Electrical communication in lymphangions

Contractions of lymphangions, i.e. the segment between two one-way lymphatic valves, generate the pressure gradients that propel lymph back to the circulation. Each lymphangion is comprised of an inner sheet of lymphatic endothelial cells (LECs) circumscribed by one or more layers of lymphatic muscle cells (LMCs). Each contraction is produced by LMC action potentials (APs) that propagate via gap junctions along the lymphangion. Yet, electrical coupling within and between cell layers and the impact on AP-waves is poorly understood.

https://ift.tt/2vpbALN

Electrostatics-driven inflation of elastic icosahedral shells as a model for swelling of viruses

We develop a clear theoretical description of radial swelling in virus-like particles which delineates the importance of electrostatic contributions to swelling in absence of any conformational changes. The model couples the elastic parameters of the capsid – represented as a continuous elastic shell – to the electrostatic pressure acting on it. We show that different modifications of the electrostatic interactions brought about by, for instance, changes in or solution ionic strength, are often sufficient to achieve the experimentally-observed swelling (about 10% of the capsid radius).

https://ift.tt/2APayOi

FEATHER: Automated Analysis of Force Spectroscopy Unbinding/Unfolding Data via a Bayesian Algorithm

Single-molecule force spectroscopy (SMFS) provides a powerful tool to explore the dynamics and energetics of individual proteins, protein-ligand interactions, and nucleic-acid structures. In the canonical assay, a force probe is retracted at constant velocity to induce a mechanical unfolding/unbinding event. Next, two energy landscape parameters, the zero-force dissociation rate constant (ko) and the distance to the transition state (Δx‡), are deduced by analyzing the most probable rupture force as a function of the loading rate, the rate of change in force.

https://ift.tt/2OMRYcl

Gestational weight gain and unplanned or emergency cesarean delivery in the United States

Publication date: Available online 6 August 2018

Source: Women and Birth

Author(s): Zelalem T. Haile, Bhakti Chavan, Asli K. Teweldeberhan, Ilana R. Azulay Chertok, John Francescon

Abstract

Background

In the United States, the rates of cesarean delivery are well above the World Health Organization recommended target. Although obesity is a widely established risk factor for cesarean delivery, there is limited population-based research that examines the relationship between gestational weight gain and cesarean delivery.

Objective

To determine the association between gestational weight gain and unplanned or emergency cesarean delivery.

Methods

We examined 2107 mothers from the Infant Feeding Practices Study II 2005–2007. The Institute of Medicine's current guidelines were used to define categories of gestational weight gain: inadequate (less than the recommended guideline), adequate (within the recommended guideline) and excessive (above the recommended guideline).

Findings

Approximately 49.3% and 13.6% of the participants had excessive weight gain and unplanned or emergency cesarean delivery, respectively. A Greater proportion of women with excessive weight gain had an unplanned or emergency cesarean delivery followed by women with adequate and inadequate weight gain, respectively (17.8%, 10.0%, 8.8%; p < 0.001). In the multivariable model, compared to women with adequate weight gain, the odds of unplanned or emergency cesarean delivery were higher among women with excessive weight gain (OR 1.56, 95% CI 1.07–2.27, p = 0.020).

Discussion

Women with excessive gestational weight gain are more likely to experience an unplanned or emergency cesarean delivery, which increases the risk for poor maternal-infant health outcomes.

Conclusion

It is critical to identify populations at increased risk of unplanned or emergency cesarean delivery and provide preconception and prenatal counseling to achieve and maintain the recommended weight gain for optimal maternal-infant health outcomes.

https://ift.tt/2OPKsxw

Midwives ‘with woman’ in the private obstetric model: Where divergent philosophies meet

Publication date: Available online 6 August 2018

Source: Women and Birth

Author(s): Zoe Bradfield, Michelle Kelly, Yvonne Hauck, Ravani Duggan

Abstract

Background

The phenomenon of being 'with woman' is central to the profession of midwifery. There is currently no available evidence that explicitly explores this phenomenon. In Western Australia, over a third of childbearing women choose to engage the services of a private obstetrician who provides antenatal care and manages the care provided by midwives during labour and birth.

Aim

The aim of this study was to explore midwives' experiences of being 'with woman' during labour and birth in the private obstetric model.

Methods

Using a descriptive phenomenological approach, 11 midwives working in the private obstetric model in Western Australia were interviewed. Data analysis was conducted using Giorgi's framework.

Findings

Two main themes emerged (1) triad of relationships and (2) the intersection between being 'with woman' and the private obstetric model; seven subthemes are reported.

Discussion

Being 'with woman' is an important element of midwifery practice and fundamental to midwifery theory and philosophy. Relationships between the woman, midwife and obstetrician are key to implementing 'with woman' practices in the private obstetric model. The interrelatedness of midwifery philosophy and practice is revealed through shared common challenges and enablers to being 'with woman' from the perspective of midwives.

Conclusion

Findings offer insight into midwives' experiences of being 'with woman' within the context of the private obstetric model. New understandings are revealed of a phenomenon central to midwifery professional philosophy that is embedded within midwifery practices which has implications for service mangers, professional leaders and educators.

https://ift.tt/2Mngi2N

Control of Domain Structures in Multiferroic Thin Films through Defect Engineering

Advanced Materials, EarlyView.


https://ift.tt/2Of94Pe

Coupling Interface Constructions of MoS2/Fe5Ni4S8 Heterostructures for Efficient Electrochemical Water Splitting

Advanced Materials, EarlyView.


https://ift.tt/2vquXnx

Anisotropic Magneto‐Coulomb Properties of 2D–0D Heterostructure Single Electron Device

Advanced Materials, EarlyView.


https://ift.tt/2Mq9UYJ

Bedside End Tidal Carbon Dioxide in Evaluation for Pulmonary Embolism

Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AUYriO

Diabetic nephropathy and hypertension in diabetes patients of sub-Saharan countries: a systematic review and meta-analysis

This meta-analysis was undertaken to estimate the prevalence of diabetic nephropathy and its association with hypertension in diabetics of sub-Saharan African countries.

https://ift.tt/2MpdTVz

Analysis of hippocampal-dependent learning and memory behaviour in mice lacking Nfix from adult neural stem cells

The active place avoidance task (APA) is a behavioural task used to assess learning and memory in rodents. This task relies on the hippocampus, a region of the cerebral cortex capable of generating new neurons...

https://ift.tt/2M9l8nB

A novel technique for isolating DNA from Tempus™ blood RNA tubes after RNA isolation

We use Tempus blood RNA tubes (Applied Biosystems) during health assessments of American moose (Alces alces spp.) as a minimally invasive means to obtain RNA. Here we describe a novel protocol to additionally iso...

https://ift.tt/2MpdRNr

Pension beneficiaries’ household food insecurity and associated factors in Debre Markos town, Northwest Ethiopia

A community based cross-sectional study was conducted from March to April, 2016 in Debre Markos town, Northwest Ethiopia to assess the level of household food insecurity and associated factors among pension be...

https://ift.tt/2OQ47NB

Late antenatal care initiation: the case of public health centers in Ethiopia

The aim of this study was to determine the magnitude of late initiation of antenatal care visit and associated factors among antenatal care follow up women in Tselemte district health facilities. The data were...

https://ift.tt/2Kudlfj

Enzymatic catalysis for sustainable production of high omega‐3 triglyceride oil using imidazolium‐based ionic liquids

Food Science &Nutrition, EarlyView.


https://ift.tt/2nhl9HW

Saturated Fat: Part of a Healthy Diet

Abstract

Purpose of Review

Despite the American public following recommendations to decrease absolute dietary fat intake and specifically decrease saturated fat intake, we have seen a dramatic rise over the past 40 years in the rates of non-communicable diseases associated with obesity and overweight, namely cardiovascular disease. The development of the diet-heart hypothesis in the mid twentieth century led to faulty but long-held beliefs that dietary intake of saturated fat led to heart disease. Saturated fat can lead to increased LDL cholesterol levels, and elevated plasma cholesterol levels have been shown to be a risk factor for cardiovascular disease; however, the correlative nature of their association does not assign causation.

Recent Findings

Advances in understanding the role of various lipoprotein particles and their atherogenic risk have been helpful for understanding how different dietary components may impact CVD risk. Numerous meta-analyses and systematic reviews of both the historical and current literature reveals that the diet-heart hypothesis was not, and still is not, supported by the evidence. There appears to be no consistent benefit to all-cause or CVD mortality from the reduction of dietary saturated fat. Further, saturated fat has been shown in some cases to have an inverse relationship with obesity-related type 2 diabetes.

Summary

Rather than focus on a single nutrient, the overall diet quality and elimination of processed foods, including simple carbohydrates, would likely do more to improve CVD and overall health. It is in the best interest of the American public to clarify dietary guidelines to recognize that dietary saturated fat is not the villain we once thought it was.

https://ift.tt/2KASfvM

Classical syphilitic lesions from the museum

Abstract

Syphilis is an increasingly diagnosed venereal disease which has four distinctive stages that may last over decades if appropriate treatment is not given. Review of the files of the Pathology Museum in the Faculty of Medicine at The University of Adelaide revealed three cases with classical cardiovascular and neurological findings. Case 1: An 80-year-old man with a large syphilitic aneurysm of the ascending aorta with a smaller aneurysm of the proximal descending aorta. Case 2: A 56-year-old man with chronic syphilitic meningoencephalitis with cerebral atrophy. Case 3: A 77-year-old man with tabes dorsalis. Given the increase in cases coming to medical attention in recent years due to high-risk sexual activity, migration, travel and reduced access to medical treatment, an awareness of the classical features of syphilis is appropriate as some cases will undoubtedly require medicolegal evaluation.

https://ift.tt/2vJ7Eod

Rapid Degradation and Non-Selectivity of Dakin's Solution Prevents Effectiveness in Contaminated Musculoskeletal Wound Models

Publication date: Available online 6 August 2018

Source: Injury

Author(s): Lee C. Mangum, Nathan A. Franklin, Gerardo R. Garcia, Kevin S. Akers, Joseph C. Wenke

ABSTRACT

Background

Dakin's solution (buffered sodium hypochlorite) has been used as a topical adjunct for the treatment of invasive fungal infections in trauma patients. Prudent use of Dakin's solution (DS) for complex musculoskeletal wound management implies balancing antimicrobial efficacy and human tissue toxicity, but little empirical evidence exists to inform clinical practice. To identify potentially efficacious DS concentrations and application methods, we conducted two animal studies to evaluate the ability of DS to reduce bacterial burden in small and large animal models of contaminated musculoskeletal wounds.

