Economic Burden of HR+/HER2- Metastatic Breast Cancer Among Adult Premenopausal Women

Abstract

Introduction

Premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) have complex treatment needs and may receive sequential combinations of endocrine therapy (ET) or chemotherapy. This study describes healthcare utilization (HRU) and costs among premenopausal women with HR+/HER2- mBC in real-world settings from a payer's perspective.

Methods

In this retrospective cohort study, premenopausal women with HR+/HER2- mBC who received ET or chemotherapy were identified from the Truven Health Analytics MarketScan database (1 January 2006–31 December 2015). The main HRU outcomes per patient per 6 months (PPP6 M) were measured during each line of therapy and included number of days in inpatient (IP) and outpatient (OP) services. Healthcare costs per patient per month (PPPM) included medical and pharmacy costs.

Results

A total of 3203 patients received first-line, 2194 received second-line, and 1242 received third-line therapy for mBC. Mean number of IP days PPP6 M were 1.6, 1.3, and 1.5 days in the first, second, and third lines, respectively. Mean number of days with OP services PPP6 M was 31.4, 30.9, and 23.3 in the first, second, and third lines, respectively. Among patients receiving ET, mean total healthcare costs were $6521, $4440, and $4555 PPPM in the first, second, and third line, respectively. Among patients receiving chemotherapy, mean total healthcare costs were $16,842, $12,868, and $16,129 PPPM in the first, second, and third line, respectively. These costs were mainly driven by treatment and OP costs.

Conclusion

Real-world HRU and costs among premenopausal women with HR+/HER2- mBC are extensive. Patients who received chemotherapy incurred approximately twice the costs of patients treated with ET.

Funding

Novartis Pharmaceutical Corp.

http://ift.tt/2prbUWy

Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study

Abstract

Background

Prediction of the outcome of sorafenib therapy using biomarkers is an unmet clinical need in patients with advanced hepatocellular carcinoma (HCC). The aim was to develop and validate a biomarker-based model for predicting sorafenib response and overall survival (OS).

Methods

This prospective cohort study included 124 consecutive HCC patients (44 with disease control, 80 with progression) with Child-Pugh class A liver function, who received sorafenib. Potential serum biomarkers (namely, hepatocyte growth factor [HGF], fibroblast growth factor [FGF], vascular endothelial growth factor receptor-1, CD117, and angiopoietin-2) were tested. After identifying independent predictors of tumor response, a risk scoring system for predicting OS was developed and 3-fold internal validation was conducted.

Results

A risk scoring system was developed with six covariates: etiology, platelet count, Barcelona Clinic Liver Cancer stage, protein induced by vitamin K absence-II, HGF, and FGF. When patients were stratified into low-risk (score ≤ 5), intermediate-risk (score 6), and high-risk (score ≥ 7) groups, the model provided good discriminant functions on tumor response (concordance [c]-index, 0.884) and 12-month survival (area under the curve [AUC], 0.825). The median OS was 19.0, 11.2, and 6.1 months in the low-, intermediate-, and high-risk group, respectively (P < 0.001). In internal validation, the model maintained good discriminant functions on tumor response (c-index, 0.825) and 12-month survival (AUC, 0.803), and good calibration functions (all P > 0.05 between expected and observed values).

Conclusions

This new model including serum FGF and HGF showed good performance in predicting the response to sorafenib and survival in patients with advanced HCC.

http://ift.tt/2G6d4RI

MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models.

Related Articles

MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models.

Oncotarget. 2018 Feb 20;9(14):11592-11603

Authors: Vena F, Jia R, Esfandiari A, Garcia-Gomez JJ, Rodriguez-Justo M, Ma J, Syed S, Crowley L, Elenbaas B, Goodstal S, Hartley JA, Hochhauser D

Abstract
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines. Apoptosis was assessed by Caspase 3/7 assay and protein expression was detected by immunoblotting. DNA damage response was monitored with γH2AX and RAD51 immunofluorescence staining. In vivo antitumor activity of pimasertib with evofosfamide were assessed in pancreatic cancer xenografts. We found that BRCA2 protein expression was downregulated following pimasertib treatment under hypoxic conditions. This translated into reduced homologous recombination repair demonstrated by levels of RAD51 foci. MEK inhibition was sufficient to induce formation of γH2AX foci, suggesting that inhibition of this pathway would impair DNA repair. When combined with olaparib or evofosfamide, pimasertib treatment enhanced DNA damage and increased apoptosis. The combination of pimasertib with evofosfamide demonstrated increased anti-tumor activity in BRCA wild-type Mia-PaCa-2 xenograft model, but not in the BRCA mutated BxPC3 model. Our data suggest that targeted MEK inhibition leads to impaired homologous recombination DNA damage repair and increased PARP inhibition sensitivity in BRCA-2 proficient cancers.

PMID: 29545922 [PubMed]

http://ift.tt/2pkYsDt

Inhibition of FASN expression enhances radiosensitivity in human non-small cell lung cancer.

Related Articles

Inhibition of FASN expression enhances radiosensitivity in human non-small cell lung cancer.

Oncol Lett. 2018 Apr;15(4):4578-4584

Authors: Zhan N, Li B, Xu X, Xu J, Hu S

Abstract
Fatty acid synthase (FASN) is the key enzyme required for the de novo synthesis of long-chain fatty acids. FASN has been observed to be overexpressed in the majority of cancer tissues, and its expression is associated with a poor prognosis, potentially mediated by resistance to drug or radiation. The present study investigated whether the downregulation of FASN in non-small cell lung cancer (NSCLC) may increase radiosensitivity. A lentiviral vector containing short hairpin RNA targeted to FASN (pSIH-H1-Puro-shFASN) was successfully constructed and transfected into A549 cells to knockdown the gene by RNA interference. pSIH-H1-Puro-shFASN was used as the experimental group, while pSIH-H1-Puro-shGFP was used as a control group. The mRNA expression levels of FASN were determined using quantitative polymerase chain reaction. In addition, cell proliferation was measured using cell counting kit-8 assay, and colony formation assay was performed to determine the radiosensitizing effect of FASN knockdown. The cell cycle distribution and apoptotic rates were analyzed using flow cytometry, while western blot analysis was used to assess the expression of DNA-dependent protein kinase catalytic subunit protein, which is associated with DNA double-strand break (DSB) repair. The results of the present study revealed that NSCLC cells are more sensitive to radiation following the knockdown of FASN. Furthermore, the increased radiosensitivity may be associated with increased proliferation, promotion of apoptosis and cell cycle arrest in the G2/M phase. Furthermore, downregulated FASN expression reduced the levels of DNA DSB repair-associated proteins following treatment with radiation. These results indicate that silencing FASN may sensitize NSCLC cells to radiation treatment. Therefore, FASN may be a potential novel therapeutic target to improve the response of NSCLCs to radiation therapy.

PMID: 29541228 [PubMed]

http://ift.tt/2GyqweC

Prognostic value of metformin for non-small cell lung cancer patients with diabetes

Abstract

Background

The anti-cancer role of metformin has been reported in many different kinds of solid tumors, but how it affects non-small cell lung cancer (NSCLC) is currently elusive. The aim of this study was to investigate the influence of metformin treatment on diabetic NSCLC.

