in mice and thus enabling efficacy studies in vivo. The overall preclinical profile of NVR 3-778 predicted antiviral activity in vivo and supported further evaluation for safety, pharmacokinetics, and antiviral activity in HBV infected patients.

https://ift.tt/2CMgpTP

Miltefosine reduces the cytolytic activity and virulence of Acinetobacter baumannii [Experimental Therapeutics]

Stagnation in antimicrobial development has led to a serious threat to public health in which some Acinetobacter baumannii infections have become untreatable. New therapeutics with alternative mechanisms of action to combat A. baumannii are therefore necessary to treat these infections. To this end, the virulence of A. baumannii isolates with varying antimicrobial susceptibilities was assessed when treated with miltefosine, a phospholipase C inhibitor. Phospholipase C activity is a contributor to A. baumannii virulence associated with hemolysis, cytolysis of A549 human alveolar epithelial cells and increased mortality in the Galleria mellonella experimental infection model. While the effects on bacterial growth were variable amongst strains, miltefosine treatment significantly reduced both the hemolytic and cytolytic activity of all treated A. baumannii strains. Additionally, scanning electron microscopy of polarized A549 cells infected with bacteria of the A. baumannii ATCC 19606^T strain or the AB5075 multidrug resistant isolate showed decrease in A549 cell damage with a concomitant increase in the presence of A549 surfactant upon administration of miltefosine. The therapeutic ability of miltefosine is further supported by the results of G. mellonella infections wherein miltefosine treatment of animals infected with ATCC 19606^T significantly decreased mortality. These data demonstrate that inhibition of phospholipase C activity results in the overall reduction of A. baumannii virulence in both in vitro and in vivo models making miltefosine a viable option for treatment of A. baumannii infections, particularly those caused by multidrug resistant isolates.

https://ift.tt/2qe8CGW

Emergence of resistance to macrolides and rifampicin in clinical isolates of Rhodococcus equi from foals in central Kentucky, USA: 1995 to 2017 [Epidemiology and Surveillance]

Objective: To determine the prevalence of R. equi strains resistant to macrolides and rifampicin over time in clinical samples from foals submitted to diagnostic laboratories in central Kentucky.

Methods: Retrospective observational study of all clinical samples from foals that were submitted to veterinary diagnostics laboratories in Kentucky between January 1995 and December 2017. Samples were included if R. equi was cultured and tested for in vitro susceptibility to erythromycin or rifampicin.

Results: In vitro susceptibility to erythromycin was available for 2169 isolates of R. equi while susceptibility to both erythromycin and rifampicin was available for 1681 isolates. Rifampicin resistance was first detected in 2000 and erythromycin resistance was first detected in 2004. Between 1995 and 2006, the proportion of resistant isolates of R. equi was 0.7% for erythromycin and 2.3% for rifampicin. There was a significant (P <0.001) increase in the proportion of resistant R. equi between 2007 and 2017, with 13.6% of isolates being resistant to erythromycin and 16.1% being resistant to rifampicin. Between 2007 and 2017, isolates of R. equi resistant to erythromycin or rifampicin were significantly less likely to be isolated from feces than from the respiratory tract, other soft tissues, or musculoskeletal infections.

Conclusions: The considerable increase in the prevalence of isolates of R. equi resistant to macrolides and rifampicin since 2007 is of concern for both human and animal health.

https://ift.tt/2CNS4x0

Spontaneous mutational frequency and FKS mutation rates vary by echinocandin agent against Candida glabrata [Mechanisms of Resistance]

Echinocandins are front-line agents for treatment of invasive candidiasis. There are no reported agent-specific differences in Candida mutational frequency of resistance or propensity to develop FKS mutations. The objective of this study was to measure spontaneous and FKS mutation rates among Candida glabrata. Twenty bloodstream isolates from patients with or without prior echinocandin exposure were included. Minimum inhibitory (MIC), minimum fungicidal (MFC) and mutation prevention concentrations were higher for caspofungin than anidulafungin (P<0.0001) and micafungin (P<0.0001). Mutational frequencies of resistance at 3x baseline MIC were highest for caspofungin and lowest for micafungin. Two-hundred and forty-seven isolates were recovered at or above the MFC for caspofungin (n=159), anidulafungin (n=74), or micafungin (n=14). Agent-specific MIC increases were noted for anidulafungin and caspofungin, but not micafungin. Thirty-three percent of isolates harbored hot spot mutations in FKS1 (n=6) or FKS2 (n=76). Mutations at the Ser629 (Fks1) or Ser663 (Fks2) loci were more common following selection with anidulafungin or micafungin than with caspofungin (P = 0.003). Four isolates demonstrated >4-fold increases in MICs without FKS hot spot mutations; 3 of these harbored Fks2 mutations upstream of hot spot 1. The final isolate was FKS1 and FKS2 wild-type, but IC₅₀s of caspofungin and micafungin were increased 2.7-fold and 8-fold, respectively. In conclusion, micafungin may be superior in vitro to the other agents in limiting the emergence of resistance among C. glabrata. On the other hand, caspofungin exposure may be most likely to promote resistance development. These data provide a foundation for future investigations of newly-developed echinocandin agents.

https://ift.tt/2qiWIeL

Population pharmacokinetic model and limited sampling strategies for personalized dosing of levofloxacin in tuberculosis patients [Clinical Therapeutics]

Levofloxacin is an anti-tuberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate area under the concentration curve for the 24 h dosing interval (AUC_0-24) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach.

The popPK model and Bayesian LSS were developed using data of 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum timespan 8 h, minimum interval 1 h, 1 to 3 samples) were tested. Performance criteria were root mean squared error (RMSE) <15%, mean prediction error (MPE) <5%, and r² > 0.95.

A one compartment model with lag time best described the data while only slightly underestimating the AUC_0-24 (mean –7.9%, SE 1.7%). The Bayesian LSS using 0 and 5 h post-dose samples (RMSE 8.8%, MPE 0.42%, r² 0.957) adequately estimated the AUC_0-24 with a mean underestimation of –4.4% (SE 2.7%). The multiple linear regression LSS using 0 and 4 h post-dose samples (RMSE 7.0%, MPE 5.5%, r² 0.977) was internally validated with a mean underestimation of -0.46% (SE 2.0%).