Methods

An established rat (Rattus norvegicus) contaminated femoral defect model was employed to evaluate the antimicrobial efficacy of DS as a topical adjunctive treatment for Staphylococcus aureus infection. A range of clinically-relevant DS concentrations (0.00025% to 0.125%) were tested, both with and without periodic replenishment during treatment. Next, an established goat (Capra hircus) musculoskeletal wound model, consisting of a Pseudomonas aeruginosa contaminated proximal tibia cortical defect, muscle crush, and thermal injury, was utilized to evaluate the antimicrobial efficacy of dilute DS (0.0025% and 0.025%) as a surgical irrigant solution. In situ reactive chlorine concentrations were monitored throughout each treatment using an automated iodometric titration approach.

Results

In a rat wound model, DS treatment did not significantly reduce S. aureus bioburden after 14 days as compared to saline control. Two treatment groups (0.01% single application and 0.025% multiple application) exhibited significantly higher bacterial burden than control. In a goat musculoskeletal wound model, neither 0.0025% nor 0.025% DS significantly altered P. aeruginosa bioburden immediately following treatment or at 48 hours post-treatment. Overall, DS applied to exposed soft tissue exhibited rapid degradation, e.g., 0.125% DS degraded 32% after 5 seconds progressing to 86% degradation after 15 minutes following single application.

Conclusions

We did not observe evidence of a therapeutic benefit following Dakin's solution treatment for any tested concentration or application method in two contaminated musculoskeletal wound models. Despite confirmation of robust bactericidal activity in vitro, our findings suggest DS at current clinically-used concentrations does not kill tissue surface-attached bacteria, nor does it necessarily cause host tissue toxicity that exacerbates infection in the setting of complex musculoskeletal injury.

https://ift.tt/2Oicfp9

MYBL2 supports DNA double strand break repair in haematopoietic stem cells

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by blood cytopenias that occur as a result of somatic mutations in hematopoietic stem cells (HSC). MDS leads to ineffective haematopoiesis, and as many as 30% of patients progress to acute myeloid leukaemia (AML). The mechanisms by which mutations accumulate in HSC during aging remain poorly understood. Here we identify a novel role for MYBL2 in DNA double-strand break (DSB) repair in HSC. In MDS patients, low MYBL2 levels associated with and preceded transcriptional deregulation of DNA repair genes. Stem/progenitor cells from these patients display dysfunctional DSB repair kinetics after exposure to ionizing radiation (IR). Haploinsufficiency of Mybl2 in mice also led to a defect in the repair of DSB induced by IR in HSC and was characterized by unsustained phosphorylation of the ATM substrate Kap1 and telomere fragility. Our study identifies MYBL2 as a crucial regulator of DSB repair and identifies MYBL2 expression levels as a potential biomarker to predict cellular response to genotoxic treatments in MDS and identify patients with defects in DNA repair. Such patients with worse prognosis may require a different therapeutic regimen to prevent progression to AML.

https://ift.tt/2OijE86

Effect of Testosterone Synthesis and Conversion on Serum Testosterone Levels in Obese Men

Horm Metab Res
DOI: 10.1055/a-0658-7712

Obesity is associated with decreased testosterone levels in males. Testosterone is synthesized by testosterone synthetic enzymes, which are stimulated by luteinizing hormone (LH). Testosterone can also be converted to estradiol via the aromatase. The objective of this study was to examine the factors related to testosterone synthesis and conversion, and to systematically evaluate the key processes that influence testosterone levels in male obesity. Three hundred and two male subjects (aged 25–45 years old) were divided according to BMI into normal weight (18.5–23.9 kg/m2), overweight (24–27.9 kg/m2), and obese (≥28 kg/m2) groups; or divided following WHR into non-abdominal obesity and abdominal obesity groups (WHR: ≥0.9). Male C57BL/6 mice were divided into normal diet (ND) and high-fat diet (HFD)-induced obesity group. Serum sex hormones and aromatase levels were measured using ELISAs. Testosterone synthetic enzymes in the testes were measured by qRT-PCR. The testosterone levels in obese men and abdominal obesity men were lower than normal men. In abdominal obesity men serum LH levels were decreased and associated with testosterone levels after multivariate regression analysis. Serum aromatase levels were increased in abdominal obesity males. In mice, compared to the ND group, the HFD group had decreased steroidogenic acute regulatory protein (StAR). However, aromatase levels in subcutaneous adipose tissue were higher in the ND group than HFD group. In conclusion, according to this study decreased testicular synthesis function and the conversion of testosterone may explain the reduction in testosterone levels in male obesity, and the decrease of testicular synthesis may change first.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Ultrasonography Classification of the American Thyroid Association for Predicting Malignancy in Thyroid Nodules >1cm with Indeterminate Cytology: A Prospective Study

Horm Metab Res 2018; 50: 597-601
DOI: 10.1055/a-0655-3016

The objective of this prospective study was to evaluate the ultrasonography classification of the American Thyroid Association (ATA) for predicting malignancy in thyroid nodules >1 cm with indication for fine-needle aspiration (FNA) whose cytology was indeterminate. Additionally, the combination of the ATA classification with Doppler analysis was evaluated. All patients with thyroid nodules >1 cm were eligible. Each nodule was assigned to one of the ATA categories. Exclusively or predominantly intranodular vascularity was considered suspicious. One hundred and thirty-seven patients with 143 nodules underwent FNA and those with indeterminate cytology (Bethesda category III or IV) were selected. All patients were referred for surgery. Among the 143 nodules evaluated, 92 were benign, 33 were malignant, 13 were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 5 were tumors of uncertain malignant potential (TUMP). The rate of malignancy, including NIFTP and TUMP in this definition, was 80%, 42.8%, 13%, 10%, and 23% for nodules with a high suspicion, intermediate suspicion, low suspicion, very low suspicion, and undefined ultrasonographic pattern, respectively. Considering NIFPT and TUMP as benign, these rates were 72%, 22.4%, 4.3%, 0%, and 15.4%, respectively. The addition of Doppler analysis did not significantly improve the prediction of malignancy obtained with the ATA classification alone. The results of this prospective study show the usefulness of the ATA ultrasonographic classification for predicting malignancy specifically in thyroid nodules >1 cm with indeterminate cytology. The ATA category of the nodule should influence the decision for follow-up, molecular tests, or surgery.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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The Effects of Vitamin D Supplementation on Markers Related to Endothelial Function Among Patients with Metabolic Syndrome and Related Disorders: A Systematic Review and Meta-Analysis of Clinical Trials

Horm Metab Res 2018; 50: 587-596
DOI: 10.1055/a-0651-4842

This systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted to summarize the effect of vitamin D supplementation on endothelial function among people with metabolic syndrome and related disorders. Cochrane library, Embase, PubMed, and Web of Science database were searched to identify related RCTs published up 20th May 2018. To check heterogeneity a Q-test and I2 statistics were used. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as summary effect size. Twenty-two trials of 931 potential citations were found to be eligible for current meta-analysis. The pooled findings by using random effects model indicated that vitamin D supplementation to individuals with MetS and related disorders significantly increased flow-mediated dilatation (FMD) (SMD=1.10; 95% CI, 0.38, 1.81, p=0.003). However, it did not affect pulse-wave velocity (PWV) (SMD=0.04; 95% CI, –0.25, 0.33, p=0.80) and augmentation index (AI) (SMD=0.07; 95% CI, –0.25, 0.40; p=0.65). Overall, this meta-analysis demonstrated that vitamin D supplementation to patients with metabolic syndrome and related disorders resulted in an improvement in FMD, but did not influence PWV and AI.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2MozXQd

Increased Numbers of Circulating Tumor Cells in Thyroid Cancer Patients

Horm Metab Res 2018; 50: 602-608
DOI: 10.1055/a-0651-4913

Circulating tumor cells (CTCs) have been shown to be a valuable prognostic marker for different solid cancers. Within the present study we quantified CTCs in thyroid cancer (TC) patients. Special focus was given to disease-free PTC patients with undetectable serum thyroglobulin (Tg) levels. Altogether, 67 TC patients (33 papillary, 20 follicular, 14 medullary) were included in the study. CTC numbers, which were normalized to 3.3×105 peripheral blood mononuclear cells, were correlated with clinical outcome. TC patients had significantly higher CTC numbers compared to controls. The number of CTCs correlated to the initial tumor stage. Importantly, in comparison to controls, differentiated TC patients with serum Tg levels<0.3 ng/ml (no evidence of tumor recurrence) revealed a significantly higher amount of CTCs, also associated to their former tumor stage. Regarding the tumor-free papillary TC (PTC) patients the number of CTCs additionally correlated to the time point of radioiodine (RI) therapy: PTC patients with RI therapies>8 years before CTC measurement had significantly higher CTC numbers compared to those with RI therapy<8 years ago. We found a clear correlation between the number of CTCs and the tumor stage. Importantly, PTC patients who are in remission may still have increased numbers of CTCs. Follow-up analyses in these patients will reveal whether these data will have a clinical impact.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2McQkSO

Thyroid Autoimmunity and Thyroid Cancer – The Pathogenic Connection: A 2018 Update

Horm Metab Res
DOI: 10.1055/a-0648-4593

The association between thyroid cancer and thyroid autoimmunity has long been suggested, but remains to be elucidated for several decades. Here the data on this issue are updated by summarizing relevant papers published between 2012 and early 2018. Although numerous papers demonstrated the significant increase in the prevalence of thyroid autoimmunity (positive intrathyroidal lymphocyte infiltration and/or anti-thyroglobulin/thyroid peroxidase antibodies) in patients with thyroid cancers as compared to those with benign nodules, and also the significant increase in the prevalence of papillary thyroid cancer (PTC) in patients with thyroid autoimmunity as compared to those without, there are some crucial biases that should be taken into account for their interpretation. However, a difference in the incidence of thyroid autoimmunity in patients with PTCs and those with other types of thyroid cancers appears to support the significant association of two conditions. Thyroid autoimmunity is, at least partly, likely to be elicited against antigens shared by normal and cancerous thyroid tissues, thereby inducing autoimmunity. At the same time, elevated TSH levels (even within the normal reference ranges), which often accompany Hashimoto's patients are a risk factor for thyroid cancer. However, it is still unclear whether or not the co-existence of thyroid autoimmunity impacts on cancer characteristics and prognosis. This issue needs to be further investigated with large-scale prospective studies.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2MozXzH