Methods

Two hundred fifty-five patients of diabetic NSCLC receiving therapy in our hospital from 2014 to 2016 were enrolled in our study. The information on clinical diagnosis, pathology, and prognosis as well as the influence of metformin in diabetic NSCLC were collected and assessed. Univariate and multivariate analytical techniques were applied to explore how metformin affect the survival of NSCLC.

Results

One hundred fifty of the 255 diabetic NSCLC patients took metformin. The median overall survival time (OST) and disease-free survival time (DFST) were significantly prolonged with metformin treatment compared to without metformin treatment (OST 25.0 vs 11.5 months, p = 0.005; DFST 15.6 vs 8.5 months, p = 0.010). Multivariate analysis indicated that metformin treatment could be used to predict the long-term outcome of diabetic NSCLC independently (HR = 0.588, 95% CI 0.466–0.895, p = 0.035).

Conclusion

Our study revealed that the metformin could help in improving the final outcome of NSCLC patients with diabetes in the long term and thus could be applied to treat NSCLC.

http://ift.tt/2G4IoAd

Perioperative Management of Patients with Inflammatory Rheumatic Diseases Undergoing Major Orthopaedic Surgery: A Practical Overview

Abstract

Patients with inflammatory rheumatic diseases often need orthopaedic surgery due to joint involvement. Total hip replacement and total knee replacement are frequent surgical procedures in these patients. Due to the complexity of the inflammatory rheumatic diseases, the perioperative management of these patients must envisage a multidisciplinary approach. The frequent association with extraarticular comorbidities must be considered when evaluating perioperative risk of the patient and should guide the clinician in the decision-making process. However, guidelines of different medical societies may vary and are sometimes contradictory. Orthopaedics should collaborate with rheumatologists, anaesthesiologists and, when needed, cardiologists and haematologists with the common aim of minimising perioperative risk in patients with inflammatory rheumatic diseases. The aim of this review is to provide the reader with simple practical recommendations regarding perioperative management of drugs such as disease-modifying anti-rheumatic drugs, corticosteroids, non-steroidal anti-inflammatory drugs and tools for a risk stratification for cardiovascular and thromboembolic risk based on current evidence for patients with inflammatory rheumatic diseases.

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Myxoid liposarcoma: local relapse and metastatic pattern in 43 patients

Abstract

Background

Liposarcomas are the second most common type of soft tissue sarcomas, 30–50% of these are of myxoid subtype. The aim of this retrospective study was to analyze the local control rate, the metastatic pattern and survival of patients in a consecutive single-institution series.

Methods

From 1983 to 2015, 43 patients with myxoid liposarcoma of the extremities and trunk wall underwent resections. The margin was defined as R0 (wide) or R1 (marginal). Patients were followed for evidence of local recurrence or distant metastasis. Overall and recurrence-free survival was calculated.

Results

The mean age was 48.6 years. The lower extremity was involved in 40 cases, the mean tumour size was 12 cm. In 31 cases a wide and in 12 cases a marginal resection was performed. Grading was G1 in 14, G2 in 25 and G3 in 4 cases.

Nine patient died in follow-up, 4 of them with metastatic disease, all nonpulmonary. 5-year local recurrence (LR) free survival was 82%. 4 (9.3%) patients developed LR (all R1). Overall survival (OS) was 81% after 5 and 72% after 10 years. In multivariate analysis age and Grading proved to be significant on OS. According to univariate analysis, only age over 48 years and distant metastasis had a significant impact on overall survival.

Conclusions

Patients with myxoid liposarcomas have a good prognosis. Myxoid liposarcoma has a distinct pattern of nonpulmonary metastatic disease. Therefore, patients with high-risk extremity myxoid liposarcoma should undergo imaging studies of the chest, abdomen, spine and pelvis as part of their staging and follow-up examinations preferably with whole body MRI, or CT scans and MRI of the spine and pelvic region for detection of suspected metastatic disease.

http://ift.tt/2G8toRW

Pretreatment prognostic factors of survival and late toxicities for patients with nasopharyngeal carcinoma treated by simultaneous integrated boost intensity-modulated radiotherapy

Abstract

Background

To scrutinize the pretreatment prognosticators on survival and late toxicities in a homogenous cohort of nasopharyngeal carcinoma (NPC) patients treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT).

Methods

A total of 219 non-distant metastatic NPC patients consecutively treated by SIB-IMRT at a single institute were collected. The pretreatment factors including the socio-demographic variables, TNM stages, gross tumor volume (GTV), Epstein-Barr virus (EBV)-DNA, and hematologic inflammatory markers were analyzed. Cox model was used to screen the prognostic factors of late toxicities and four survival outcomes including locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), failure-free survival (FFS), and overall survival (OS).

Results

Statistically significant inter-correlations were observed between the values of EBV-DNA, some hematologic inflammatory markers, GTV, and N classification. The 5-year LRRFS, DMFS, FFS, and OS rates were 87.9%, 89.4%, 79.4%, and 81.3%, respectively. Multivariate analysis revealed that advanced N classification (N2–3 vs. N0–1) remained the only significant negative prognosticator for all the four survival outcomes. An increased monocyte percentage and a decreased lymphocyte-to-monocyte ratio were significantly associated with poorer FFS and OS, respectively. Larger GTV was observed to be predictive of poorer LRRFS. Patients with T3–4 (HR: 3.5, 95% CI: 1.0–12.1, p = 0.048) or higher GTV (HR: 1.006, 95% CI: 1.001–1.011, p = 0.027) were associated with higher incidence of radiation neuropathy.

Conclusion

N classification remains the most significant survival predictor for NPC patients treated by SIB-IMRT after adjusting these biomarkers. GTV impacts not only on locoregional control but also radiation neuropathy.

http://ift.tt/2G8B2vu

Underutilization and disparities in access to EGFR testing among Medicare patients with lung cancer from 2010 – 2013

Abstract

Background

Tumor testing for mutations in the epidermal growth factor receptor (EGFR) gene is indicated for all newly diagnosed, metastatic lung cancer patients, who may be candidates for first-line treatment with an EGFR tyrosine kinase inhibitor. Few studies have analyzed population-level testing.

Methods

We identified clinical, demographic, and regional predictors of EGFR & KRAS testing among Medicare beneficiaries with a new diagnosis of lung cancer in 2011–2013 claims. The outcome variable was whether the patient underwent molecular, EGFR and KRAS testing. Independent variables included: patient demographics, Medicaid status, clinical characteristics, and region where the patient lived. We performed multivariate logistic regression to identify factors that predicted testing.