In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin.

https://ift.tt/2CMrp3o

Outcomes by Minimum Inhibitory Concentrations for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials [Susceptibility]

This pooled analysis evaluated the relationship of isavuconazole and voriconazole minimum inhibitory concentrations (MICs) of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with MICs ≥16 µg/mL, but there was no relationship in cases where the MIC was <16 µg/mL with clinical outcomes for either drug.

https://ift.tt/2qe8xmC

Use of Translational PK/PD Infection Models to Understand Impact of Neutropenia on Efficacy of Tedizolid Phosphate [Pharmacology]

Tedizolid phosphate, the prodrug of the active antibiotic tedizolid, is an oxazolidinone for the treatment of acute bacterial skin and skin structure infections. Studies in a mouse thigh infection model demonstrated improved potency and pharmacokinetics-pharmacodynamics (PK/PD) vs linezolid. Subsequent studies showed that the efficacy of tedizolid was enhanced in immune competent (IC) compared with neutropenic (IS) mice, with stasis at clinically relevant doses being achieved only in the presence of granulocytes. The tedizolid label therefore contains a warning about use in neutropenic patients. This study reevaluated the PK/PD of tedizolid and linezolid in the mouse thigh infection model in IC and IS mice using a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591) and a methicillin-susceptible S. aureus (MSSA) strain (ATCC 29213). The antistaphylococcal effect of doses ranging from 1–150 mg/kg of tedizolid (once daily) or linezolid (twice daily) was determined at 24, 48, and 72 hours after initiating treatment. In IC mice, stasis was achieved in the absence of antibiotics, and both tedizolid and linezolid reduced the burden further beyond a static effect. In IS mice, tedizolid achieved stasis at 72 hours at a human clinical dose of 200 mg against MRSA ATCC 33591 and MSSA ATCC 29213, several-fold lower than in earlier studies. Linezolid achieved a static effect against MRSA ATCC 33591 in IS mice at a dose lower than that used clinically. This study demonstrates that with time both tedizolid and linezolid at clinically relevant exposures achieve stasis in neutropenic mice with MRSA or MSSA thigh infection.

https://ift.tt/2CNfjXW

Efficacy of azithromycin and miltefosine in experimental systemic pythiosis in immunosuppressed mice [Experimental Therapeutics]

We evaluated the efficacy of azithromycin (50 mg/kg q12h orally) and miltefosine (25 mg/kg q24h orally) treatment in an experimental model of vascular/disseminated pythiosis in immunosuppressed mice. Azithromycin was the only treatment able to reduce mortality. Histopathological findings showed acute vascular inflammation, pathogen dissemination, necrotizing myositis, neuritis, and arteritis. The results suggest that azithromycin, but not miltefosine, may have clinical relevance in the treatment of vascular/disseminated pythiosis.

https://ift.tt/2qhTyYE

Optimization of cellulase production under solid‐state fermentation by a new mutant strain of Trichoderma reesei

Food Science &Nutrition, EarlyView.


https://ift.tt/2yGLYvz

Low Levels of Flu Reported in U.S. From May to October

MONDAY, Oct. 29, 2018 -- From May 20 to Oct. 13, 2018, low levels of influenza activity were reported in the United States, according to a study published online Oct. 25 in Morbidity and Mortality Weekly Report. Eric J. Chow, M.D., from the U.S....

https://ift.tt/2DbDbpd

Prospective Genotyping of Hepatocellular Carcinoma: Clinical Implications of Next Generation Sequencing for Matching Patients to Targeted and Immune Therapies

Purpose:: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Methods: Matched tumor/normal DNA from HCC patients (N=127) were analyzed using a hybridization capture-based, NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: WNT/β-catenin pathway (45%) and TP53 (35%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib treated patients (N=81), oncogenic PI3K-MTOR pathway alterations were associated with lower disease control rates (DCR, 8.3 vs. 40.2%), shorter median PFS (1.9 vs 5.3 months) and OS (10.4 vs 17.9 months). For patients treated with immune checkpoint inhibitors (N=31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0 vs 53%), shorter median PFS (2.0 vs 7.4 months) and OS (9.1 vs 15.2 months). 24% of patients harbored potentially actionable alterations including TSC1/2 (8.5%)inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (<1%). 6% of patients treated with systemic therapy were matched to targeted therapeutics. Conclusion: Linking NGS to routine clinical care has the potential to identify those HCC patients likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.

https://ift.tt/2OjsYbu

A Novel Engineered Small Protein for Positron Emission Tomography Imaging of Human Programmed Death Ligand-1 : Validation in Mouse Models and Human Cancer Tissues

Purpose: To design and evaluate a small engineered protein binder targeting human programmed death-1 ligand (hPD-L1) in vivo for PET imaging in four mouse tumor models, and in situ in human cancer specimens. Experimental Design: The hPD-L1 protein binder, FN3hPD-L1, was engineered using a 12 kDa human fibronectin type-3 domain (FN3) scaffold. The binder's affinity was assayed in CT26 mouse colon carcinoma cells stably expressing hPD-L1 (CT26/hPD-L1). 64Cu-FN3hPD-L1 was assayed for purity, specific activity, and immunoreactivity. Four groups of NSG mice (n=3-5/group) were imaged with 64Cu-FN3hPD-L1 PET imaging (1-24 hours post-injection of 3.7 MBq/7 μg of Do-FN3 in 200 µL PBS): Nod SCID Gamma (NSG) mice bearing (1) syngeneic CT26/hPD-L1tumors, (2) CT26/hPD-L1 tumors blocked (blk) by pre-injected non-radioactive FN3hPD-L1 binder, (3) hPD-L1-negative Raji xenografts, and (4) MDA-MB-231 xenografts. The FN3hPD-L1 binder staining was evaluated against validated hPD-L1 antibodies by immunostaining in human cancer specimens. Results: FN3hPD-L1 bound hPD-L1 with 1.4±0.3 nM affinity in CT26/hPD-L1 cells. 64Cu-FN3hPD-L1 radiotracer showed >70% yield and >95% purity. 64Cu-FN3hPD-L1 PET imaging of mice bearing CT26/hPD-L1 tumors showed tumor-to-muscle ratios of 5.6±0.9 and 13.1±2.3 at 1 and 4 hours post-injection, respectively. The FN3hPD-L1 binder detected hPD-L1 expression in human tissues with known hPD-L1 expression status based on two validated antibodies. Conclusions: The 64Cu-FN3hPD-L1 radiotracer represents a novel, small, and high-affinity binder for imaging hPD-L1 in tumors. Our data support further exploration and clinical translation of this binder for non-invasive identification of cancer patients who may respond to immune checkpoint blockade therapies.

https://ift.tt/2Of7fBj

Ibrutinib therapy releases leukemic surface IgM from antigen drive in chronic lymphocytic leukemia patients.