Family history of breast or prostate cancer and prostate cancer risk

Purpose: Breast and prostate cancer co-occur in families, and women with a family history of prostate cancer are at increased breast cancer risk. Prostate cancer is among the most heritable cancers, but few studies have investigated its association with familial breast cancer. The objective of this study is to investigate the extent to which familial breast or prostate cancer in first-degree relatives increases prostate cancer risk. Experimental Design: A prospective study of 37,002 U.S. men in the Health Professionals Follow-up Study. During 16-year follow-up to 2012, 4,208 total and 344 lethal cases were diagnosed. Using cause-specific hazards regression, we estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for associations between familial breast or prostate cancer and total and lethal prostate cancer. Results: Those with familial breast cancer had a 21% greater risk of prostate cancer overall (95% CI 1.10-1.34), and a 34% greater risk of lethal disease (HR 1.34; 95% CI 0.96-1.89). Family history of prostate cancer alone was associated with a 68% increased risk of total disease (95% CI 1.53-1.83) and a 72% increased risk of lethal disease (95% CI 1.25-2.38). Men with a family history of both cancers were also at elevated risk. Conclusions: Our study found that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including risk of lethal disease. These findings have translational relevance for cancer risk prediction in men.

https://ift.tt/2Mofpas

A visually apparent and quantifiable CT imaging feature identifies biophysical subtypes of pancreatic ductal adenocarcinoma

Background and aims: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Methods: We developed a quantitative method to categorize the PDAC morphology on pre-therapy CT scans from multiple datasets of patients with resectable and metastatic disease, and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphological patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low delta) tumors. Pathological measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusion: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

https://ift.tt/2M7k5oh

Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non-Small Cell Lung Cancer: A Phase 1b Study

Abstract Introduction: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase 1b study was conducted to test safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1,8 ramucirumab (8mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combinations agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies.

https://ift.tt/2Mq0Mn0

Circulating biomarkers and resistance to endocrine therapy in metastatic breast cancers: correlative results from AZD9496 oral SERD Phase I trial

BACKGROUND: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER) positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1_LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERDs). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) were explored as potential non-invasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. METHODS: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch^® in serial blood draws. ctDNA was assessed for the most common ESR1_LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11/43 (25%) patients had ≥5CTC/7.5mL whole blood (WB), none of whom underwent reduction to <5CTC/7.5mL WB on C1D15. 5/11 patients had baseline CTC-ER+, 2 of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5CTC/7.5mL WB pre-treatment had worse progression-free survival (PFS) than patients with <5CTC (p=0.0003). Fourteen of 45 (31%) patients had ESR1_LBDm+ ctDNA at baseline, 5 of whom had ≥2 unique mutations. Baseline ESR1_LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1_LBDm+ ctDNA at C1D15 had worse PFS than patients who did not (p=0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1_LBDm+ ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.

https://ift.tt/2M686aA

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/vincristine in Relapsed/refractory Aggressive B-cell Lymphoma

Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin's lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. Experimental Design: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg BID days 1-7, plus IV rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3+3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) BID days 1-7 plus rituximab and vincristine (1.4 mg/m2 [maximum 2 mg] days 1, 8) for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 immunohistochemistry was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg BID. For MRV (n = 32) the RP2D was determined as 40 mg BID (1 DLT at 40 mg; 2 DLTs at 50 mg). Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CRs), seven had partial responses (PRs); 9/20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) DLBCL. Conclusions: The combination of alisertib 50 mg BID plus rituximab or alisertib 40 mg BID plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

https://ift.tt/2OiryOv

Issue Information

International Endodontic Journal, Volume 51, Issue 9, Page i-iii, 953, Septenber 2018.


https://ift.tt/2M8YWdh

Validation of novel Mycobacterium tuberculosis isoniazid resistance mutations not detectable by common molecular tests [PublishAheadOfPrint]

Resistance to the first-line anti-tuberculosis (TB) drug, isoniazid (INH), is widespread, and the mechanism of resistance is unknown in approximately 15% of INH-resistant (INH-R) strains. To improve molecular detection of INH-R TB, we used whole genome sequencing (WGS) to analyze 52 phenotypically INH-R Mycobacterium tuberculosis complex (MTBC) clinical isolates that lacked the common katG S315T or inhA promoter mutations. Approximately 94% (49/52) of strains had mutations at known INH-associated loci that were likely to confer INH resistance. All such mutations would be detectable by sequencing more DNA adjacent to existing target regions. Use of WGS minimized the chances of missing infrequent INH resistance mutations outside commonly targeted hotspots. We used recombineering to generate 12 observed clinical katG mutations in the pansusceptible H37Rv reference strain and determined their impact on INH resistance. Our functional genetic experiments have confirmed the role of seven suspected INH resistance mutations and discovered five novel INH resistance mutations. All recombineered katG mutations conferred resistance to INH at a minimum inhibitory concentration of ≥0.25 μg/mL and should be added to the list of INH resistance determinants targeted by molecular diagnostic assays. We conclude that WGS is a useful tool for detecting uncommon INH resistance mutations that would otherwise be missed by current targeted molecular testing methods, and suggest that its use (or use of expanded conventional or NGS-based targeted sequencing) may provide earlier diagnosis of INH-R TB.

https://ift.tt/2Ms6Taf

Mutation-driven evolution of Pseudomonas aeruginosa in the presence of either ceftazidime or ceftazidime/avibactam [PublishAheadOfPrint]

Ceftazidime/avibactam is a combination of beta-lactam/beta-lactamases inhibitor, which use is restricted to some clinical cases including cystic fibrosis patients infected with multidrug resistant Pseudomonas aeruginosa, in which mutation is the main driver of resistance. This study aims to predict the mechanisms of mutation-driven resistance that are selected for when P. aeruginosa is challenged with either ceftazidime or ceftazidime/avibactam. For this purpose, P. aeruginosa PA14 was submitted to experimental evolution in the absence of antibiotics and in the presence of increasing concentrations of ceftazidime or ceftazidime/avibactam for 30 consecutive days. Final populations were analysed by whole-genome sequencing. All evolved populations reached similar levels of ceftazidime resistance. Besides, they were more susceptible to amikacin and produced pyomelanin. A first event in the evolution was the selection of large chromosomal deletions containing hmgA (involved in pyomelanin production), galU (involved in β-lactams resistance) and mexXY-oprM (involved in aminoglycoside resistance). Besides mutations in mpl and dacB that regulate β-lactamase expression, mutations related to MexAB-OprM overexpression were prevalent. Ceftazidime/avibactam challenge selected mutants in the putative efflux pump PA14_45890-45910 and in a two-component system (PA14_45870-45880), likely regulating its expression. All populations produce pyomelanin and were more susceptible to aminoglycosides likely due to the selection of large chromosomal deletions. Since pyomelanin-producing mutants, presenting similar deletions are regularly isolated from infections, the potential aminoglycosides hyper-susceptiblity and reduced β-lactams susceptibility of pyomelanin-producing P. aeruginosa should be taken into consideration for treating infections by these isolates.

https://ift.tt/2M8YPyr

Genetic and Biochemical Characterization of OXA-535, a distantly-related OXA-48-like {beta}-lactamase. [PublishAheadOfPrint]

OXA-535, a chromosome-encoded OXA-48-like carbapenemase of Shewanella bicestrii JAB-1, shared only 91.3% of amino-acid sequence identity, but displayed similar catalytic efficiencies as compared to OXA-48, except for ertapenem. OXA-535 and OXA-436, a plasmid-encoded variant of OXA-535 differing by three amino acids, form a novel cluster of distantly-related OXA-48-like carbapenemases. Comparison of bla_OXA-535 and bla_OXA-436 genetic environments suggests that an ISCR1 may be responsible of bla_OXA-436 gene mobilization from the chromosome of Shewanella spp. to plasmids.

https://ift.tt/2Ms7fO7

Ex vivo characterisation of effects of renal replacement therapy modalities and settings on pharmacokinetics of meropenem and vaborbactam [PublishAheadOfPrint]

The combination product meropenem/vaborbactam, with activity against KPC-producing carbapenem resistant Enterobacteriaceae, is likely to be used during renal replacement therapy. The aim of this work was to describe the extracorporeal removal (adsorption and clearance) of meropenem/vaborbactam during continuous venovenous hemofiltration (CVVH). An ex vivo model was used to examine the effects of a matrix of operational settings. Vaborbactam did not adsorb to AN69 (acrylonitrile and sodium-methallylsulfonate copolymer) ST100 (surface area, 1m²) hemofilter; whilst mean (± SD) meropenem adsorption was 9% (± 1%). The mean (± SD) sieving coefficients with AN69 ST100 and ST150 (surface area, 1.5m²) filters ranged from 0.97 ± 0.16 to 1.14 ± 0.12 and from 1.13 ± 0.01 to 1.53 ± 0.28, respectively, for meropenem; and for vaborbactam from 0.64 ± 0.39 to 0.90 ± 0.14 and 0.78 ± 0.18 to 1.04 ± 0.28, respectively. At identical settings, vaborbactam sieving coefficients were 25% to 30% lower than that of meropenem. Points of dilution, blood flow rates or effluent flow rates did not affect sieving coefficients for either drug. However, doubling the effluent flow rate resulted in > 50 to 100% increase in filter clearance for both drugs. Post-filter dilution resulted in 40 to 80% increase in filter clearance at high effluent flow rate (4000mL/h) compared with ~15% increase at low effluent flow rate (1000mL/h) for both drugs. For all combinations of setting and filters tested, vaborbactam clearance was lower than that of meropenem by ~20 to 40 %. Overall, meropenem/vaborbactam is efficiently cleared in CVVH mode.

https://ift.tt/2vlKvZY

Effect of pregnancy on the pharmacokinetic interaction between efavirenz and lumefantrine in HIV-malaria co-infection [PublishAheadOfPrint]

Background: Artemether-lumefantrine is often co-administered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in non-pregnant adults. The influence of pregnancy on this interaction has not been reported.

Method: This pharmacokinetic study involved 35 pregnant and 34 non-pregnant HIV-malaria co-infected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received three-day standard regimen of artemether-lumefantrine for malaria treatment and intensive pharmacokinetic sampling was conducted 0.5-96 hours after the last dose. Plasma efavirenz, lumefantrine and desbutyl-lumefantrine were quantified using validated assays and pharmacokinetic parameters were derived using noncompartmental analysis.

Results: Median (interquartile range) mid-dose plasma concentrations of efavirenz was significantly lower in pregnant (n = 32) compared with non-pregnant (n = 32) women at 1820 (1300-2610) ng/mL vs 2760 (2020-5640) ng/mL, p = 0.006. Lumefantrine AUC_0-96 was significantly higher in pregnant women (n = 27) at 155,832 (102,400-214,011) ng/mL*h compared with non-pregnant women at 90,594 (58,869-149,775) ng/mL*h, p = 0.03. A similar trend was observed for lumefantrine C₁₂, 2870 (2180-4880) vs 2080 (1190-2970) ng/mL, respectively (p = 0.02). Lumefantrine to desbutyl-lumefantrine ratio also tended to be lower in pregnant than non-pregnant women (P = 0.076).