Results

From 2011 to 2013, there was a 19.7% increase in the rate of EGFR testing. Patient zip code had the greatest impact on odds to undergo testing; for example, patients who lived in the Boston, Massachusetts hospital referral region were the most likely to be tested (odds ratio (OR) of 4.94, with a 95% confidence interval (CI) of 1.67–14.62). Patient demographics also impacted odds to be tested. Asian/Pacific Islanders were most likely to be tested (OR 1.63, CI 1.53–1.79). Minorities and Medicaid patients were less likely to be tested. Medicaid recipients had an OR of 0.74 (CI 0.72–0.77). Hispanics and Blacks were also less likely to be tested (OR 0.97, CI 0.78–0.99 and 0.95, CI 0.92–0.99), respectively. Clinical procedures were also correlated with testing. Patients who underwent transcatheter biopsies were 2.54 times more likely to be tested (CI 2.49–2.60) than those who did not undergo this type of biopsy.

Conclusions

Despite an overall increase in EGFR testing, there is widespread underutilization of guideline-recommended testing. We observed racial, income, and regional disparities in testing. Precision medicine has increased the complexity of cancer diagnosis and treatment. Targeted interventions and clinical decision support tools are needed to ensure that all patients are benefitting from advances in precision medicine. Without such interventions, precision medicine may exacerbate racial disparities in cancer care and health outcomes.

http://ift.tt/2G9LGlA

Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer

Abstract

Background

To investigate the relationship between time elapsed since completion of radiotherapy (RT) and quality of life (QOL) of patients with breast cancer.

Methods

A total of 300 patients with breast cancer were treated at the First Affiliated Hospital of Anhui Medical University between January 2013 and April 2016. Of these, 212 patients were included in the study. Patients were divided into 4 groups based on the time elapsed since completion of RT. The generic cancer questionnaire, EORTC QLQ-30, and the breast cancer-specific questionnaire, QLQ-BR23, were used to assess the QOL.

Results

Analysis of time elapsed since completion of RT and QOL revealed changes in the scores for role function with passage of time; the third year's scores were the highest. Pain symptoms during the 3rd and 4th years after RT were lower than those during the 1st and 2nd years after RT; scores for financial difficulties fluctuated with passage of time; perception of own body scores improved within first 3 years; sexual activity and enjoyment of sexual activity showed a significant decrease during the 2nd to 4th year post RT. Scores pertaining to concerns about future state of health showed a significant increase during the 2nd to 4th year after RT, while breast symptoms score showed fluctuations with passage of time.

Conclusions

Social function, pain symptoms, and concerns about future state of health tended to improve with passage of time after RT. Other scales showed no correlation with time elapsed since completion of RT.

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CD33-Specific Chimeric Antigen Receptor T Cells with Different Co-Stimulators Showed Potent Anti-Leukemia Efficacy and Different Phenotype

Human Gene Therapy, Ahead of Print.


http://ift.tt/2FWw55s

Safety and Efficacy of OXB-202, a Genetically Engineered Tissue Therapy for the Prevention of Rejection in High-Risk Corneal Transplant Patients

Human Gene Therapy, Ahead of Print.


http://ift.tt/2FMpO0m

Recent advances in medical therapy for metastatic urothelial cancer

Abstract

Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice. The paradigm of medical treatment for patients with metastatic UC is dramatically changing through the introduction of this and other immune-checkpoint inhibitors. In this article, we provide a brief overview of these immune-checkpoint inhibitors and a comprehensive summary of the use of cytotoxic chemotherapy for metastatic urothelial cancer, including ongoing clinical trials.

http://ift.tt/2u4hDqM

Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways

Abstract

Background

Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-tumor effects in many cancers, including multiple myeloma (MM); however, the underlying molecular mechanisms have not been clearly elucidated.

Methods

The anti-myeloma effects of metformin were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo NOD-SCID murine xenograft MM model. Cell viability was assessed with CCK8 and cell proliferation was measured by EdU incorporation assay. Cell cycle distribution and apoptosis were examined by flow cytometry. Transmission electron microscopy was used to visualized autophagosomes. Activation of AMPK and inhibition of mTORC1/C2 pathways was assessed by Western blot analysis. RPMI8226 cells and U266 cell lines with AMPK knockdown were generated by transfection with small interfering RNA targeting the AMPK-α1 and α2 subunits using Lipofectamine 2000 reagent.

Results

Metformin effectively inhibited the proliferation of MM cell lines, an effect that was associated with the induction of autophagy and G0/G1 cell cycle arrest, but not apoptosis. Metformin activated AMPK and repressed both mTORC1 and mTORC2 signaling pathways in myeloma cells as well as downstream molecular signaling pathways, such as p-4EBP1 and p-AKT. AMPK activation resulted in direct phosphorylation and activation of tuberous sclerosis complex 2 (TSC2), leading to inhibition of the mammalian target of rapamycin (mTOR). In addition, metformin inhibited myeloma cell growth in an AMPK-dependent manner. The xenograft mouse model further confirmed that metformin inhibited tumor growth by upregulation of AMPK and downregulation of mTOR.

Conclusions

Metformin inhibits the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest. Our results suggest that the molecular mechanism involves dual repression of mTORC1 and mTORC2 pathways via AMPK activation. Our study provides a theoretical basis for the development of novel strategies for the treatment of MM using metformin as an already approved and safe drug.

http://ift.tt/2pnEmt4

Induction of apoptosis in imatinib sensitive and resistant chronic myeloid leukemia cells by efficient disruption of bcr-abl oncogene with zinc finger nucleases

Abstract

Background

The bcr-abl fusion gene is the pathological origin of chronic myeloid leukemia (CML) and plays a critical role in the resistance of imatinib. Thus, bcr-abl disruption-based novel therapeutic strategy may warrant exploration. In our study, we were surprised to find that the characteristics of bcr-abl sequences met the design requirements of zinc finger nucleases (ZFNs).

Methods

We constructed the ZFNs targeting bcr-abl with high specificity through simple modular assembly approach. Western blotting was conducted to detect the expression of BCR-ABL and phosphorylation of its downstream STAT5, ERK and CRKL in CML cells. CCK8 assay, colony-forming assay and flow cytometry (FCM) were used to evaluate the effect of the ZFNs on the viablity and apoptosis of CML cells and CML CD34⁺ cells. Moreover, mice model was used to determine the ability of ZFNs in disrupting the leukemogenesis of bcr-abl in vivo.

Results

The ZFNs skillfully mediated 8-base NotI enzyme cutting site addition in bcr-abl gene of imatinib sensitive and resistant CML cells by homology-directed repair (HDR), which led to a stop codon and terminated the translation of BCR-ABL protein. As expected, the disruption of bcr-abl gene induced cell apoptosis and inhibited cell proliferation. Notably, we obtained similar result in CD34⁺ cells from CML patients. Moreover, the ZFNs significantly reduced the oncogenicity of CML cells in mice.

Conclusion

These results reveal that the bcr-abl gene disruption based on ZFNs may provide a treatment choice for imatinib resistant or intolerant CML patients.

http://ift.tt/2FM25gB

CircRNAs as biomarkers of cancer: a meta-analysis

Abstract

Background

The expression of circular RNA (circRNA) may affect tumor progression. However, there have been no systemic meta-analysis for cancer diagnosis by using circRNAs in clinical till now. Herein, we aimed to collect and examined all the evidence on the potential role of circRNA as novel biomarker in human cancers.