Purpose:In chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably down-modulated in vivo and recover in vitro, suggesting a reversible influence of tissue-located antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM. Experimental Design: We investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of CLL patients. Results: At week 1, there was a significant increase of sIgM expression (64% increase from pre-therapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, sIgD and a range of other receptors, did not change. SIgM levels remained higher than pre-therapy in the following 3 months, despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK which lies upstream of BTK in the B-Cell Receptor pathway. Conclusions: This specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy.

https://ift.tt/2yI4inR

Fetal/Neonatal Pericardial Effusion in Down's Syndrome: Case Report and Review of Literature

AJP Rep 2018; 08: e301-e306
DOI: 10.1055/s-0038-1675337

We report a preterm (35 4/7 weeks) male neonate with Down's syndrome (DS) diagnosed with isolated pericardial effusion (PE) at 20 weeks of gestation. He was born by precipitous delivery, needed no resuscitation and presented within first 24 hours of life with respiratory distress, anemia due to feto-maternal bleed, hypotension, hepatomegaly, and coagulopathy. Postnatal echocardiography confirmed a 5 mm rim of PE without tamponade, normal cardiac structure, and function. He was stabilized with ventilation, packed red cell, fresh frozen plasma, inotropes (dopamine, dobutamine, and adrenaline), and steroid (hydrocortisone). Subsequent evaluation confirmed hypothyroidism, transient myeloproliferative disorder (TMD), hepatic failure due to fibrosis/cirrhosis with portal hypertension, and steroid sensitive hypotension on two occasions possibly due to adrenal insufficiency. PE completely resolved over 2 weeks. In view of progressively worsening liver failure with ascites and portal hypertension, the family opted for palliation. Literature review has been discussed regarding perinatal onset of PE in DS.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Clinical Insights for Cervical Ripening and Labor Induction Using Prostaglandins

AJP Rep 2018; 08: e307-e314
DOI: 10.1055/s-0038-1675351

Cervical ripening is often the first component of labor induction and is used to facilitate the softening and thinning of the cervix in preparation for labor. Common methods used for cervical ripening include both mechanical (e.g., Foley or Cook catheters) and pharmacologic (e.g., prostaglandins) methods. The choice of method(s) for ripening should take into account the patient's medical and obstetric history, clinical characteristics, and risk of adverse effects if uterine tachysystole were to occur. In this narrative review, we highlight the differences between the prostaglandins dinoprostone and misoprostol with respect to pharmacology and pharmacokinetics, efficacy, and potential safety concerns. Practical guidance on choosing an appropriate prostaglandin agent for cervical ripening and labor induction is provided via the use of clinical vignettes. Considering the advantages and disadvantages of each preparation allows clinicians to individualize treatment, depending on the indications for induction and unique characteristics of each patient.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Importance of Individual Elements for Perineal Protection in Childbirth: An Interventional, Prospective Trial

AJP Rep 2018; 08: e289-e294
DOI: 10.1055/s-0038-1675352

Objective To analyze the association between each element of a hands-on intervention in childbirth and the incidence of obstetric anal sphincter injuries (OASIS). Study Design We conducted a prospective, interventional quality improvement project and implemented a care bundle with five elements at an obstetric department in Denmark with 3,000 deliveries annually. We aimed at reducing the incidence of OASIS. In the preintervention period, 355 vaginally delivering nulliparous women were included. Similarly, 1,622 nulliparous women were included in the intervention period. The association of each element with the outcome was estimated using a regression analysis. Results The incidence of OASIS went down from 7.0 to 3.4% among nulliparous women delivering vaginally (p = 0.003; relative risk = 0.48; 95% confidence interval [CI]: 0.30–0.76). Number needed to treat was 28. Logistic regression analysis showed that using hand on the head of the child significantly reduced the risk of OASIS (odds ratio = 0.28; 95% CI: 0.14–0.58). Conclusion Using a quality improvement framework, we documented the individual elements of the intervention. Hand on the infant's head reduced the risk of OASIS.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Comparison of Birth Outcomes by Gestational Diabetes Screening Criteria

AJP Rep 2018; 08: e280-e288
DOI: 10.1055/s-0038-1675343

Objectives This study is to examine the association between different diagnostic criteria for gestational diabetes mellitus (GDM) and adverse birth outcomes. Study Design A retrospective cohort study of 5,937 women with a singleton pregnancy was conducted, who completed GDM screening between 24 to 32 weeks gestational age. Four nonoverlapping groups of women defined as: 1) Normal: glucose challenge test (GCT) <130 mg/dL, 2) elevated GCT + normal oral glucose tolerance test (OGTT): abnormal 1 hour GCT + normal 3 hour OGTT, 3) GDM/International Association of Diabetes in Pregnancy Study Group (IADPSG): abnormal 3 hour OGTT by the IADPSG criteria, and 4) GDM/Carpenter-Coustan (CC): diagnosis per CC criteria. We used logistic regression to examine the association between GDM group classification and main outcome of macrosomia and secondary birth outcomes. Results Prevalences were GDM/CC 4.6%, GDM/IADPSG 3.0, and 7.6% overall. GDM/IADPSG group was associated with increased macrosomia (adj OR [odd ratio] 1.87; 95% CI [confidence interval]: 1.08–3.25; p = 0.02), while GDM/CC group was associated with increased preterm birth (adj OR 1.75; 95% CI: 1.05–2.80; p = 0.03). Conclusion Little difference in birth outcomes was found between the two criteria, GDM/CC and GDM/IADPSG. Randomized controlled trials are needed to clarify the risks and benefits of these screening paradigms before their incorporation into clinical practice.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Early-Onset Neonatal Sepsis with Extended Spectrum Beta-Lactamase Producing Escherichia Coli in Infants Born to South and South East Asian Immigrants: A Case Series