Conclusion: Overall, pregnancy tempered the extent of efavirenz-lumefantrine interactions resulting in increased lumefantrine exposure. However, any consideration of dosage adjustment for artemether-lumefantrine to enhance exposure in this population needs to be based on data from a prospective study with safety and efficacy end points.

https://ift.tt/2OgTYZc

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats. 6. Aminoglycosides [PublishAheadOfPrint]

Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intra-tracheal and intravenous administrations. ELF areas under concentrations time-curves were 874 and 162 times higher after nebulization than after IV administration for amikacin and gentamicin respectively. Even if both molecules appear as good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.

https://ift.tt/2M3CrGC

PA3177 encodes an active diguanylate cyclase that contributes to the biofilm antimicrobial tolerance but not biofilm formation by P. aeruginosa [PublishAheadOfPrint]

A hallmark of biofilms is their heightened resistance to antimicrobial agents. Recent findings suggested a role of c-di-GMP in the susceptibility of bacteria to antimicrobial agents, however, no c-di-GMP modulating enzyme(s) contributing to the drug tolerance phenotype of biofilms has been identified. The goal of this study was to determine whether c-di-GMP modulating enzyme(s) specifically contribute to the biofilm drug tolerance of Pseudomonas aeruginosa. Using RNA-Seq combined with biofilm susceptibility assays, we identified PA3177 encoding a probable diguanylate cyclase. PA3177 was confirmed to be an active diguanylate cyclase, with overexpression affecting swimming and swarming motility, and inactivation affecting cellular c-di-GMP levels of biofilm but not planktonic cells. Inactivation of PA3177 rendered P. aeruginosa PAO1 biofilms susceptible to tobramycin and hydrogen peroxide. Inactivation of PA3177 furthermore eliminated the recalcitrance of biofilms to killing by tobramycin, with multicopy expression of PA3177 but not PA3177_GGAAF harboring substitutions in the active site, restoring tolerance to wild-type levels. Susceptibility was linked to BrlR, a previously described transcriptional regulator contributing to biofilm tolerance, with inactivation of PA3177 negatively impacting BrlR levels and BrlR-DNA binding. While PA3177 contributed to biofilm drug tolerance, inactivation of PA3177 had no effect on attachment and biofilm formation. Our findings demonstrate for the first time that biofilm drug tolerance by P. aeruginosa is linked to a specific c-di-GMP modulating enzyme, PA3177, with the pool of PA3177-generated c-di-GMP only contributing to biofilm drug tolerance but not to biofilm formation.

https://ift.tt/2Mt0BaJ

Clinical and molecular correlates of Escherichia coli bloodstream infection from two geographically diverse centers in Rochester, Minnesota and Singapore [PublishAheadOfPrint]

Escherichia coli bacteremia is caused mainly by sequence type complex (STc) 131 and two clades within its fluoroquinolone resistance-associated H30 subclone, H30R1 and H30Rx. We examined clinical and molecular correlates of E. coli bacteremia in two geographically distinct centers. We retrospectively studied 251 unique E. coli bloodstream isolates from 246 patients (48 from the Mayo Clinic, Rochester, Minnesota [MN], 198 from Tan Tock Seng Hospital, Singapore [SG]), from October 2013 through March 2014. Isolates underwent PCR for phylogroup, STc, bla_CTX-M type, and virulence gene profiles, and medical records reviewed. Although STc131 accounted for 25-27% of all E. coli bacteremia isolates at each site, its extended-spectrum β-lactamase-associated H30Rx clade was more prominent in SG than MN (15% versus 4%, P = 0.04). In SG only, patients with STc131 (versus other E. coli) were more likely to receive inactive initial antibiotics (odds ratio [OR] 2.8, P = 0.005); this was true specifically for patients with H30Rx (OR 7.0, P = 0.005). H30Rx comprised 16% of community-onset bacteremia episodes in SG, but none in MN. In SG, virulence scores were higher for H30Rx, as compared to H30R1, non-H30 STc131, and non-STc131 isolates (P < 0.02, all comparisons). At neither site did mortality differ by clonal status. The ESBL-associated H30Rx clade was more prevalent and more often of community-onset in SG, where it predicted inactive empiric treatment. Clonal distribution varies geographically and has potentially important clinical implications. Rapid susceptibility testing and clonal diagnostics for H30/H30Rx might facilitate earlier prescribing of active therapy.

https://ift.tt/2M5QF9V

Assessing the effectiveness of curative benznidazole treatment in preventing chronic cardiac pathology in experimental models of Chagas disease [PublishAheadOfPrint]

Chagasic heart disease develops in 30% of those infected with the protozoan parasite Trypanosoma cruzi, but can take decades to become symptomatic. Because of this, it has been difficult to assess the extent to which anti-parasitic therapy can prevent the development of pathology. We sought to address this question using experimental murine models, exploiting highly sensitive bioluminescent imaging to monitor curative efficacy. Mice were inoculated with bioluminescent parasites and then cured with benznidazole in either the acute or chronic stage of infection. At the experimental end-point (5-6 months post-infection), heart tissue was removed and assessed for inflammation and fibrosis, two widely used markers of cardiac pathology. Infection of BALB/c and C3H/HeN mice with distinct T. cruzi lineages resulted in greatly increased myocardial collagen content at a group level, indicative of fibrotic pathology. When mice were cured by benznidazole in the acute stage, the development of pathology was completely blocked. However, if treatment was delayed until the chronic stage, cardiac fibrosis was observed in the BALB/c model, although the protective effect was maintained in the case of C3H/HeN mice. These experiments therefore demonstrate that curative benznidazole treatment early in murine T. cruzi infections can prevent the development of cardiac fibrosis. They also show that treatment during the chronic stage can block pathology, but the effectiveness varies between infection models. If these findings are extendable to humans, it implies that widespread chemotherapeutic intervention targeted at early-stage infections could play a crucial role in reducing Chagas disease morbidity at a population level.

https://ift.tt/2Ms6zbx

First clinical isolation of an azole-resistant Aspergillus fumigatus harboring a TR46/Y121F/T289A mutation in South America. [PublishAheadOfPrint]

One of the most recently described Aspergillus fumigatus CYP51A-mediated azole resistance mechanism is the named TR46/Y121F/T289A. Clinical A. fumigatus strains harboring these substitutions were reported worldwide with the exception of South-America. We describe the first clinical A. fumigatus strain with this resistance mechanism isolated from an Argentinian patient. The strain was isolated in 2009 (one year later than the firstly described mutant in US) demonstrating that these alleles were scattered worldwide before than previously thought.

https://ift.tt/2M8XSGj

Studies on Aminoglycoside Susceptibility Identified a Novel Function of KsgA to Secure Translational Fidelity during Antibiotic Stress [PublishAheadOfPrint]

Antibiotic resistance has become a global crisis. Studies on the mechanism of bacterial tolerance to antibiotics will not only increase our conceptual understanding of bacterial death but also provide potential targets for novel inhibitors. We screened a mutant library containing a full set of in-frame deletion mutants of Escherichia coli K-12 and identified 140 genes that possibly contribute to gentamicin tolerance. Deletion of ksgA increased the inhibition and killing potency against mid-log phase bacteria by aminoglycosides. Initially identified as a 16S rRNA methyltransferase, KsgA also has additional functions as a ribosomal biogenesis factor and a DNA glycosylase. We found that the methyltransferase activity of KsgA is responsible for the tolerance, as demonstrated by a site-directed mutagenesis analysis. In contrast to the mechanism for cold sensitivity, the decreased tolerance to aminoglycoside is not related to the failure of ribosomal biogenesis. Furthermore, the DNA glycosylase activity of KsgA plays little role in kanamycin tolerance. Importantly, we discovered that KsgA secures protein translational fidelity upon kanamycin killing, in contrast to its role during cold stress and kasugamycin treatment. The results suggest that the compromise in protein translational fidelity in the absence of KsgA is the root cause of increased sensitivity to a bactericidal aminoglycoside. In addition, KsgA in the pathogenic Acinetobacter baumannii contributes not only to the tolerance against aminoglycoside killing but also to virulence in the host, warranting potential application as a target for inhibitors that potentiate aminoglycoside therapeutic killing as well as disarm bacterial virulence simultaneously.

https://ift.tt/2MmHuPb

Trend and pattern of antimicrobial resistance in molluscan Vibrio species sourced to Canadian estuaries [PublishAheadOfPrint]

Emergence of antimicrobial resistance (AMR) in foodborne bacteria is a growing concern worldwide. AMR surveillance is a key element in understanding the implications resulting from the use of antibiotics for therapeutic as well as prophylactic needs. The emergence and spread of AMR in foodborne human pathogens is an indirect health hazard. This surveillance study reports the trend and pattern of AMR detected in Vibrio species isolated from molluscs harvested in Canada, between 2006 and 2012, against 19 commonly used antibiotics. Five common antibiotics, ampicillin, cephalothin, erythromycin, kanamycin and streptomycin, predominantly contributed to AMR including multi-drug resistance (MDR) in the molluscan Vibrio spp. isolated in 2006. A prospective follow-up analysis of these drugs showed a declining trend in the frequency of MDR/AMR-Vibrio spp. in subsequent years until 2012. The observed decline appears to have been influenced by the specific downturn in resistance to the aminoglycosides, kanamycin and streptomycin. Frequently observed MDR/AMR-Vibrio spp. in seafood is a potential health concern associated with seafood consumption. Our surveillance study provided an indication of the antibiotics that challenged the marine bacteria, sourced to Canadian estuaries, during and/or prior to the study period.

https://ift.tt/2vq0kyz

Crystal structures of penicillin-binding protein D2 from Listeria monocytogenes: Structural basis for antibiotic specificity [PublishAheadOfPrint]

β-lactam antibiotics that inhibit penicillin-binding proteins (PBPs) have been widely used in the treatment of bacterial infections. However, the molecular basis underlying the different inhibitory potencies of β-lactams against specific PBPs is not fully understood. Here, we present the crystal structures of PBPD2 from Listeria monocytogenes, a Gram-positive food-borne bacterial pathogen that causes listeriosis in humans. The acylated structures in complex with four antibiotics (penicillin G, ampicillin, cefotaxime, and cefuroxime) revealed that the β-lactam core structures were recognized by a common set of residues; however, the R1 side chains of each antibiotic participate in different interactions with PBPD2. In addition, the structural complementarities between the side chains of β-lactams and the enzyme were found to be highly correlated with the relative reactivities of penam or cephem antibiotics against PBPD2. Our study provides the structural basis for the inhibition of PBPD2 by clinically important β-lactam antibiotics that are commonly used in listeriosis treatment. Our findings imply that the modification of β-lactam side chains based on structural complementarity could be useful for the development of potent inhibitors against β-lactam-resistant PBPs.

https://ift.tt/2OhevNv

Local skin inflammation in cutaneous leishmaniasis as a source of variable pharmacokinetics and therapeutic efficacy of liposomal amphotericin B [PublishAheadOfPrint]