Methods

A comprehensive search strategy was used to search relevant literatures in the databases of PubMed, Embase, and the Web of Science from 2015 to August 2017. The correlation between circRNA expression and the diagnostic accuracy of tumor markers was analyzed. The methodological quality of each study was assessed by quality assessment for the diagnostic accuracies of the eligible studies (QUADAS-2). Statistical analysis was performed by applying the STATA (version 12.0) software.

Results

The present meta-analysis included 1752 patients with circRNA expression data of tumor and paired adjacent non-tumorous tissues from 17 publications (19 studies). The pooled sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic OR (DOR) with their 95% confidential intervals (95%CIs), and AUC values were 0.72 (0.67–0.76), 0.74 (0.69–0.78), 2.80 (2.40–3.10), 0.38 (0.33–0.44), 7.00 (6.00–9.00), and 0.79, respectively. Subgroup analyses showed that the expression of circRNA in tissues of hepatocellular carcinoma (HCC) group was more prone to be detected than other tumor types, with a high values of the specificity, DOR, and AUC.

Conclusions

circRNAs might be suitable as diagnostic biomarkers for tumors, especially in HCC diagnosis. Further prospective studies on the diagnostic value of circRNAs from the different tumors are needed in the future.

http://ift.tt/2Iz0vN7

Re-challenging immune checkpoint inhibitor in a patient with advanced non-small cell lung cancer: a case report

Abstract

Background

Currently, immune checkpoint (ICP) inhibitors are essential drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICP inhibitors, the efficacy and safety of re-challenging the same or another ICP inhibitor remain unclear.

Case presentation

We present the case of a patient treated with nivolumab for advanced NSCLC who was previously treated with an ICP inhibitor as the first-line chemotherapy along with heavy cytotoxic chemotherapy. After the failure of five lines of chemotherapy, 3 cycles of nivolumab, as the ICP inhibitor re-challenge, the patient achieved a partial response.

Conclusions

This case might suggest that re-challenging an ICP inhibitor could be clinically active in selected patients with advanced NSCLC who progress after achieving an initial clinical benefit with an ICP inhibitor.

http://ift.tt/2prdqYD

Information for Readers

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Classified

FLORIDA, Port Charlotte: Stable, 22 year old, progressive independent group seeking residency trained, board certified EM physicians for expansion to second facility. 27k and 22k volume EDs. Full specialty backup. Excellent compensation based on productivity with full time income potential exceeding 350k. Flexible scheduling. Documentation by EMR. Malpractice, Health Insurance, Dental provided. Located on Charlotte Harbor with saltwater access to the Gulf. Short drive to Tampa, Sarasota, Fort Myers, Naples.

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Resuscitation of a Patient With an Implanted Electronic Device

A 21-year-old woman with a neurodegenerative disorder and severe dystonia was brought in by ambulance from a nursing home to our hospital. At the nursing home, the alarm for the intrathecal baclofen pump indicated malfunction, and emergency medical services (EMS) was notified. The patient had been fitted with a deep-brain stimulation device at age 9 years to control her dystonia, as well as an intrathecal baclofen pump. Baseline neurologic function was severely impaired; she was nonambulatory and nonverbal, with preserved consciousness and social nonverbal communication.

http://ift.tt/2ppjCAi

Defer Urgent Noninvasive Testing in Low-Risk Chest Pain Patients

To minimize missed acute coronary syndrome, the American Heart Association endorses noninvasive cardiac testing (eg, treadmill ECG, stress echocardiogram, stress myocardial perfusion, coronary computed tomography [CT] angiogram) before discharge or within 72 hours after discharge, after acute myocardial infarction has been excluded by serial biomarker tests (Class 2A recommendation).1 The fundamental assumption is that early identification of obstructive coronary artery disease may lead to coronary revascularization, with a subsequent reduction in acute myocardial infarction and cardiac death.

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Editors

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Getting to the Point of Ultrasonography in Cardiac Arrest

We enjoyed the recent article by Hu et al.1 This study addresses a common question encountered by emergency physicians. Although we are concerned that the disparate definitions of "cardiac activity" provided to the audience before testing may have increased, by priming, the level of observed disagreement, the article highlights an important concept: what appears to be a basic and readily answered question is actually quite nuanced. Thus, our belief is that dichotomous interpretation of bedside ultrasonography in the setting of cardiac arrest (ie, cardiac standstill: yes or no?) is an oversimplification of an inordinately complex process.

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Table of Contents

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Out With the Old, In With the Flu

SEE RELATED ARTICLE, P. 509.

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What's Coming in Annals ● May 2018

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Closing the Circle

The rescue team brought Shristi to the emergency department (ED) of our tent hospital in Kathmandu after she was dug out from the ruins of a collapsed building where she lay buried for 132 hours. We smoothly transferred her to the military stretcher held up by 2 metal stands. There was a single IV in her left hand. We sprang into action. Airway: clear; she was confused, mumbling basic phrases in Nepalese. Breath sounds: bilaterally clear to auscultation. Circulation: weak pulses. A nurse slammed in another IV and pushed fluids.

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Peer Reviewers

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Classified 2018 Advertising Rates & Information

Ads and complete payments must be received in writing by the issue's deadline date. These deadlines apply to insertions, cancellations, and changes.

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Transcription factor FoxM1 is the downstream target of c-Myc and contributes to the development of prostate cancer

Abstract

Background

Prostate cancer is a common malignancy and the second leading cause of cancer death in men. Elevated expression of the transcription factor FoxM1 and c-Myc has been identified in prostate cancer. However, the potential mechanism of elevated FoxM1 and c-Myc to the development of prostate cancer has not been identified.

Methods

In this report, the mRNA level of FoxM1 and c-Myc was detected in 30 prostate cancer and para-cancer tissues. Then, we detected the expression level of FoxM1 by real-time PCR and Western blot after disturbance of the expression level of c-Myc in PC-3 cells. Whether c-Myc could bind to FoxM1 promoter was identified by ChIP assay. Finally, the migratory, invasive, and proliferative abilities in FoxM1 overexpressing and silencing PC-3 cells were detected by wound healing, transwell assay, CCK-8 assays, and Ki-67 protein level.

Results

We found that the expression level of FoxM1 and c-Myc were both increased in prostate cancer samples compared with para-cancer samples. The expression level of FoxM1 was changed consistent with the protein level of c-Myc. ChIP assay detected the direct binding of c-Myc in FoxM1 gene promoter. Lastly, overexpression of FoxM1 increased the migratory, invasive, and proliferative abilities of PC-3 cells, and its downregulation significantly decreased the migratory, invasive, and proliferative abilities.