AJP Rep 2018; 08: e277-e279
DOI: 10.1055/s-0038-1675336

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae represent a major worldwide threat. We present three cases of early onset ESBL Escherichia coli sepsis in infants born to families from South and Southeast Asia to inform the practitioner community about this emerging threat. Infants with suspected sepsis, whose mother is from Asia or Southeast Asia, should be suspected of having an infection with an ESBL-producing organism, and practitioners should strongly consider adding a carbapenem to their usual initial antibiotic regimen.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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Fetal MRI in the Identification of a Fetal Ventral Wall Defect Spectrum

AJP Rep 2018; 08: e264-e276
DOI: 10.1055/s-0038-1675353

Objective To ascertain if useful criteria for prenatal diagnosis of fetal ventral body wall defects (VBWDs) exists by reviewing published literature on diagnosis of VBWD as compared with our own diagnostic experience. Study Design A comprehensive literature review of diagnostic criteria of fetal VBWD including pentalogy of Cantrell (POC), omphalocele, exstrophy, imperforate anus, spina bifida (OEIS), cloacal exstrophy, limb–body wall complex (LBWC), and body stalk anomaly was performed followed by a retrospective review of all fetal magnetic resonance imaging (MRI) examinations from our medical center over a 2-year period. Results Classically, OEIS is omphalocele, bladder exstrophy, imperforate anus, and spina bifida. POC is defects of the supraumbilical abdomen, sternum, diaphragm, pericardium, and heart. LBWC is two of the following: exencephaly or enencephaly with facial clefts, thoracoschisis or abdominoschisis, and limb defects. Twenty-four cases of VBWD on MRI over a 24-month period were identified with seven cases involving defects of additional organ systems. Six of these seven cases demonstrated findings from two or more of the traditional diagnoses POC, OEIS, and LBWC making diagnosis and counseling difficult. Conclusion There is a lack of consensus on useful diagnostic criteria within the published literature which is reflected in our own diagnostic experience and poses a challenge for accurate prenatal counseling.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
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An Out-of-Season Case of Coxsackie B Myocarditis with Severe Rhabdomyolysis

A 21-year-old woman was found to have fulminant myocarditis as a result of Coxsackie B infection (a virus shown to exhibit summer-fall seasonality) in mid-December. In this case report, seasonality of enteroviruses is examined, as well as additional factors which may contribute to sporadic cases during winter months. The case report also discusses clinical criteria for endomyocardial biopsy, utility of PCR vs. antibody serological tests, coinfection with multiple serotypes, and rhabdomyolysis in Coxsackie B.

https://ift.tt/2OfhoOf

Loss of GAS5 tumour suppressor lncRNA: an independent molecular cancer biomarker for short-term relapse and progression in bladder cancer patients

https://ift.tt/2qklYBv

WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer

https://ift.tt/2CN015u

Radiation Dose-Response For Risk Of Myocardial Infarction In Breast Cancer Survivors

Previous reports suggest that radiotherapy for breast cancer (BC) can cause ischemic heart disease, with radiation-related risk increasing linearly with mean whole heart dose (MWHD). This study aimed to validate these findings and assesses additional risk factors for radiation-related myocardial infarction (MI) in a case-control study nested within a cohort of BC survivors treated ≤70 years of age during 1970-2009. The study confirms a linear relationship between MWHD and MI risk after radiation for BC.

https://ift.tt/2yEXKpW

Coronary flow reserve in patients with Primary Biliary Cholangitis

It is still not clear whether primary biliary cholangitis (PBC) is associated with abnormalities of the cardiovascular system. We aimed to assess the relationship between PBC and coronary flow reserve (CFR).

https://ift.tt/2AzCCmH

ERECTILE DYSFUNCTION IN COMPENSATED LIVER CIRRHOSIS

Data on erectile dysfunction (ED) in cirrhotic patients are limited as yet. Aim of this study was to investigate the prevalence of ED and the factors potentially involved in its development in compensated cirrhosis.

https://ift.tt/2ENEv3i

Endosheath ultrathin transnasal endoscopy is a cost-effective method for screening for Barrett’s esophagus in patients with GERD symptoms

Barrett's esophagus (BE) screening is currently not considered to be cost effective in the general population but may be effective in high-risk subgroups, such as 50-year-old white men with chronic reflux disease (GERD). A new modality for screening is unsedated transnasal endoscopy using endosheath technology (uTNE), which has been shown to be safe and effective in clinical practice. In this study, we determined the cost-utility of uTNE in a high-risk subgroup compared with no screening or screening with standard endoscopy (SE).

https://ift.tt/2AzsD0t

Physical–Mental Comorbidity of Pediatric Migraine in the Philadelphia Neurodevelopmental Cohort

To examine the associations between headaches and migraine with physical and mental disorders in a large pediatric registry.

https://ift.tt/2Q3FJZb

PCORnet Bariatric Surgery Outcomes: Strength in Numbers

In this issue, a study done in the National Patient-Centered Clinical Research Network compares weight loss outcomes up to 5 years after Roux-en-Y gastric bypass, sleeve gastrectomy, and adjustable gastric banding. The editorialists discuss the ways in which the findings should affect decisions about bariatric treatment and questions future studies should aim to answer.

https://ift.tt/2D90xM0

Clinical Outcomes Associated With Sickle Cell Trait A Systematic Review

Background:

Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes.

Purpose:

To evaluate associations between SCT and clinical outcomes in children and adults.

Data Sources:

English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles.

Study Selection:

Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality.

Data Extraction:

A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus.

Data Synthesis:

Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low.

Limitation:

Publication bias was possible, and high-quality evidence was scant.

Conclusion:

Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT.