Disfiguring skin lesions caused by several species of the Leishmania parasite characterize cutaneous leishmaniasis (CL). Successful treatment of CL with intravenous (IV) liposomal amphotericin B (LAmB) relies on the presence of adequate antibiotic concentrations at the dermal site of infection within the inflamed skin. Here, we have investigated the impact of the local skin inflammation on the pharmacokinetics (PK) and efficacy of LAmB in two murine models of localized CL (Leishmania major and Leishmania mexicana) at three different stages of disease (papule, initial nodule and established nodule). Twenty-four hours after administration of 1 x 25 mg/kg LAmB (IV) to infected BALB/c mice (n=5), drug accumulation in skin was found to be dependent on the causative parasite species (L. major > L. mexicana) and the disease stage (papule > initial nodule > established nodule > healthy skin). Elevated tissue drug levels were associated with increased vascular permeability (Evans Blue assay) and macrophage infiltration (histomorphometry) in the infected skin, two pathophysiological parameters linked to tissue inflammation. After identical treatment of CL in the two models with 5 x 25 mg/kg LAmB (IV), intralesional drug concentrations and reductions in lesion size and parasite load (qPCR) were all ≥ 2-fold higher for L. major compared to L. mexicana. In conclusion, drug penetration of LAmB into CL skin lesions could depend on the disease stage and the causative Leishmania species due to the influence of local tissue inflammation.

https://ift.tt/2vpTqt7

Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility [PublishAheadOfPrint]

Multiple Erg11 amino acid substitutions were identified within clinical isolates of Candida auris originating from India and Colombia. Elevated azole MICs were detected in Saccharomyces cerevisiae upon heterologous expression of C. auris ERG11 alleles that encoded for Y132F or K143R substitutions; however, expression of alleles encoding for I466M, Y501H, or other clade-defined amino acid differences yielded susceptible MICs. Similar to other Candida species, specific C. auris ERG11 mutations directly resulted in reduced azole susceptibility.

https://ift.tt/2MpGJFb

Linkage Disequilibrium and Evaluation of Genome-Wide Association Mapping Models in Tetraploid Potato

Genome-wide association studies (GWAS) have become a powerful tool for analysing complex traits in crop plants. The current study evaluates the efficacy of various GWAS models and methods for elucidating population structure in potato. The presence of significant population structure can lead to detection of spurious marker-trait associations, as well as mask true ones. While appropriate statistical models are needed to detect true marker-trait associations, in most published potato GWAS, a 'one model fits all traits' approach has been adopted. We have examined various GWAS models on a large association panel comprising diverse tetraploid potato cultivars and breeding lines, genotyped with single nucleotide polymorphism (SNP) markers. Phenotypic data was generated for 20 quantitative traits assessed in different environments. Best Linear Unbiased Estimates (BLUEs) for these traits were obtained for use in assessing GWAS models. Goodness of fit of GWAS models, derived using different combinations of kinship and population structure for all traits, was evaluated using Quantile-Quantile (Q-Q) plots and genomic control inflation factors (_GC). Kinship was found to play a major role in correcting population confounding effects and results advocate a 'trait-specific' fit of different GWAS models. A survey of genome-wide linkage disequilibrium (LD), one of the critical factors affecting GWAS, is also presented and our findings are compared to other recent studies in potato. The genetic material used here, and the outputs of this study represent a novel resource for genetic analysis in potato.

https://ift.tt/2Oiqn1x

Null Mutation of the Fascin2 Gene by TALEN Leading to Progressive Hearing Loss and Retinal Degeneration in C57BL/6J Mice

Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 (FSCN2) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice. To explore the function of the gene, Fscn2 was knocked out using TALEN (transcription activator-like effector nucleases) on the C57BL/6J background. Four mouse strains with deletions of 1, 4, 5, and 41 nucleotides in the target region of Fscn2 were developed. F1 heterozygous (Fscn2^+/-) mice carrying the same deletion of 41 nucleotides were mated to generate the Fscn2^-/- mice. As a result, the Fscn2^-/-mice showed progressive hearing loss, as measured in the elevation of auditory brainstem-response thresholds. The hearing impairment began at age 3 weeks at high-stimulus frequencies and became most severe at age 24 weeks. Moreover, degeneration of hair cells and loss of stereocilia were remarkable in Fscn2^-/-mice, as revealed by F-actin staining and scanning electron microscopy. Furthermore, compared to the controls, the Fscn2^-/-mice displayed significantly lower electroretinogram amplitudes and thinner retinas at 8, 16, and 24 weeks. These results demonstrate that, in C57BL/6Jmice, Fscn2 is essential for maintaining ear and eye function and that a null mutation of Fscn2 leads to progressive hearing loss and retinal degeneration.

https://ift.tt/2LU4MQx

Dendritic cells pulsed with generated tumor cell lysate from Phyllanthus amarus Schum. & Thonn. induces anti-tumor immune response

Dendritic cells (DCs) are unique antigen presenting cells (APC) which play a pivotal role in immunotherapy and induction of an effective immune response against tumors. In the present study, 80% ethanol extrac...

https://ift.tt/2vlKqWa

Investigation of biological activities of the flowers of Lagerstroemia speciosa, the Jarul flower of Bangladesh

Lagerstroemia speciosa (L.) Pers. (Family: Lythraceae) is used in traditional medicine in the treatment of diarrhea, diabetes and other diseases. The study was performed to conduct antioxidant, cytotoxic, thrombo...

https://ift.tt/2Mt1dx2

Serum Lipidomics Profiling to Identify Biomarkers for Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, which ranks top in both incidence and mortality. To broaden our understanding of the lipid metabolic alterations in NSCLC and to identify potential biomarkers for early diagnosis, we performed nontargeted lipidomics analysis in serum from 66 early-stage NSCLC, 40 lung benign disease patients (LBD), and 40 healthy controls (HC) using Ultrahigh Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-Q-TOF/MS). The identified biomarker candidates of phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) were further externally validated in a cohort including 30 early-stage NSCLC, 30 LBD, and 30 HC by a targeted lipidomic analysis. We observed a significantly altered lipid metabolic profile in early-stage NSCLC and identified panels of PCs and PEs to distinguish NSCLC patients and HC. The levels of PCs and PEs were found to be dysregulated in glycerophospholipid metabolism, which was the top altered pathway in early-stage NSCLC. Receiver operating characteristic (ROC) curve analysis revealed that panels of PCs and PEs exhibited good performance in differentiating early-stage NSCLC and HC. The levels of PE(16:0/16:1), PE(16:0/18:3), PE(16:0/18:2), PE(18:0/16:0), PE(17:0/18:2), PE(18:0/17:1), PE(17:0/18:1), PE(20:5/16:0), PE(18:0/18:1), PE(18:1/20:4), PE(18:0/20:3), PC(15:0/18:1), PC(16:1/20:5), and PC(18:0/20:1) in early-stage NSCLC were significantly increased compared with HC (p

https://ift.tt/2KyFxxx

The impact of accountable care organizations on spine care

Publication date: Available online 6 August 2018

Source: Seminars in Spine Surgery

Author(s): Daniel G. Tobert, Andrew J. Schoenfeld

Abstract

Objectives

The purpose of this manuscript is to describe the origins of accountable care organizations and summarize their impact on spine care.

Findings

The unmitigated rise in capital expenditures for health care services in the latter half of the twentieth century gave rise to the development of cost-saving measures, including accountable care organizations. These have shown modest cost savings and improvements in quality measures but have largely ignored surgeons and surgical care.

Conclusions

As alternative payment models expand, spine surgery will be targeted for improvements. Spine surgeons should be involved in the structuring of those efforts.

https://ift.tt/2niEuZy

AT&T and RapidDeploy Team Up to Advance Emergency Response Capabilities With Cloud-Based Solutions

Cloud-Based Computer-Aided Dispatch Solution Helps Boost Situational Awareness for Dispatchers and First Responders DALLAS, Aug. 6, 2018 - AT&T* and RapidDeploy formed a new relationship that enables AT&T to provide Public Safety Answering Points (PSAPs) access to RapidDeploy's cloud-based Computer-Aided Dispatch (CAD) platform. RapidDeploy is a modern update to the dispatch solutions...

https://ift.tt/2vKhs1p

Female Internists Consistently Earn Less Than Men

MONDAY, Aug. 6, 2018 -- Female internists earn less than men, across many demographic and employment indicators, according to a research letter published online Aug. 7 in the Annals of Internal Medicine. Susan Read, Ph.D., from the American College...

https://ift.tt/2M545mF

Combined Digital Screening Best for Detecting Breast Cancers

MONDAY, Aug. 6, 2018 -- The combination of digital mammography (DM) and digital breast tomosynthesis (DBT) detects 90 percent more breast cancers than digital mammography alone, according to a study published in the August issue of...

https://ift.tt/2OfTB16

Thirteen Confirmed Ebola Cases in Latest Congo Outbreak

MONDAY, Aug. 6, 2018 -- The number of confirmed cases in a new Ebola outbreak in Congo has reached 13, including three deaths, the country's health ministry said late Saturday. It also said there were 30 probable cases and 33 suspected cases, the...

https://ift.tt/2vokYzh

Many Youths Believe Gun Control Would Decrease Mass Shootings

MONDAY, Aug. 6, 2018 -- Most youths in a recent survey support the right to own guns, but the majority believe that gun control laws would reduce mass shootings, according to a research letter published online July 30 in JAMA Pediatrics. Murphy Van...

https://ift.tt/2Mrfvya

Good Outcomes for HCV-Negative Recipients of HCV Kidneys

MONDAY, Aug. 6, 2018 -- Hepatitis C virus (HCV)-negative recipients of HCV-infected kidneys experience HCV cure and good quality of life, according to research published online Aug. 7 in the Annals of Internal Medicine. Peter P. Reese, M.D., from...

https://ift.tt/2M54Z2y

Including women in research. It's necessary, and really not so hard to do

Experimental Physiology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2M54khz

MiR-532-5p suppresses renal cancer cell proliferation by disrupting the ETS1-mediated positive feedback loop with the KRAS-NAP1L1/P-ERK axis

https://ift.tt/2vlwVps

Bacterial contamination of frequently touched objects in a tertiary care hospital of Pokhara, Nepal: how safe are our hands?