Conclusions

In conclusion, FoxM1 was significantly increased in prostate cancer samples, and it could regulate the proliferative and invasive ability of prostate cancer cells which might be a new target for prostate cancer. Besides, c-Myc could regulate the expression level of FoxM1 by directly binding to its gene promoter.

http://ift.tt/2pq4McJ

Programmable Single and Multiplex Base-Editing in Bombyx mori Using RNA-Guided Cytidine Deaminases

Genome editing using standard tools (ZFN, TALEN, and CRISPR/Cas9) rely on double strand breaks to edit the genome. A series of new CRISPR tools that convert cytidine to thymine (C to T) without the requirement for DNA double-strand breaks was developed recently and quickly applied in a variety of organisms. Here, we demonstrate that CRISPR/Cas9-dependent base editor (BE3) converts C to T with a high frequency in the invertebrate Bombyx mori silkworm. Using BE3 as a knock-out tool, we inactivated exogenous and endogenous genes through base-editing-induced nonsense mutations with an efficiency of up to 66.2%. Furthermore, genome-scale analysis showed that 96.5% of B. mori genes have one or more targetable sites that can be edited by BE3 for inactivation, with a median of 11 sites per gene. The editing window of BE3 reached up to 13 bases (from C1 to C13 in the range of gRNA) in B. mori. Notably, up to 14 bases were substituted simultaneously in a single DNA molecule, with a low indel frequency of 0.6%, when 32 gRNAs were co-transfected. Collectively, our data show for the first time that RNA-guided cytidine deaminases are capable of programmable single and multiplex base editing in an invertebrate model.

http://ift.tt/2DJlppe

Impact of donor type in patients with AML given allogeneic hematopoietic cell transplantation after low-dose TBI based regimen

Purpose: We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen. Experimental Design: Data from 1715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey. Results: Donors consisted either of HLA-matched sibling donors (MSD, n=701), 10/10 HLA-matched unrelated donors (MUD, n=611), HLA-haplo-identical donors (haplo, n=112) or single or double umbilical cord bloods (CBT, n=291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P<0.001). Two-year incidence of relapse was 32%, 30%, 34% and 34% in MSD, MUD, CBT and haplo patients, respectively (P=0.7). Two-year overall (OS) and GVHD-free relapse free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P=0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P=0.002).  Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Further, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD.

http://ift.tt/2G5SMrf

Targeting bromodomain and extra-terminal (BET) family proteins in castration resistant prostate cancer (CRPC)

Purpose: Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. Experimental Design: We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models. Results:  Nuclear BRD4 protein expression increases significantly (p=<0.01) with castration resistance in same patient treatment naïve (median H-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR 3.25, 95% CI 1.50-7.01; p=<0.001). BRD2, BRD3 and BRD4 RNA expression in CRPC biopsies correlates with AR driven transcription (all p=<0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression.  Furthermore, BETi reduce growth of PC cells and patient derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (p=<0.001) of a patient derived xenograft model of CRPC with AR amplification and AR-V7 expression. Conclusion: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof of mechanism pharmacodynamic studies. 

http://ift.tt/2HPnkuJ

Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene fusions associated with tumor progression

Purpose: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however current models are limited both in their availability and suitability to characterize these rare cells. Experimental Design: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq. Sphere formation potential and in vivo tumorigenicity was assessed by sorting for Aldefluor (ALDH) activity and CD44 expressing subpopulations. Results: For successive MEC relapses we found a time-dependent increase in CSCs (ALDH+CD44high), increasing from 0.2% to 4.5% (P=0.033), but more importantly we observed an increase in individual CSC sphere formation and tumorigenic potential. A 50% increase in mutational burden was documented in subsequent MEC tumors, and this was associated with increased expression of tumor promoting genes (MT1E, LGR5, LEF1), decreased expression of tumor suppressor genes (CDKN2B, SIK1, TP53), and higher expression of CSC-related proteins such as SOX2, MYC, and ALDH1A1. Finally, genomic analyses identified a novel NFIB-MTFR2 fusion in an ACC tumor and confirmed previously reported fusions (NTRK3-ETV6 and MYB-NFIB). Conclusions: Sequential MEC PDX models preserved key patient features and enabled the identification of genetic events putatively contributing to increases in both CSC proportion and intrinsic tumorigenicity, which mirrored the patient's clinical course. 

http://ift.tt/2G4d5W6

6-Gingerol Activates PI3K/Akt and Inhibits Apoptosis to Attenuate Myocardial Ischemia/Reperfusion Injury

6-Gingerol (6-G) is known to alleviate myocardial ischemia/reperfusion injury. However, the underlying molecular mechanisms of 6-G myocardial protection are not known. In this study, the protective effect of 6-G on ischemia/reperfusion (I/R) damage and whether such a mechanism was related to apoptosis inhibition and activation of phosphoinositide 3-kinases (PI3K)/serine/threonine kinase (Akt) signaling pathway were investigated. Rats were subjected to I/R in the presence or absence of 6-G and the changes of cardiac function, infarct size and histopathological changes, and the levels of cardiac troponin T, creatine kinase-MB, and myocardial apoptosis were examined. The expression of caspase-3, PI3K, p-Akt, and Akt was also determined. We found that 6-G (6 mg/kg) pretreatment significantly improved heart function and ameliorated infarct size and histopathological changes and cardiac troponin T and creatine kinase-MB levels induced by I/R. Moreover, pretreatment with 6-G significantly inhibited myocardial apoptosis and caspase-3 activation induced by I/R. 6-G also upregulated expression of PI3K, p-Akt, and Akt in myocardial tissues. Taken together, these findings suggest that 6-G inhibits apoptosis and activates PI3K/Akt signaling in response to myocardial I/R injury as a possible mechanism to attenuate I/R-induced injury in heart. These results might be important for developing novel strategies for preventing myocardial I/R injury.

http://ift.tt/2HPiBJh

Elevated circulatory levels of leptin and resistin impair therapeutic efficacy of dacarbazine in melanoma under obese state

Abstract

Background

Obesity is associated with increased risk, poor prognosis and outcome of therapy, in various cancers. Obesity-associated factors or adipokines, especially leptin and resistin, are purported to promote growth, survival, proliferation, and invasiveness of cancer cells. However, the mechanistic link between these adipokines and therapeutic response in malignancies is not clearly understood.

Methods

ob/ob and db/db mouse models were used in this study to evaluate the role of leptin and resistin towards the outcome of dacarbazine (DTIC) therapy in melanoma. Unique in vitro approaches were employed to complement in vivo findings by culturing melanoma cells in the serum collected from the experimental mice.

Results

Here, we have shown the role of important adipokines leptin and resistin in growth and the outcome of DTIC therapy in melanoma. Both leptin and resistin not only enhance proliferation of melanoma cells but also are involved in impairing the therapeutic efficacy of DTIC. Leptin and resistin treatment caused an increase in the protein levels of fatty acid synthase (FASN) and caveolin 1 (Cav-1) respectively, through their stabilization in A375 cells. Further, it was observed that leptin and resistin impaired the response of melanoma cells to DTIC via upregulation of heat shock protein 90 (Hsp90) and P-glycoprotein (P-gp) respectively.