Primary Funding Source:

National Human Genome Research Institute.

https://ift.tt/2Da9Awb

Reducing Firearm Injuries and Deaths in the United States: A Position Paper From the American College of Physicians

For more than 20 years, the American College of Physicians (ACP) has advocated for the need to address firearm-related injuries and deaths in the United States. Yet, firearm violence continues to be a public health crisis that requires the nation's immediate attention. The policy recommendations in this paper build on, strengthen, and expand current ACP policies approved by the Board of Regents in April 2014, based on analysis of approaches that the evidence suggests will be effective in reducing deaths and injuries from firearm-related violence.

https://ift.tt/2Jntm7T

Expanding the Public Health Approach to Gun Violence Prevention

The editorialist discusses the American College of Physicians' position paper on reducing the public health crisis of firearm-related injury and how the focus and efforts of physicians and others should consider additional factors to help address the crisis.

https://ift.tt/2Dc0LC7

What Can I Do as a Physician to Prevent Firearm Injury?

This issue includes a position paper from the American College of Physicians on the health care crisis of firearm-related injury and a research study assessing perceptions of the problem among physicians and the public. The editorialist describes how and why he asks his patients about firearm safety in his medical practice.

https://ift.tt/2JoUinB

On-Demand Sildenafil as a Treatment for Raynaud Phenomenon A Series of n -of-1 Trials

Background:

Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk–benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative.

Objective:

To assess the efficacy and safety of on-demand sildenafil in RP.

Design:

Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360)

Setting:

Outpatients at a French university hospital.

Participants:

Patients with primary or secondary RP.

Intervention:

Each trial consisted of a multiple crossover study in a single patient. Repeat blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily.

Measurements:

Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy.

Results:

38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients.

Limitation:

The response to sildenafil was substantially heterogeneous among patients.

Conclusion:

Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP.

Primary Funding Source:

GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.

https://ift.tt/2JsuJSQ

Comparative Effectiveness and Safety of Bariatric Procedures for Weight Loss A PCORnet Cohort Study

Background:

There has been a dramatic shift in use of bariatric procedures, but little is known about their long-term comparative effectiveness.

Objective:

To compare weight loss and safety among bariatric procedures.

Design:

Retrospective observational cohort study, January 2005 to September 2015. (ClinicalTrials.gov: NCT02741674)

Setting:

41 health systems in the National Patient-Centered Clinical Research Network.

Participants:

65 093 patients aged 20 to 79 years with body mass index (BMI) of 35 kg/m² or greater who had bariatric procedures.

Intervention:

32 208 Roux-en-Y gastric bypass (RYGB), 29 693 sleeve gastrectomy (SG), and 3192 adjustable gastric banding (AGB) procedures.

Measurements:

Estimated percent total weight loss (TWL) at 1, 3, and 5 years; 30-day rates of major adverse events.

Results:

Total numbers of eligible patients with weight measures at 1, 3, and 5 years were 44 978 (84%), 20 783 (68%), and 7159 (69%), respectively. Thirty-day rates of major adverse events were 5.0% for RYGB, 2.6% for SG, and 2.9% for AGB. One-year mean TWLs were 31.2% (95% CI, 31.1% to 31.3%) for RYGB, 25.2% (CI, 25.1% to 25.4%) for SG, and 13.7% (CI, 13.3% to 14.0%) for AGB. At 1 year, RYGB patients lost 5.9 (CI, 5.8 to 6.1) percentage points more weight than SG patients and 17.7 (CI, 17.3 to 18.1) percentage points more than AGB patients, and SG patients lost 12.0 (CI, 11.6 to 12.5) percentage points more than AGB patients. Five-year mean TWLs were 25.5% (CI, 25.1% to 25.9%) for RYGB, 18.8% (CI, 18.0% to 19.6%) for SG, and 11.7% (CI, 10.2% to 13.1%) for AGB. Patients with diabetes, those with BMI less than 50 kg/m², those aged 65 years or older, African American patients, and Hispanic patients lost less weight than patients without those characteristics.

Limitation:

Potential unobserved confounding due to nonrandomized design; electronic health record databases had missing outcome data.

Conclusion:

Adults lost more weight with RYGB than with SG or AGB at 1, 3, and 5 years; however, RYGB had the highest 30-day rate of major adverse events. Small subgroup differences in weight loss outcomes were observed.

Primary Funding Source:

Patient-Centered Outcomes Research Institute.

https://ift.tt/2Da0dg1

Public Perceptions of Firearm- and Non–Firearm-Related Violent Death in the United States: A National Study

https://ift.tt/2JsuI1e

Effectiveness and Safety of Bariatric Procedures for Weight Loss

https://ift.tt/2DaBacQ

Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation A Systematic Review

Background:

The comparative safety and effectiveness of treatments to prevent thromboembolic complications in atrial fibrillation (AF) remain uncertain.

Purpose:

To compare the effectiveness of medical and procedural therapies in preventing thromboembolic events and bleeding complications in adults with nonvalvular AF.

Data Sources:

English-language studies in several databases from 1 January 2000 to 14 February 2018.

Study Selection:

Two reviewers independently screened citations to identify comparative studies of treatments to prevent stroke in adults with nonvalvular AF who reported thromboembolic or bleeding complications.

Data Extraction:

Two reviewers independently abstracted data, assessed study quality and applicability, and rated strength of evidence.

Data Synthesis:

Data from 220 articles were included. Dabigatran and apixaban were superior and rivaroxaban and edoxaban were similar to warfarin in preventing stroke or systemic embolism. Apixaban and edoxaban were superior and rivaroxaban and dabigatran were similar to warfarin in reducing the risk for major bleeding. Treatment effects with dabigatran were similar in patients with renal dysfunction (interaction P > 0.05), and patients younger than 75 years had lower bleeding rates with dabigatran (interaction P < 0.001). The benefit of treatment with apixaban was consistent in many subgroups, including those with renal impairment, diabetes, and prior stroke (interaction P > 0.05 for all). The greatest bleeding risk reduction was observed in patients with a glomerular filtration rate less than 50 mL/min/1.73 m² (P = 0.003). Similar treatment effects were observed for rivaroxaban and edoxaban in patients with prior stroke, diabetes, or heart failure (interaction P > 0.05 for all).