Objects frequently touched by patients and healthcare workers in hospitals harbor potential pathogens and may act as source of infectious agents. This study aimed to determine the bacterial contamination of co...

https://ift.tt/2MnR7NO

Myroides odoratimimus urinary tract infection in an immunocompromised patient: an emerging multidrug-resistant micro-organism

Myroides spp. are common environmental organisms and they can be isolated predominantly in water, soil, food and in sewage treatment plants. In the last two decades, an increasing number of infections such as uri...

https://ift.tt/2KzHf1H

Periorbital infections and conjunctivitis due to Panton-Valentine Leukocidin (PVL) positive Staphylococcus aureus in children

Colonisation with Panton-Valentine Leukocidin expressing strains of Staphylococcus aureus (PVL + SA) is characterised by recurrent skin and soft tissue infections. While periorbital and orbital infections are com...

https://ift.tt/2vIY2tQ

Restriction of in vivo infection by antifouling coating on urinary catheter with controllable and sustained silver release: a proof of concept study

Catheter Associated Urinary Tract Infections are among the most common urological infections world-wide. Bacterial biofilms and encrustation cause significant complications in patients with urinary catheters. ...

https://ift.tt/2nisdE8

Embolizing pulmonary aspergillosis, mycobacterial & aspergillous splenic abscess and cytomegalovirus co-infection following steroid induced immunosuppression: a case report

Aspergillosis is a serious infection particularly affecting the immunodeficient host. Its co-infection with tuberculosis and cytomegalovirus has not been reported before. Embolic events are well recognized wit...

https://ift.tt/2vJrvUB

Identifying heterogeneity in the Hawthorne effect on hand hygiene observation: a cohort study of overtly and covertly observed results

Observation and feedback are core strategies of hand hygiene (HH) improvement. Direct overt observation is currently the gold standard method. Observation bias, also known as the Hawthorne effect, is a major d...

https://ift.tt/2M0HQyY

Transcranial alternating current stimulation modulates auditory temporal resolution in elderly people

European Journal of Neuroscience, EarlyView.


https://ift.tt/2Mr8KMO

Firefly Tips and Tricks: How to record videos in FireflyPro

Every Firefly devices includes a snapshot button, which allows the user to take pictures and send them directly to a hard drive. But what about recording videos? It's actually pretty simple! Just follow the steps below:

1. While running FireflyPro, click on the Record Video button in the top left of your screen. If you're not sure which button it is, it looks like this:

2. A popup will appear with a few options. You can change where the video will be stored or start recording. Clicking START will start recording. When you are done, click STOP. The recording can also be paused with the PAUSE button.

And that's it! Your recorded videos can be found by default in your Documents folder and can be viewed in any preferred media player.

– The Firefly Team

https://ift.tt/2Ok75cv

Semiconducting Photosensitizer‐Incorporated Copolymers as Near‐Infrared Afterglow Nanoagents for Tumor Imaging

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2OOD8lJ

Self‐Assembled Nanomedicines for Anticancer and Antibacterial Applications

Advanced Healthcare Materials, EarlyView.


https://ift.tt/2MlDVck

Altered levels of circulating insulin-like growth factor I (IGF-I) following ischemic stroke are associated with outcome - a prospective observational study

Insulin-like growth factor I (IGF-I) has neuroprotective effects in experimental ischemic stroke (IS). However, in patients who have suffered IS, various associations between the levels of serum IGF-I (s-IGF-I...

https://ift.tt/2M4QmME

Nanocrystals: A Shape‐Induced Orientation Phase within 3D Nanocrystal Solids (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


https://ift.tt/2vHhjvz

Wear: Achieving Ultralow Wear with Stable Nanocrystalline Metals (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


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Contents: (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


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Optical Waveguides: Flexible Transient Optical Waveguides and Surface‐Wave Biosensors Constructed from Monocrystalline Silicon (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


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Masthead: (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


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Organic Field‐Effect Transistors: Triple Acceptors in a Polymeric Architecture for Balanced Ambipolar Transistors and High‐Gain Inverters (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


https://ift.tt/2OPF3X5

Photocatalysis: Homojunction of Oxygen and Titanium Vacancies and its Interfacial n–p Effect (Adv. Mater. 32/2018)

Advanced Materials, Volume 30, Issue 32, August 9, 2018.


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Ultrathin PtPd‐Based Nanorings with Abundant Step Atoms Enhance Oxygen Catalysis

Advanced Materials, EarlyView.


https://ift.tt/2AOSzHG

Electrostatic Force–Driven Oxide Heteroepitaxy for Interface Control

Advanced Materials, EarlyView.


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Endoscopic mucosal resection for intra‐ductal growing type intrahepatic cholangiocarcinoma under direct per‐oral cholangioscopy

Digestive Endoscopy, Volume 0, Issue ja, -Not available-.


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Outcomes of Bariatric Surgery in Patients With Diabetes

https://ift.tt/2OIK43T

Value-Based Health Care Meets Cost-Effectiveness Analysis

Value-based health care (VBHC) has recently emerged as a prominent movement within health care. Value-based health care focuses on maximizing outcomes achieved per dollar spent. As such, it bears many similarities to a well-established method, cost-effectiveness analysis (CEA), which provides a framework for comparing the relative value of different diagnostic or treatment interventions. Both approaches address "bang for the health care buck," but although they overlap in many ways, VBHC and CEA differ with regard to their main applications, their perspective, and the types of costs and outcomes they consider. For example, CEA generally considers costs and benefits from the societal or health care sector perspectives, whereas VBHC is intended to adopt the patient perspective. As such, CEA is intended to inform coverage decisions at a group or population level and VBHC is intended to be implemented at the level of clinician–patient interactions. Meanwhile, value-based payment has emerged as a visible component of VBHC and is gaining a foothold in the United States in various forms, particularly bundled payments, and accountable care organizations in an effort to reward high-value care and disincentivize low-value care. Differences aside, as the worlds of VBHC and CEA begin to intersect, each discipline can learn from the other.

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Unequal Pay for Equal Work: Where Are We Now?

Read and colleagues report on a cross-sectional 2017 survey of internists that shows that the salary gap between women and men in the medical profession has long been an unfortunate, unconscionable norm that persists in internal medicine. The editorialists discuss the findings and speculate about strategies that could promote gender equity in physician compensation.

https://ift.tt/2vnGfJ5

Twelve-Month Outcomes After Transplant of Hepatitis C–Infected Kidneys Into Uninfected Recipients A Single-Group Trial

Background:

Organs from hepatitis C virus (HCV)–infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected kidneys could be safely transplanted into HCV-negative patients. However, intermediate-term data on quality of life and renal function are needed to counsel patients about risk.

Objective:

To describe 12-month HCV treatment outcomes, estimated glomerular filtration rate (eGFR), and quality of life for the 10 kidney recipients in THINKER-1 and 6-month data on 10 additional recipients.

Design:

Open-label, nonrandomized trial. (ClinicalTrials.gov: NCT02743897)

Setting:

Single center.

Participants:

20 HCV-negative transplant candidates.

Intervention:

Participants underwent transplant with kidneys infected with genotype 1 HCV and received elbasvir–grazoprevir on posttransplant day 3.

Measurements:

The primary outcome was HCV cure. Exploratory outcomes included 1) RAND-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) quality-of-life scores at enrollment and after transplant, and 2) posttransplant renal function, which was compared in a 1:5 matched sample with recipients of HCV-negative kidneys.

Results:

The mean age of THINKER participants was 56.3 years (SD, 6.7), 70% were male, and 40% were black. All 20 participants achieved HCV cure. Hepatic and renal complications were transient or were successfully managed. Mean PCS and MCS quality-of-life scores decreased at 4 weeks; PCS scores then increased above pretransplant values, whereas MCS scores returned to baseline values. Estimated GFRs were similar between THINKER participants and matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs. 66.2 mL/min/1.73 m²; 95% CI for between-group difference, −4.2 to 7.5 mL/min/1.73 m²) and 12 months (median, 72.8 vs. 67.2 mL/min/1.73 m²; CI for between-group difference, −7.2 to 9.8 mL/min/1.73 m²).

Limitation:

Small trial.

Conclusion:

Twenty HCV-negative recipients of HCV-infected kidneys experienced HCV cure, good quality of life, and excellent renal function. Kidneys from HCV-infected donors may be a valuable transplant resource.

Primary Funding Source:

Merck.

https://ift.tt/2AIgTuG

Transplanting Kidneys From Hepatitis C–Infected Donors Into Uninfected Recipients: Ready for the Mainstream

Despite favorable short-term results with transplant of hepatitis C virus (HCV)–positive kidneys into HCV-negative recipients, the American Society of Transplantation's enthusiasm for this approach is muted. In this issue, Reese and colleagues provide evidence for the benefits of this approach in the current era of direct-acting antiviral agents. The editorialist discusses the promise these results hold for improving outcomes among patients requiring kidney transplant.

https://ift.tt/2AIgqsq

Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care A Matched Cohort Study

Background:

Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes.

Objective:

To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM.

Design:

Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015.

Setting:

4 integrated health systems in the United States.

Participants:

Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A_1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059).

Intervention:

Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care.

Measurements:

Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy.

Results:

Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio [HR], 0.41 [95% CI, 0.34 to 0.48]). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 [CI, 0.30 to 0.47]), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 [CI, 0.29 to 0.58]), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 [CI, 0.42 to 0.73]).

Limitation:

Electronic health record databases could misclassify microvascular disease status for some patients.

Conclusion:

In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care.

Primary Funding Source:

National Institute of Diabetes and Digestive and Kidney Diseases.

https://ift.tt/2ANbAu1

Compensation Disparities by Gender in Internal Medicine

https://ift.tt/2vmB5xa

The Actomyosin Cytoskeleton Drives Micron‐Scale Membrane Remodeling In Vivo Via the Generation of Mechanical Forces to Balance Membrane Tension Gradients

BioEssays, EarlyView.


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Optimization of the extraction of natural antioxidants from Coffea robusta leaves and evaluation of their ability to preserve palm olein from oxidation during accelerated storage

Food Science &Nutrition, EarlyView.


https://ift.tt/2KwWHM6

Heavy metal and microbial safety assessment of raw and cooked pumpkin and Amaranthus viridis leaves grown in Abakaliki, Nigeria

Food Science &Nutrition, EarlyView.


https://ift.tt/2njptXk

Let's Get a Hand on this: Review of the Clinical Anatomy of “Knuckle Cracking”

Clinical Anatomy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2vKntv7

Prognostic implications of MRI‐detected lateral nodal disease and extramural vascular invasion in rectal cancer

BJS, EarlyView.


https://ift.tt/2LTU9x7

PCA and deep learning based myoelectric grasping control of a prosthetic hand

For the functional control of prosthetic hand, it is insufficient to obtain only the motion pattern information. As far as practicality is concerned, the control of the prosthetic hand force is indispensable. ...

https://ift.tt/2vplQnc

Preparation for colonoscopy: recommendations by an expert panel in Italy

Despite several guidelines on bowel preparation being available, their applicability in Italy is poorly investigated.

https://ift.tt/2MsEUYl

So-called “non-classic” ciliated Muconodular papillary tumors: a comprehensive comparison of the Clinicopathological and molecular features with classic ciliated Muconodular papillary tumors

Ciliated muconodular papillary tumors (CMPTs) are characterized by tripartite cellular components of ciliated columnar cells, mucinous cells, and basal cells with predominantly papillary architecture. Some peripheral lung nodules may not demonstrate papillary architecture and tripartite cells that show bronchiolar differentiation; these nodules are termed "CMPTs with non-classic morphology" by some authors. To validate the rationality of "non-classic" CMPTs and to analyze the clinicopathological features of CMPTs, we enrolled 21 cases of lung nodules, comprising classic CMPTs (n=11) and so-called "non-classic" CMPTs (n=10).