Conclusion

These findings unraveled the involvement of adipokines (leptin and resistin) in melanoma progression, and more importantly, in the outcome of DTIC therapy.

http://ift.tt/2DJk2a4

Reactivation of mutant-EGFR degradation through clathrin inhibition overcomes resistance to EGFR tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) targeting mutant-EGFR in NSCLC have been successful to control cancer growth, but acquired resistance inevitably occurs, including mutations directly on EGFR e.g. T790M and C797S. Strategies to prevent such acquired mutations by reducing mutant-EGFR expression have met limited success. Here we propose a new model of mutant-EGFR trafficking and demonstrate that clathrin inhibition induces rapid degradation across a large panel of endogenous mutant-EGFR (Ex19del, L858R, Ex20Ins). This panel included mutant-EGFR (T790M) resistant to the first- and second-generation EGFR inhibitors and to the third-generation TKI osimertinib, and occurs through both mutational (C797S) and non-mutational EGFR mechanisms. Clathrin-mediated endocytosis inhibition of mutant-EGFR induced a macropinocytosis-dependent lysosomal pathway associated with a loss of mutant-EGFR dependent signalling (pAKT, pERK). Moreover, induction of this macropinocytic pathway led to robust apoptosis-dependent death across all mutant-EGFR cell lines tested, including those resistant to TKIs. We therefore propose a novel strategy to target mutant-EGFR refractory to approved existing TKI treatments in NSCLC and where new treatment strategies remain a key area of unmet need.

http://ift.tt/2poR1fs

Pain: A Neglected Problem in the Low-Resource Setting

Approximately 80% of the world's population lives in countries with little or no access to pain management. These countries also have 74% of the world's deaths from cancer and human immunodeficiency virus. Appropriate use of oral opioids can control 80%–90% of cancer pain. However, only 6.7% of the world's medical opioids are available in these low-resource countries. With the Lancet Commission on Global Surgery calling for a significant expansion of surgical services, postoperative pain management will need to be an increasing focus of our attention. There are multiple barriers to providing effective pain management. These include the type and funding of the health care system, the size and educational level of the workforce, the ease of access to effective medications, and the expectations and knowledge base of the community. Some barriers can be addressed by education at the undergraduate level, postgraduate level, and community level. Others will require continued advocacy at government level. Only when we tackle these problems will the considerable neglect of access to effective pain treatment in low- and middle-income countries be lessened.

http://ift.tt/2HNnSBm

Strengthening the Anesthesia Workforce in Low- and Middle-Income Countries

The majority of the world's population lacks access to safe, timely, and affordable surgical care. Although there is a health workforce crisis across the board in the poorest countries in the world, anesthesia is disproportionally affected. This article explores some of the key issues that must be tackled to strengthen the anesthesia workforce in low- and lower-middle-income countries. First, we need to increase the overall number of safe anesthesia providers to match a huge burden of disease, particularly in the poorest countries in the world and in remote and rural areas. Through using a task-sharing model, an increase is required in both nonphysician anesthesia providers and anesthesia specialists. Second, there is a need to improve and support the competency of anesthesia providers overall. It is important to include a broad base of knowledge, skills, and attitudes required to manage complex and high-risk patients and to lead improvements in the quality of care. Third, there needs to be a concerted effort to encourage interprofessional skills and the aspects of working and learning together with colleagues in a complex surgical ecosystem. Finally, there has to be a focus on developing a workforce that is resilient to burnout and the challenges of an overwhelming clinical burden and very restricted resources. This is essential for anesthesia providers to stay healthy and effective and necessary to reduce the inevitable loss of human resources through migration and cessation of professional practice. It is vital to realize that all of these issues need to be tackled simultaneously, and none neglected, if a sustainable and scalable solution is to be achieved.

http://ift.tt/2FNOuFA

Safe Surgery Globally by 2030: The View From Anesthesia

No abstract available

http://ift.tt/2FNVVwM

Global Access to Safe Anesthesia: Addressing the Gap

No abstract available

http://ift.tt/2HLIXMl

Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata [PublishAheadOfPrint]

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three IV rezafungin dosing regimens: (i) single 400-mg dose, (ii) 400 mg for Week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the non-clinical PK-PD targets associated with net fungal stasis and 1-log₁₀ CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin dosing regimen. At the MIC₉₀ for C. albicans and C. glabrata, single dose rezafungin 400 mg achieved probabilities of PK-PD target attainment ≥90% through Week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through Week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through Week 6 following administration of the weekly dosing regimens at or above the MIC₁₀₀ values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin dosing regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.

http://ift.tt/2FVHK4G

Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data [PublishAheadOfPrint]

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent in vitro activity against Candida albicans and Candida glabrata, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration. Data from two Phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via IV infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles across a population and can provide dose selection decision support for future clinical studies.

http://ift.tt/2FVHFOq

Cell swelling induced by the antimalarial KAE609 (cipargamin) and other PfATP4-associated antimalarials [PublishAheadOfPrint]

For an increasing number of antimalarial agents identified in high throughput phenotypic screens there is evidence that they target PfATP4, a putative Na⁺ efflux transporter on the plasma membrane of the human malaria parasite, Plasmodium falciparum. For several such 'PfATP4-associated' compounds it has been noted that their addition to parasitised erythrocytes results in cell swelling. Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling both of isolated blood-stage parasites and of intact parasitised erythrocytes. The swelling of isolated parasites is dependent on the presence of Na⁺ in the external environment and may be attributed to the osmotic consequences of Na⁺ uptake. The swelling of the parasitised erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds.

http://ift.tt/2GLiwac

Design of a broad-range bacteriophage cocktail that reduces Pseudomonas aeruginosa biofilms and treats acute infections in two animal models. [PublishAheadOfPrint]

The alarming diffusion of multidrug resistant (MDR) bacterial strains requires investigations on non-antibiotic therapies. Amongst them, the use of bacteriophages (phages) as antimicrobial agents, namely phage therapy, is a promising treatment strategy with support by recent successful compassionate treatments in Europe and the U.S.A. In this work, we combined host range and genomic information to design a 6-phage cocktail killing several clinical strains of P. aeruginosa, including those collected from Italian cystic fibrosis (CF) patients, and analyzed the cocktail performance. We demonstrated that the cocktail composed of four novel (PYO2, DEV, E215 and E217) and two previously characterized (PAK_P1 and PAK_P4) phages was able to lyse P. aeruginosa both in planktonic liquid cultures and in biofilm. In addition, we showed that the phage cocktail could cure acute respiratory infection in mouse and treat bacteremia in the wax moth Galleria mellonella larvae. Furthermore, administration of the cocktail to larvae prior to bacterial infection provided prophylaxis. In this regard, efficiency of the phage cocktail was found to be unaffected by the MDR or mucoid phenotype of the pseudomonal strain. The cocktail was found to be superior to individual phages in destroying biofilms and providing a faster treatment in mice. We also found the Galleria larvae model to be cost-effective for testing clinical strains susceptibility to phages, suggesting that it could be implemented in the frame of developing personalized phage therapies.

http://ift.tt/2HPkO7L

Genetic determinants of high-level oxacillin resistance in MRSA [PublishAheadOfPrint]