Limitation:

Heterogeneous study populations, interventions, and outcomes.

Conclusion:

The available direct-acting oral anticoagulants (DOACs) are at least as effective and safe as warfarin for patients with nonvalvular AF. The DOACs had similar benefits across several patient subgroups and seemed safe and efficacious for a wide range of patients with nonvalvular AF.

Primary Funding Source:

Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42017069999)

https://ift.tt/2JsuDus

The Gut Microbiome and Digestive Health – A New Frontier

https://ift.tt/2zbAL5A

Egg yolk immunoglobulin interactions with Porphyromonas gingivalis to impact periodontal inflammation and halitosis

Porphyromonas gingivalis is a pathogenic Gram-negative anaerobic bacterium that colonizes the subgingival region of gums. These bacteria can invade periodontal tissues, form plaques, and produce volatile sulfur c...

https://ift.tt/2Su0ZsM

Introduction: Special Issue—The Origins of Macrophages and Their Roles Beyond Immunology

In the context of ontogeny and phylogeny, macrophages emerge much earlier than other hematopoietic cells, including monocytes, implying that their roles extend beyond immunology. Phagocytosis, a representative function of macrophages, has been examined since the late 19th century and such studies were the basis of characterizing innate immunity. Macrophages also make a range of cytokines important in both innate and adaptive immunity. Recently, their non-immunological homeostatic roles in organ development, angiogenesis, tissue repair/regeneration and metabolism have also become clear. This involvement in so many responses in virtually all tissues requires them to be enormously flexible but their phenotypic and functional heterogeneity have made it difficult to delineate the origins of macrophages in specific sites under different circumstances.

https://ift.tt/2yHFSe8

Paramedic Chief Digital: How to improve patient and provider safety on the road

This issue features articles highlighting the importance of patient and provider safety during ambulance transport and the need for an EMS overhaul

https://ift.tt/2OUx2UB

A Loop-mediated Isothermal Amplification (LAMP) Assay for Rapid Identification of Bemisia tabaci

This paper reports the protocol for a rapid identification assay for Bemisia tabaci based on loop-mediated isothermal amplification (LAMP) technology. The protocol requires minimal laboratory training and can, therefore, be implemented on-site at points of entry for plant imports such as seaports and airports.

https://ift.tt/2JoDXPW

Rapid Response: Is EMS response different when the active shooter survives?

Despite the shooter's despicable intent and multiple murders, he becomes another patient to triage, treat and transport

https://ift.tt/2yF6LPR

Cognitive load and emotional processing in psoriasis: a thermal imaging study

Abstract

Psoriasis is a chronic dermatologic disease which is frequently associated with psychological distress. Although studies suggest a relationship between this condition and difficulties in emotion regulation, behavioral and physiological evidence about this link is scarce. We measured implicit emotion regulation abilities of psoriasis patients and a healthy control group by examining the impact of distracting emotional (positive, negative or neutral) images on a working memory task ("Emotional N-Back") which could present high (2-back) or low (1-back) cognitive workload. Moreover, we used Functional Infrared Thermal Imaging to record participants' facial temperature and obtain a measure of the activation of the autonomic system. Rising of temperature over the peri-orbital areas and the nose tip are believed to reflect the activation and the de-activation of the sympathetic system, respectively. Patients scored higher than controls on the "Lack of emotional clarity" sub-scale of the Difficulties in Emotion Regulation Scale. Compared to controls, who performed much better in the low vs. high cognitive load condition, patients showed a smaller accuracy difference between the two conditions. Moreover, patients showed less sympathetic (lower peri-orbital and higher nasal tip temperature) activity (especially in the negative and neutral blocks) during the high vs. low cognitive load condition, suggesting that the former condition might be less emotionally demanding for them. Patients benefit more than controls from the load-dependent interference effect when dealing with emotional information; thus, therapeutic techniques aiming at teaching how to use cognitive strategies to downregulate emotions might be particularly appropriated for them.

https://ift.tt/2yFbpgL

Quantitative Analysis by Thermogravimetry-Mass Spectrum Analysis for Reactions with Evolved Gases

Precise determination of the evolved gases' flow rate is key to study the details of reactions. We provide a novel quantitative analysis method of equivalent characteristic spectrum analysis for thermogravimetry-mass spectrum analysis by establishing the calibration system of the characteristic spectrum and relative sensitivity, for obtaining the flow rate.

https://ift.tt/2Psd8Q9

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

Abstract

Background

Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with ¹⁷⁷Lu-PSMA RLT in a mouse model of prostate cancer.

Methods

Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by ⁶⁸Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) ¹⁷⁷Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints.

Results

Tumor growth was delayed by ARB while ⁶⁸Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT.

Conclusion

ARB-mediated increases in PSMA expression in PC xenografts were evident by ⁶⁸Ga-PSMA11 PET imaging and flow cytometry. ¹⁷⁷Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.

https://ift.tt/2COc820

Integrate Imaging Flow Cytometry and Transcriptomic Profiling to Evaluate Altered Endocytic CD1d Trafficking

Imaging flow cytometry provides an ideal approach to detect the morphological and functional alteration of cells at individual and populational levels. Disrupted endocytic function for lipid antigen presentation in pollutant-exposed human dendritic cells was demonstrated with a combined transcriptomic profiling of gene expression and morphological demonstration of protein trafficking.

https://ift.tt/2qp5p7D

Paid Family Leave Policies May Modestly Increase Breastfeeding

MONDAY, Oct. 29, 2018 -- Women in states with paid family leave (PFL) policies have a modestly greater likelihood of exclusively breastfeeding at six months, according to a study published online Oct. 25 in the American Journal of Public...

https://ift.tt/2zchAsi

Hypofractionated Radiation OK for Localized Prostate CA

MONDAY, Oct. 29, 2018 -- A new clinical guideline for early-stage prostate cancer supports the use of shortened courses of radiation therapy, according to an article published in Practical Radiation Oncology. Scott C. Morgan, M.D., from the...