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Hormone Therapy for Menopausal Symptoms

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Annals Graphic Medicine - Critical Space

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Prognostic Implications of Single-Sample Confirmatory Testing for Undiagnosed Diabetes A Prospective Cohort Study

Background:

Current clinical definitions of diabetes require repeated blood work to confirm elevated levels of glucose or hemoglobin A_1c (HbA_1c) to reduce the possibility of a false-positive diagnosis. Whether 2 different tests from a single blood sample provide adequate confirmation is uncertain.

Objective:

To examine the prognostic performance of a single-sample confirmatory definition of undiagnosed diabetes.

Design:

Prospective cohort study.

Setting:

The ARIC (Atherosclerosis Risk in Communities) study.

Participants:

13 346 ARIC participants (12 268 without diagnosed diabetes) with 25 years of follow-up for incident diabetes, cardiovascular outcomes, kidney disease, and mortality.

Measurements:

Confirmed undiagnosed diabetes was defined as elevated levels of fasting glucose (≥7.0 mmol/L [≥126 mg/dL]) and HbA_1c (≥6.5%) from a single blood sample.

Results:

Among 12 268 participants without diagnosed diabetes, 978 had elevated levels of fasting glucose or HbA_1c at baseline (1990 to 1992). Among these, 39% had both (confirmed undiagnosed diabetes), whereas 61% had only 1 elevated measure (unconfirmed undiagnosed diabetes). The confirmatory definition had moderate sensitivity (54.9%) but high specificity (98.1%) for identification of diabetes cases diagnosed during the first 5 years of follow-up, with specificity increasing to 99.6% by 15 years. The 15-year positive predictive value was 88.7% compared with 71.1% for unconfirmed cases. Confirmed undiagnosed diabetes was significantly associated with cardiovascular and kidney disease and mortality, with stronger associations than unconfirmed diabetes.

Limitation:

Lack of repeated measurements of fasting glucose and HbA_1c.

Conclusion:

A single-sample confirmatory definition of diabetes had a high positive predictive value for subsequent diagnosis and was strongly associated with clinical end points. Our results support the clinical utility of using a combination of elevated fasting glucose and HbA_1c levels from a single blood sample to identify undiagnosed diabetes in the population.

Primary Funding Source:

National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute.

https://ift.tt/2I2iCJz

A Physician's Grammar

https://ift.tt/2LY0t6O

Comparative Benefits and Harms of Basal Insulin Analogues for Type 2 Diabetes A Systematic Review and Network Meta-analysis

Background:

Basal insulin analogues aim for protracted glycemic control with minimal adverse effects.

Purpose:

To assess the comparative efficacy and safety of basal insulin analogues for adults with type 2 diabetes mellitus (T2DM).

Data Sources:

Several databases from inception to April 2018 without language restrictions, ClinicalTrials.gov to April 2018, references of reviews, and meeting abstract books.

Study Selection:

Randomized trials lasting at least 12 weeks that compared efficacy (change in hemoglobin A_1c [HbA_1c] level from baseline [primary outcome]; percentage of patients with HbA_1c level <7% at end of study and change in body weight [secondary outcomes]) and safety (hypoglycemia) of basal insulin analogues.

Data Extraction:

Two authors independently extracted data and assessed risk of bias for each outcome. All authors evaluated overall confidence in the evidence.

Data Synthesis:

Thirty-nine trials (26 195 patients) assessed 10 basal insulin analogues. Low- to very-low-quality evidence indicated that thrice-weekly degludec (Deg-3TW) was inferior to most other regimens for reducing HbA_1c level, with mean differences ranging from 0.21% (vs. degludec, 100 U/mL [Deg-100]) to 0.32% (vs. glargine, 300 U/mL [Glar-300]). High- to moderate-quality evidence suggested that detemir had a favorable weight profile versus all comparators, and Glar-300 was associated with less weight gain than glargine, 100 U/mL (Glar-100); Deg-100; degludec, 200 U/mL (Deg-200); Deg-3TW; and LY2963016. Low- and very-low-quality evidence suggested that Deg-100, Deg-200, and Glar-300 were associated with lower incidence of nocturnal hypoglycemia than detemir, Glar-100, LY2963016, and neutral protamine lispro (NPL). Incidence of severe hypoglycemia did not differ among regimens, except NPL, which was associated with increased risk versus Deg-100, detemir, Glar-100, and Glar-300.

Limitations:

Results are based mostly on indirect comparisons. Confidence in summary estimates is low or very low due to individual-study limitations, imprecision, or inconsistency.

Conclusion:

Low-quality evidence suggests that basal insulin analogues for T2DM do not substantially differ in their glucose-lowering effect. Low- and very-low-quality evidence suggests some regimens may be associated with lower risk for nocturnal hypoglycemia (Deg-100, Deg-200, and Glar-300) or less weight gain (detemir and Glar-300).

Primary Funding Source:

None. (PROSPERO: CRD42016037055)

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Politics and Professionalism

https://ift.tt/2nhxxrs

Herpes Zoster

Primary care providers and hospitalists frequently encounter older or immunocompromised patients with herpes zoster accompanied by debilitating pain. Atypical presentations and zosteriform herpes simplex may present diagnostic challenges to clinicians. This article summarizes the background, evidence, and guidelines for the diagnosis, complications, treatment, and prevention of herpes zoster. Diagnosis of challenging cases relies on polymerase chain reaction as the preferred test. Treatment focuses on optimal use of antiviral therapy and analgesics. Prevention emphasizes utilization of a new recombinant zoster vaccine, which reduces the incidence of herpes zoster by more than 90% and is preferred to the live attenuated herpes zoster vaccine.

https://ift.tt/2LVL32I

Guidelines Versus Guidelines: What's Best for the Patient?

Expert clinicians counter some of the recommendations regarding hemoglobin A_1c targets for type 2 diabetes that were proposed in a recent American College of Physicians guideline.

https://ift.tt/2x74qie

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Syndrome Treated With Sirolimus

https://ift.tt/2IHz1E9

Opioid Use Disorder, Stigma, and Transplantation: A Call to Action

Should people with opioid use disorder who are being treated with opioid agonist therapy be deemed ineligible for organ transplant? This commentary proposes an answer.

https://ift.tt/2NCscac

Provider Types and Outcomes in Obstructive Sleep Apnea Case Finding and Treatment

https://ift.tt/2LWWAio

Overdose Prevention Through Medical Treatment of Opioid Use Disorders

In their article, Larochelle and colleagues provided convincing evidence of the benefits of methadone and buprenorphine in preventing opioid-related deaths in patients with a history of nonfatal opioid overdose. The editorialists discuss the findings and what they reveal about the challenges of overcoming barriers to broader use of medication-assisted treatment of opioid use disorder.

https://ift.tt/2I0OgHv

Hormone Therapy for Menopausal Symptoms

https://ift.tt/2nhxV9o

Two in One: Diagnosing Type 2 Diabetes With Single-Sample Testing

Selvin and colleagues reported the prognostic capability of "single-sample" definitions of confirmed (elevated levels of both fasting glucose and hemoglobin A_1c) and unconfirmed (elevated level of fasting glucose level or hemoglobin A_1c) undiagnosed diabetes to identify future risk for diagnosed diabetes and its complications. The editorialists discuss the promise of these findings (if they are confirmed in other populations) to improve the timing and efficiency of diabetes diagnosis.

https://ift.tt/2K17lP2

Politics and Professionalism

https://ift.tt/2LWWnf6

Radiation Induced Cerebral Microbleeds in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy

This study investigates radiation-induced cerebral microbleeds (CMBs) in pediatric patients with primary brain tumors treated with proton radiotherapy. This complication of radiotherapy has not been significantly studied following proton radiotherapy in the pediatric patient population, particularly with regards to timing, incidence and associated risk factors. CMBs have been associated with decreased neurocognitive function indicating the potential clinical significance. This research establishes an estimate for the timing and incidence of CMBs, evaluates how CMBs accrue over time, investigates risk factors associated with development of CMBs, and allows for a comparison between photon and proton radiotherapy.

https://ift.tt/2nhScfb

Effectiveness of Rotating Shield Brachytherapy for Prostate Cancer Dose Escalation and Urethral Sparing

A 26-patient treatment planning study comparing rotating shield brachytherapy (RSBT) to conventional high-dose-rate brachytherapy (HDR-BT) for dose escalation, simulating monotherapy, and urethra sparing, simulating boost therapy. The radiobiological effects of dose protraction and source age were accounted for. RSBT can increase PTV EQD90% or decrease urethral D10% relative to HDR-BT at the cost of increased treatment time. Source aging reduces RSBT benefit, but RSBT remains theoretically superior to HDR-BT by >20% after one-half-life has elapsed.

https://ift.tt/2Oi8qAl

Development of a “ready to use” graphical tool based on artificial neural network classification: application for the prediction of late fecal incontinence after prostate cancer radiotherapy

Artificial Neural Networks (ANNs) are a valid tool to develop predictive models of radiotherapy outcomes, especially when complex nonlinear relationships between input and output variables are present. However, they are often considered as impenetrable "black boxes", with the original information being inscrutably elaborated throughout the network of neurons. In this study, we develop a readable ANN-based graphical tool for the prediction of late faecal incontinence after prostate cancer radiotherapy.

https://ift.tt/2ng0rZd

Dimethyl Sulfoxide Prevents Radiation-induced Oral Mucositis through Facilitating DNA Double-strand Break Repair in Epithelial Stem Cell

We show that dimethyl sulfoxide (DMSO) exhibits marked protective activity against radiation-induced oral mucositis in mice without tumor protection, and the efficacy of DMSO is superior to that of rhKGF and amifostine. Administration of DMSO significantly prevents the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation by facilitating DNA double-strand breaks repair. High efficacy and low toxicity of DMSO suggest possible therapeutic application.

https://ift.tt/2OddvKa

Measurement of Ultrafast Vibrational Coherences in Polyatomic Radical Cations with Strong-Field Adiabatic Ionization

We present a protocol for probing ultrafast vibrational coherences in polyatomic radical cations that result in molecular dissociation.

https://ift.tt/2OdrPT4

Analyzing Dynamic Protein Complexes Assembled On and Released From Biolayer Interferometry Biosensor Using Mass Spectrometry and Electron Microscopy