Methicillin-resistant Staphylococcus aureus (MRSA) strains carry either a mecA- or a mecC-mediated mechanism of resistance to beta-lactam antibiotics and the phenotypic expression of resistance shows extensive strain-to-strain variation. In recent communications we identified genetic determinants associated with the stringent stress response that play a major role in the antibiotic resistant phenotype of the historically earliest "archaic" clone of MRSA and in the mecC carrying MRSA strain LGA251. Here, we sought to test whether or not the same genetic determinants also contribute to the resistant phenotype of highly and homogeneously resistant (H*R) derivatives of a major contemporary MRSA clone USA300. We found that the resistance phenotype was linked to six genes (fruB, gmk, hpt, purB, prsA, and relA), which were most frequently targeted among the analyzed 20 H*Rs (one mutation per clone in 19 out of the 20 H*Rs). Besides the strong parallels with our previous findings (five out of the six genes matched), all but one of the repeatedly targeted genes were found to be linked to guanine metabolism pointing to the key role that this pathway plays in defining the level of antibiotic resistance independent of the clonal type of MRSA.

http://ift.tt/2Gb0PDv

Comparison of septic shock due to MDR Acinetobacter baumannii or Klebsiella pneumoniae carbapenemase--producing K. pneumoniae in ICU patients [PublishAheadOfPrint]

Objectives: a significant cause of mortality in intensive care unit (ICU) is represented by multidrug-resistant (MDR) gram-negative bacteria, such as MDR Acinetobacter baumannii (MDR-AB) and Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp). Aim of the present study was the comparison of clinical features, therapy and outcome of patients who developed septic shock due to either MDR-AB or KPC-Kp.

Methods: were retrospectively analyzed patients admitted to the intensive care unit (ICU) of a teaching hospital, from November 2010 to December 2015, who developed septic shock due to MDR-AB or KPC-Kp infection.

Results: data from 220 patients were analyzed: 128 (58.2%) were diagnosed with septic shock due to KPC-Kp and 92 (41.8%) were diagnosed with septic shock due to MDR-AB, respectively. The 30-day mortality rate was significantly higher for the MDR-AB group (84.8% Vs 44.5%, p<0.001). Steroid exposure and pneumonia were associated with MDR-AB infection, whereas hospitalization in the previous 90 days, primary bacteremia, and KPC-Kp colonization were associated with KPC-Kp infection. For patients with KPC-Kp infections, the use of ≥ 2 antibiotics active in vitro as empiric or definitive therapy was associated with higher 30-day survival, while isolation of colistin-resistant strains was linked to mortality. For patients with MDR-AB infections, age >60 years and SAPS II >45 points were associated with increased mortality rates.

Conclusions: septic shock due to MDR-AB infection is associated with very high mortality rates, compared to septic shock due to KPC-Kp. Analysis of clinical features of these critically-ill patients might help physicians in choosing appropriate empirical antimicrobial therapy.

http://ift.tt/2FVHv9M

Outcome of E1224/benznidazole combination treatment upon infection with multi-drug resistant Trypanosoma cruzi strain in mice. [PublishAheadOfPrint]

Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. A first set of experiments assessed the range of E1224 doses required to induce parasitological cure using T. cruzi strains with different susceptibilities to benznidazole (Y and Colombian). All E1224 doses were effective in suppressing the parasitemia and preventing the death, however, parasitological cure was observed only in mice infected with Y strain. Considering these results, we evaluated the effect of combined treatment against Colombian, a multi-drug-resistant T. cruzi strain. After exclusion of antagonistic effects using in vitro assays, infected mice were treated with E1224 and benznidazole in monotherapy or combination, at day 4 or 10 post-inoculation. All treatments were well tolerated and effective in suppressing parasitemia, however, parasitological and PCR assays indicated no cure among mice treated with monotherapies. Intriguingly, the outcome of combination therapy was dependent on treatment onset. Early treatment using optimal doses of E1224/benznidazole induced a 100% cure rate, but this association could not eliminate a well-established infection. The beneficial effect of combination therapy was evidenced by further reductions of the patent parasitemia period in the group receiving combined therapy compared with monotherapies. Our results demonstrated a positive interaction between E1224/benznidazole against murine T. cruzi infection using a multi-drug resistant strain and highlighted the importance of a stringent experimental model in the evaluation of new therapies.

http://ift.tt/2FVHqmu

Preclinical profile of AB-423, an inhibitor of Hepatitis B virus pgRNA encapsidation [PublishAheadOfPrint]

AB-423 is a sulfamoylbenzamide (SBA) class of HBV capsid inhibitor in Phase 1 clinical trials. In cell culture models AB-423 showed potent inhibition of HBV replication (EC₅₀/EC₉₀ = 0.08-0.27 μM/0.33-1.32 μM) with no significant cytotoxicity (CC₅₀ >10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC₅₀ values. AB-423 inhibited HBV genotypes A through D and nucleos/tide-resistant variants in vitro. Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pgRNA and rcDNA indicating it is a class II capsid inhibitor. In a de novo infection model AB-423 prevented the conversion of encapsidated rcDNA to cccDNA presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer:dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents such as nucleos/tide analogs, RNAi agents, or interferon-α resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher liver accumulation. A 7-day BID administration of AB-423 in a hydrodynamic injection mouse model of HBV model resulted in a dose-dependent reduction in serum HBV DNA levels and combination with ETV or ARB-1467 resulted in a trend towards greater antiviral activity than either agent alone consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports further evaluation for safety, pharmacokinetics and antiviral activity in CHB patients.

http://ift.tt/2GKLs2q

Beta-Lactams combinations with Vancomycin provide synergy against VSSA, hVISA, and VISA [PublishAheadOfPrint]

Background: Increasing utilization of vancomycin due to the high prevalence of methicillin-resistant S. aureus (MRSA) infections has lead to the emergence of vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA). In vitro data suggest the potential for potent synergy between several beta-lactams and vancomycin. The objective of this study is to evaluate the synergy between beta-lactams and vancomycin against MRSA that is vancomycin susceptible, vancomycin susceptible Staphylococcus aureus (VSSA), hVISA, and VISA.

Methods: Fifty randomly selected clinical MRSA strains with varying susceptibility to vancomycin were evaluated for vancomycin alone and vancomycin in combination with varying concentrations of cefazolin (CFZ), cefepime (FEP), ceftaroline (CPT), and nafcillin (NAF) minimum inhibitory concentration (MIC). The potential for synergy was assessed by 24h time-kills.

Results: Beta-lactams reduced vancomycin MIC values against all strains (4-16 fold reduction). In time-kill studies against MRSA, CFZ, FEP, CPT, and NAF all demonstrated a similar extent of killing at 24h, and all showed synergistic activity with vancomycin against VSSA, hVISA, and VISA. Each of these combinations was also superior to any single agent against isolates of all three phenotypes, and each was bactericidal (P < 0.001 for all comparisons). All single agent exposures demonstrated no activity at 24h.