https://ift.tt/2PsKMW2

Nurse-Led Care Efficacious, Cost-Effective for Gout

MONDAY, Oct. 29, 2018 -- For patients with gout, nurse-led care is efficacious and cost-effective compared with usual care led by general practitioners (GPs), according to a study published Oct. 20 in The Lancet. Michael Doherty, M.D., from the...

https://ift.tt/2zlIYnV

Odds of Overweight/Obesity Up for Children With Autism

MONDAY, Oct. 29, 2018 -- Children with autism spectrum disorder (ASD) have increased odds of overweight/obesity compared with general population controls after adjustment for child co-occurring conditions, according to a study published online Oct....

https://ift.tt/2PrKwGY

ASN: Kidneys Transplanted in France Would Be Discarded in US

MONDAY, Oct. 29, 2018 -- Many kidneys transplanted in France would be discarded in the United States, according to a study presented at the American Society of Nephrology's Kidney Week, held Oct. 23 to 28 in San Diego. Olivier Aubert, M.D., Ph.D.,...

https://ift.tt/2z7wC2g

Durvalumab Extends Survival in Stage III Non-Small Cell Lung CA

MONDAY, Oct. 29, 2018 -- Durvalumab results in significantly longer overall survival than placebo among patients with stage III, unresectable non-small cell lung cancer who did not have disease progression after concurrent chemoradiotherapy,...

https://ift.tt/2PrSM9J

ASN: Home Dialysis Associated With Improved Survival

MONDAY, Oct. 29, 2018 -- Home hemodialysis (HHD) is associated with better survival than in-center hemodialysis (IHD) among incident dialysis patients, according to a study presented at the American Society of Nephrology's Kidney Week, held Oct. 23...

https://ift.tt/2zdFjIJ

Smoking Associated With Head, Neck Surgery Complications

MONDAY, Oct. 29, 2018 -- Smoking is associated with increased rates of postoperative wound disruption and subsequent reoperation among patients undergoing free flap reconstruction of the head and neck, according to a study published online Oct. 18...

https://ift.tt/2PrKv5S

Healthier Diet Tied to Lower Mortality Risk in CRC Patients

MONDAY, Oct. 29, 2018 -- Colorectal cancer (CRC) patients who follow healthy diets before or after diagnosis have a decreased risk for mortality, according to a study published online Oct. 19 in the Journal of Clinical Oncology. Mark A. Guinter,...

https://ift.tt/2z9WScD

In Complicated UTI, Cefiderocol Noninferior to Imipenem-Cilastin

MONDAY, Oct. 29, 2018 -- For complicated urinary tract infections caused by multidrug-resistant Gram-negative uropathogens, the siderophore cephalosporin cefiderocol is non-inferior to imipenem-cilastatin, according to a study published online Oct....

https://ift.tt/2PtbPk9

A Method to Study Adaptation to Left-Right Reversed Audition

The present study proposes a protocol to investigate the adaptation to left-right reversed audition achieved only by wearable devices, using neuroimaging, which can be an effective tool for uncovering the adaptability of humans to a novel environment in the auditory domain.

https://ift.tt/2CNkvuN

Verification of the diagnostic strategy for anterior mediastinal tumors

Abstract

Background

For thymic epithelial tumors (TETs), the National Comprehensive Cancer Network guideline has suggested that complete excision of the tumor should be performed without a preoperative biopsy when resectable. However, little evidence has been provided to support this strategy. The purpose of this study was to review our diagnostic process and to evaluate the validity of radical resection of anterior mediastinal masses (AMMs) without pathological confirmation.

Methods

A total of 254 patients underwent surgical resection for AMMs between 2004 and 2015. This study included 181 patients with likely TETs according to clinical features, serum levels of tumor markers and autoimmune-antibodies, and radiological findings. In addition, AMMs likely TETs were classified into resectable or unresectable tumors. We retrospectively reviewed the diagnostic process of those patients and validated surgical resection of AMMs without a definitive diagnosis.

Results

Among 254 patients, 181 were suspected of having a TET based on the serum levels of tumor markers and autoimmune-antibodies and the radiological findings. Of them, 157 patients were deemed resectable and underwent surgical resection without histological confirmation, and 144 (92%) were diagnosed with TETs in the final pathological examinations. In 13 patients with non-TETs, the tumors were difficult to differentiate from TETs by imaging and clinical findings alone.

Conclusions

A total of 92% of patients suspected of having a TET and who underwent complete resection without pathological confirmation were accurately diagnosed and properly treated. Surgical resection without a definitive diagnosis was feasible in patients suspected of having a TET when they were considered resectable.

https://ift.tt/2zeJp2W

Lentinan inhibits tumor angiogenesis via interferon γ and in a T cell independent manner

Abstract

Background

Antiangiogenic agents are commonly used in lung and colon cancer treatments, however, rapid development of drug resistance limits their efficacy.

Methods

Lentinan (LNT) is a biologically active compound extracted from Lentinus edodes. The effects of LNT on tumor angiogenesis were evaluated by immunohistochemistry in murine LAP0297 lung and CT26 colorectal tumor models. The impacts of LNT on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR, and ELISA. Nude mice and IFNγ blockade were used to investigate the mechanism of LNT affecting on tumor angiogenesis. The data sets were compared using two-tailed student's t tests or ANOVA.

Results

We found that LNT inhibited tumor angiogenesis and the growth of lung and colon cancers. LNT treatments elevated the expression of angiostatic factors such as IFNγ and also increased tumor infiltration of IFNγ-expressing T cells and myeloid cells. Interestingly, IFNγ blockade, but not T cell deficiency, reversed the effects of LNT treatments on tumor blood vessels. Moreover, long-lasting LNT administration persistently suppressed tumor angiogenesis and inhibited tumor growth.

Conclusions

LNT inhibits tumor angiogenesis by increasing IFNγ production and in a T cell-independent manner. Our findings suggest that LNT could be developed as a new antiangiogenic agent for long-term treatment of lung and colon cancers.

https://ift.tt/2OeLi5t

Apigenin suppresses PD-L1 expression in melanoma and host dendritic cells to elicit synergistic therapeutic effects

Abstract

Background

The PD-L1/PD-1 pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma. The present study investigated the effects of the flavonoid apigenin on the PD-L1 expression and the tumorigenesis of melanoma.