Here we present a protocol to monitor the assembly and disassembly of the anthrax toxin using biolayer interferometry (BLI). Following assembly/disassembly on the biosensor surface, the large protein complexes are released from the surface for visualization and identification of components of the complexes using electron microscopy and mass spectrometry, respectively.

https://ift.tt/2vJXL9N

Quantifying Plant Soluble Protein and Digestible Carbohydrate Content, Using Corn (Zea mays) As an Exemplar

The protocols described herein provide a clear and approachable methodology for measuring soluble protein and digestible (non-structural) carbohydrate content in plant tissues. The ability to quantify these two plant macronutrients has significant implications for advancing the fields of plant physiology, nutritional ecology, plant-herbivore interactions and food-web ecology.

https://ift.tt/2LZkBFB

2 in 1: One-step Affinity Purification for the Parallel Analysis of Protein-Protein and Protein-Metabolite Complexes

Protein-protein and protein-metabolite interactions are crucial for all cellular functions. Herein, we describe a protocol that allows parallel analysis of these interactions with a protein of choice. Our protocol was optimized for plant cell cultures and combines affinity purification with mass spectrometry-based protein and metabolite detection.

https://ift.tt/2vIl3gu

EMS coordination: Healthcare coalitions provide organized cooperation

Healthcare coalitions offer EMS a "seat at the table" for regional emergency planning

https://ift.tt/2ON7rco

MLKL mediates apoptosis via a mutual regulation with PERK/eIF2α pathway in response to reactive oxygen species generation

Abstract

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a core effector of necroptosis, and its function in necroptosis is widely studied. However, the function of MLKL in apoptosis remains unclear. In the present study, the role of MLKL in chelerythrine (CHE)-promoted apoptosis was studied. A special band of MLKL (i.e., *MLKL) was observed after treatment with CHE. MLKL and *MLKL were accumulated in the nucleus upon treatment with CHE and MLKL silencing reversed the CHE-induced apoptosis. Blockade of CHE-triggered reactive oxygen species (ROS) generation or inhibition of CHE-activated protein kinase-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α subunit (eIF2α) pathway reversed the apoptosis. A decreased ROS level inhibited CHE-mediated nuclear translocation of MLKL and *MLKL and the activation of eIF2α, whereas MLKL or eIF2α silencing did not affect the CHE-triggered ROS generation. Furthermore, MLKL silencing prevented the CHE-activated eIF2α signal, and eIF2α silencing blocked the CHE-induced nuclear translocation of MLKL and *MLKL. Our studies suggested that CHE possibly induces apoptosis through the nuclear translocation of MLKL and *MLKL, which is promoted by a mutual regulation between MLKL and PERK–eIF2α pathway in response to ROS formation. The present study clarified the new function of MLKL in apoptosis.

https://ift.tt/2LUSvLA

Measuring the Flight Ability of the Ambrosia Beetle, Platypus Quercivorus (Murayama), Using a Low-Cost, Small, and Easily Constructed Flight Mill

We developed a low cost and small flight mill, constructed with commonly available items and easily used in experimentation. Using this apparatus, we measured the flight ability of an ambrosia beetle, Platypus quercivorus.

https://ift.tt/2OLi1Rb

Measurement of circulating tumor cells in squamous cell carcinoma of the head and neck and patient outcomes

Abstract

Objectives

We report the outcomes of patients with squamous cell carcinoma of the head and neck (HNSCC) whose circulating tumor cells (CTCs) were quantified using surface-enhanced Raman scattering (SERS) nanotechnology.

Methods

SERS tagged with EGF was used to directly measure targeted CTCs. Patient charts were retrospectively reviewed. An optimal cut point for CTCs in 7.5 ml of peripheral blood predictive of for distant metastasis-free survival (DMFS) was identified by maximizing the log-rank statistic. An ROC analysis was also performed.

Results

Of 82 patients, 13 experienced metastatic progression. The optimal cut point for DMFS was 675 CTCs (p = 0.047). For those with distant recurrence (n = 13) versus those without distant recurrence (n = 69), the CTC cut point which results in the largest combined sensitivity and specificity values is also 675 (sensitivity = 69%, specificity = 68%).

Conclusion

Liquid biopsy techniques in HNSCC show promise as a means of identifying patients at greater risk of disease progression.

https://ift.tt/2vFtfhv

CDC: Half of U.S. Adults Tried to Lose Weight From 2013 to 2016

MONDAY, Aug. 6, 2018 -- Nearly half of U.S. adults have tried to lose weight from 2013 to 2016, according to a July data brief published by the U.S. Centers for Disease Control and Prevention's National Center for Health Statistics. Crescent B....

https://ift.tt/2vGMwPy

Increase in Proportion of TAVR Used From 2012 to 2015

MONDAY, Aug. 6, 2018 -- From 2012 to 2015, there was an increase in the number of patients overall and age 65 years and younger receiving transcatheter aortic valve replacement (TAVR), according to a research letter published online July 23 in the...

https://ift.tt/2LWVTFX

About Half of Child Caregivers Use Cellphones While Driving

MONDAY, Aug. 6, 2018 -- Inconsistent use of a child restraint system and negligent use of a seat belt are associated with parent/caregiver cellphone use while driving children, according to a study published online July 12 in The Journal of...

https://ift.tt/2vJM7Mp

Advance Care Planning Doesn't Aid Quality of Life

MONDAY, August 2, 2018 -- Advance care planning in frail older adults does not increase patient activation or quality of life, according to a study published in the June issue of the Journal of the American Geriatrics Society. Anouk Overbeek, from...

https://ift.tt/2nflOcX

Rifampin Effective for Latent Tuberculosis in Children

MONDAY, Aug. 6, 2018 -- In children with latent tuberculosis, a regimen of four months of rifampin has better rates of completion than nine months of isoniazid, with similar safety profiles, according to a study published in the Aug. 2 issue of the...

https://ift.tt/2nhEoS0

Biomarker Panel May Improve Lung Cancer Risk Assessment

MONDAY, Aug. 6, 2018 -- Biomarker-based risk profiling has the potential to improve lung cancer risk assessment, according to a study published online July 12 in JAMA Oncology. Florence Guida, Ph.D., from the International Agency for Research on...

https://ift.tt/2LWVPpH

Cohesive Teams Can Help Blend Clinical Care With Education

MONDAY, Aug. 6, 2018 -- Building cohesive teams in teaching clinics can help blend clinical care with education for residents, according to an article published in the American Medical Association's AMA Wire. A group of physician-educators visited...

https://ift.tt/2vJM2s5

Surgical Price Transparency Tied to Improved Volume, Revenue

MONDAY, Aug. 6, 2018 -- Ambulatory surgery centers experience increases in patient volume, patient satisfaction, and revenue after adopting price transparency, according to a study published recently in The American Surgeon. Ambar Mehta, M.D., from...

https://ift.tt/2vGMnM0

Plasma Copeptin More Accurate for Diabetes Insipidus Diagnosis

MONDAY, Aug. 6, 2018 -- In patients with hypotonic polyuria, the direct measurement of hypertonic saline-stimulated plasma copeptin has better diagnostic accuracy than the water-deprivation test, according to a study published in the Aug. 2 issue of...

https://ift.tt/2LTxDUW

Favorable mortality-to-incidence ratios of kidney Cancer are associated with advanced health care systems

Abstract

Background

The advancements in cancer therapy have improved the clinical outcomes of cancer patients in recent decades. However, advanced cancer therapy is expensive and requires good health care systems. For kidney cancer, no studies have yet established an association between clinical outcome and health care disparities.

Methods

We used the mortality-to-incidence ratio (MIR) for kidney cancer as a marker of clinical outcome to compare World Health Organization (WHO) country rankings and total expenditures on health/gross domestic product (e/GDP) using linear regression analyses.

Results

We included 57 countries based on data from the GLOBOCAN 2012 database. We found that more highly developed regions have higher crude and age-standardized rates of kidney cancer incidence and mortality, but a lower MIR, when compared to less developed regions. North America has the highest crude rates of incidence, but the lowest MIRs, whereas Africa has the highest MIRs. Furthermore, favorable MIRs are correlated with countries with good WHO rankings and high e/GDP expenditures (p < 0.001 and p = 0.013, respectively).

Conclusions

Kidney cancer MIRs are positively associated with the ranking of health care systems and health care expenditures.

https://ift.tt/2nhnaEd

Aberrant DNA methylation of ADAMTS16 in colorectal and other epithelial cancers

Abstract

Background

ADAMs (a disintegrin and metalloproteinase) have long been associated with tumor progression. Recent findings indicate that members of the closely related ADAMTS (ADAMs with thrombospondin motifs) family are also critically involved in carcinogenesis. Gene silencing through DNA methylation at CpG loci around e.g. transcription start or enhancer sites is a major mechanism in cancer development. Here, we aimed at identifying genes of the ADAM and ADAMTS family showing altered DNA methylation in the development or colorectal cancer (CRC) and other epithelial tumors.

Methods

We investigated potential changes of DNA methylation affecting ADAM and ADAMTS genes in 117 CRC, 40 lung cancer (LC) and 15 oral squamous-cell carcinoma (SCC) samples. Tumor tissue was analyzed in comparison to adjacent non-malignant tissue of the same patients. The methylation status of 1145 CpGs in 51 ADAM and ADAMTS genes was measured with the HumanMethylation450 BeadChip Array. ADAMTS16 protein expression was analyzed in CRC samples by immunohistochemistry.

Results

In CRC, we identified 72 CpGs in 18 genes which were significantly affected by hyper- or hypomethylation in the tumor tissue compared to the adjacent non-malignant tissue. While notable/frequent alterations in methylation patterns within ADAM genes were not observed, conspicuous changes were found in ADAMTS16 and ADAMTS2. To figure out whether these differences would be CRC specific, additional LC and SCC tissue samples were analyzed. Overall, 78 differentially methylated CpGs were found in LC and 29 in SCC. Strikingly, 8 CpGs located in the ADAMTS16 gene were commonly differentially methylated in all three cancer entities. Six CpGs in the promoter region were hypermethylated, whereas 2 CpGs in the gene body were hypomethylated indicative of gene silencing. In line with these findings, ADAMTS16 protein was strongly expressed in globlet cells and colonocytes in control tissue but not in CRC samples. Functional in vitro studies using the colorectal carcinoma cell line HT29 revealed that ADAMTS16 expression restrained tumor cell proliferation.

Conclusions

We identified ADAMTS16 as novel gene with cancer-specific promoter hypermethylation in CRC, LC and SCC patients implicating ADAMTS16 as potential biomarker for these tumors. Moreover, our results provide evidence that ADAMTS16 may have tumor suppressor properties.

https://ift.tt/2vLHuRO