Methods

The influence of flavonoids on melanoma cell growth and apoptosis was investigated using cell proliferation and flow cytometric analyses. The differential IFN-γ-induced PD-L1 expression and STAT1 activation were examined in curcumin and apigenin-treated melanoma cells using immunoblotting or immunofluorescence assays. The effects of flavonoid treatment on melanoma sensitivity towards T cells were investigated using Jurkat cell killing, cytotoxicity, cell viability, and IL-2 secretion assays. Melanoma xenograft mouse model was used to assess the impact of flavonoids on tumorigenesis in vivo. Human peripheral blood mononuclear cells were used to examine the influence of flavonoids on PD-L1 expression in dendritic cells and cytotoxicity of cocultured cytokine-induced killer cells by cell killing assays.

Results

Curcumin and apigenin showed growth-suppressive and pro-apoptotic effects on melanoma cells. The IFN-γ-induced PD-L1 upregulation was significantly inhibited by flavonoids, especially apigenin, with correlated reductions in STAT1 phosphorylation. Apigenin-treated A375 cells exhibited increased sensitivity towards T cell-mediated killing. Apigenin also strongly inhibited A375 melanoma xenograft growth in vivo, with enhanced T cell infiltration into tumor tissues. PD-L1 expression in dendritic cells was reduced by apigenin, which potentiated the cytotoxicity of cocultured cytokine-induced killer cells against melanoma cells.

Conclusions

Apigenin restricted melanoma growth through multiple mechanisms, among which its suppression of PD-L1 expression exerted a dual effect via regulating both tumor and antigen presenting cells. Our findings provide novel insights into the anticancer effects of apigenin and might have potential clinical implications.

https://ift.tt/2yHohmD

Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages

Abstract

Background

Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment.

Methods

The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry.

Results

HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8⁺ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8⁺ T cell infiltration into the tumour microenvironment.

Conclusions

HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8⁺ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.

https://ift.tt/2OdojaY

Feasibility, validity and reliability of objective smartphone measurements of physical activity and fitness in patients with cancer

Abstract

Background

A patient's physical function plays a leading role in the treatment prescription for patients with cancer. Objective assessments of physical function may be more predictive for treatment tolerability and survival than frequently used subjective measures, such as the Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance score. The use of smartphones to measure physical activity and fitness may provide an excellent opportunity to objectively estimate a patient's physical function against low costs and little time. We investigated feasibility, validity and reliability of smartphone measurements of step count and physical fitness in patients with cancer.

Methods

In total, 72 patients participated. They wore a smartphone for 14 days to measure the mean number of steps per day, concomitant with an accelerometer during the first 7 days. Patients performed a six-minute walk test (6MWT) twice outdoors via a smartphone application and once in a test environment in the hospital. Feasibility was evaluated by the proportion of patients who completed the study as well as smartphone assessments of step count and physical fitness. Validity was assessed with the intraclass correlation coefficient (ICC) between the accelerometer and the first week of the smartphone for step count, and between the 6MWT in the hospital and via the application for physical fitness. Test-retest reliability was assessed with the ICC between step count levels of the first and second week of smartphone assessments, and between the first and second six-minute walk test in the home environment.

Results

The completeness of smartphone measurements was approximately 90% for step count and 64% for physical fitness assessments. Validity was excellent for step count (ICC = 0.97, p < 0.001) and fair for fitness (ICC = 0.47, p < 0.001). We found excellent test-retest reliability for step count (ICC = 0.91, p < 0.001) and physical fitness (ICC = 0.88, p < 0.001).

Conclusions

This study showed that objective smartphone measurements of step count in clinical practice are feasible, valid and reliable. These findings indicate that the use of smartphones to objectively assess physical activity in clinical cancer practice is promising and may be used to select patients for treatment and study participation, to monitor patients during treatment and to guide treatment decisions.

https://ift.tt/2DadIwe

Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer

Abstract

Background

It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer.

Methods

A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed.

Results

The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1–2 vs. G3 (P_interaction = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy.

Conclusions

This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used.

https://ift.tt/2JruNCo

Effect of COPD on symptoms, quality of life and prognosis in patients with advanced non-small cell lung cancer

Abstract

Background

Many studies have reported the prevalence of chronic obstructive pulmonary disease (COPD) and its effects and prognosis in patients with lung cancer, but few have considered quality of life and survival of patients with lung cancer according to severity of airway obstruction. This study investigated the presence of COPD and the severity of airway obstruction in patients with non-small cell lung cancer (NSCLC), and analyzed how these factors affected symptoms, quality of life, and prognosis.

Methods

We retrospectively reviewed the prospective lung cancer database of the Catholic Medical Centers at the Catholic University of Korea from 2014 to 2017. We enrolled patients with advanced NSCLC and evaluated quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. We also estimated pulmonary function and analyzed survival data.

Results

Of the 337 patients with advanced NSCLC, 170 (50.5%) had COPD and 167 (49.5%) did not. Significant differences were observed in symptoms between the two groups. The COPD group complained of more symptoms, such as cough, sputum, and dyspnea, than those in the non-COPD group. The distribution according to the severity of obstruction in the COPD group was as follows: Grade 1 (FEV₁ ≥ 80%) 35 patients (20.6%), Grade 2 (50% ≤ FEV₁ < 80%) 103 patients (60.6%), Grade 3 (30% ≤ FEV₁ < 50%) 24 patients (14.1%), and Grade 4 (FEV₁ < 30%) 8 patients (4.7%). The presence of COPD did not affect overall quality of life in patients with NSCLC, but as the airway obstruction increased, physical function decreased, and fatigue and dyspnea were more frequent. The overall median survival of the COPD group was shorter than that of the non-COPD group (median survival, 224 vs. 339 days, p = 0.035).

Conclusions

In this study, a high prevalence of COPD was found among patients with advanced NSCLC, and COPD patients complained about various symptoms and had diminished quality of life in several sectors. Therefore, it is necessary to actively evaluate quality of life, lung function, and symptoms in patients with lung cancer and reflect them in the treatment and management plans of these patients.

https://ift.tt/2Dbn5f4