Conclusions: The combination of vancomycin and beta-lactams significantly improved antibacterial activity against VSSA, hVISA, and VISA compared to any agent alone, supporting the potential use of vancomycin/beta-lactams combination therapy in infections caused by MRSA. Further clinical research is warranted to investigate the synergy of vancomycin against these Staphylococcus strains.

http://ift.tt/2HLKORm

Mid-Trimester Cervical Consistency Index and Cervical Length to Predict Spontaneous Preterm Birth in a High-Risk Population

AJP Rep 2018; 08: e43-e50
DOI: 10.1055/s-0038-1636993

Background Short cervical length (CL) has not been shown to be adequate as a single predictor of spontaneous preterm birth (sPTB) in high-risk pregnancies. Objective The objective of this study was to evaluate the performance of the mid-trimester cervical consistency index (CCI) to predict sPTB in a cohort of high-risk pregnancies and to compare the results with those obtained with the CL. Study Design Prospective cohort study including high-risk singleton pregnancies between 19+0 and 24+6 weeks. The ratio between the anteroposterior diameter of the uterine cervix at maximum compression and at rest was calculated offline to obtain the CCI. Results Eighty-two high sPTB risk women were included. CCI (%) was significantly reduced in women who delivered <37+0 weeks compared with those who delivered at term, while CL was not. The area under the curve (AUC) of the CCI to predict sPTB <37+0 weeks was 0.73 (95% confidence interval [CI], 0.61–0.85), being 0.51 (95% CI, 0.35–0.67), p = 0.03 for CL. The AUC of the CCI to predict sPTB <34+0 weeks was 0.68 (95% CI, 0.54–0.82), being 0.49 (95% CI, 0.29–0.69), p = 0.06 for CL. Conclusion CCI performed better than sonographic CL to predict sPTB. Due to the limited predictive capacity of these two measurements, other tools are still needed to better identify women at increased risk.
[...]

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

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

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Betweenness Centrality of Intracranial Electroencephalography Networks and Surgical Epilepsy Outcome

Epilepsy is a neurological disorder in which patients suffer from recurrent seizures. Pharmacologically resistant epilepsy patients have been increasingly referred for surgical options, but despite many advances in non-invasive pre-operative localization modalities, the rate of seizure freedom after epilepsy surgery has been relatively stagnant at 60-70% after the first year, and decreasing with post-operative follow-up.(Spencer et al., 2008, Bulacio et al., 2012) The goal of surgery is to identify discrete parts of the brain that give rise to seizures (frequently with intracranial EEG - iEEG) and resect them.(Luders et al., 2001) Surgical failures are most frequently attributed to either incomplete resection of a seizure focus or missed identification of additional foci.(Englot et al., 2014a; Englot et al., 2014b)

http://ift.tt/2FSGmjf

Targeting high frequency oscillations in epilepsy

Human brain oscillations organize across multiple temporal scales that can be measured directly with EEG. Once considered inessential epiphenomena, recent work has highlighted cortical oscillations as primary phenomena that cause and direct essential brain processes. Pioneering work has shown that brain rhythms can be augmented by external manipulation with direct cognitive impact. For example, auditory enhancement of slow wave oscillations during NREM sleep improves declarative memory (Ngo et al., 2013).

http://ift.tt/2FOe7Xb

SLIDING WINDOW AVERAGING IN NORMAL AND PATHOLOGICAL MOTOR UNIT ACTION POTENTIAL TRAINS

The analysis of motor unit action potential (MUAP) is one of the fundamental tests in routine clinical neurophysiology. Electromyography (EMG) signals are recorded intramuscularly with conventional concentric needle electrodes. These signals usually contain several MUAP trains. Manual, semi or completely automatic techniques (Nandedkar, 2002; Merletti and Parker, 2004) are used for decompose EMG signals into different MUAP trains. From each MUAP train a representative waveform is formed (Malanda et al., 2015) and characterized with clinically useful parameters (Stålberg et al., 1986; Zalewska and Hausmanowa-Petrusewicz, 1995; Nandedkar, 2002; Kimura, 2002).

http://ift.tt/2FYtOag

Prospective evaluation of plasma Epstein–Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma

http://ift.tt/2GIafE9

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

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Sprue-like enteropathy, do not forget olmesartan!

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P.06.28 PREDICTIVE FACTORS FOR THE ERADICATION OF ESOPHAGEAL VARICES IN CIRRHOTIC PATIENT UNDERGOING ENDOSCOPIC BAND LIGATION

http://ift.tt/2u0WhdP

P.05.25 EFFECTS OF BIOFEEDBACK THERAPY ON CLINICAL AND MANOMETRIC PARAMETERS IN PELVIC FLOOR DYSFUNCTIONS

http://ift.tt/2IBEfCf

P.08.19 ENDOSCOPIC MANAGEMENT WITH PLASTIC STENTS OF NONANASTOMOTIC BILIARY STRICTURES FOLLOWING LIVER TRANSPLANTATION: A SINGLE CENTER EXPERIENCE

http://ift.tt/2pqYw4N

P.07.14 MANAGEMENT OF INFLAMMATORY BOWEL DISEASE DURING PREGNANCY: A SINGLE CENTER EXPERIENCE

http://ift.tt/2IBEdKD

P.09.15 NEW EXPERIENCES IN HCV TREATMENT AND FIBROSIS EVALUATION: COMPARISON BETWEEN NON-INVASIVE METHODS

http://ift.tt/2IErerE

P.08.27 20G-PROCORE NEEDLES FOR EUS-FNA: OUR EXPERIENCE IN TISSUE SAMPLING AND PATHOLOGICAL SIGNIFICANCE

http://ift.tt/2poscPZ

P.07.22 ANTI-TNF-ALFA SECOND-LINE INFLIXIMAB THERAPY IN PATIENTS AFFECTED BY CROHN'S DISEASE AND ULCERATIVE COLITIS: WHO AND HOW RECOVERS REMISSION?

http://ift.tt/2poLMeM

P.06.20 GERD DIAGNOSIS IN 340 PATIENTS WITH ATYPICAL OR EXTRA-ESOPHAGEAL SYMPTOMS BY USING A NON INVASIVE SURROGATE TEST

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P.06.4 USE OF THE PEPTEST™ TOOL IN PATIENTS ADMITTED FOR CHEST PAIN IN THE EMERGENCY DEPARTMENT: A PILOT STUDY

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P.05.17 EFFICACY OF DIVER-100 IN PATIENTS WITH SYMPTOMATIC UNCOMPLICATED DIVERTICULAR DISEASE (SUDD): PRELIMINARY RESULTS FROM A PROSPECTIVE OBSERVATIONAL COHORT

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P.09.11 HIGH PREVALENCE OF DEFECTIVE SPLEEN FUNCTION IN AUTOIMMUNE GASTROINTESTINAL AND LIVER DISEASES

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P.09.3 LACK OF NLRP3-INFLAMMASOME LEADS TO GUT-LIVER AXIS DERANGEMENT, GUT DYSBIOSIS AND A WORSENED PHENOTYPE IN A MOUSE MODEL OF NAFLD

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P.08.23 WIRELESS CAPSULE ENDOSCOPY IN CROHN'S DISEASE: A SINGLE CENTER EXPERIENCE

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Reply

We appreciate the comments of Dr Weinberger; he raises an important question regarding the role of corticosteroids in the treatment of acute asthma exacerbation, especially in preschool-aged children. International guidelines1,2 recommend the use of oral corticosteroids in children with moderate-to-severe asthma exacerbations and those with mild exacerbations and incomplete response to bronchodilators. There is a strong evidence of their efficacy in reducing relapses, admissions, and the need for beta-agonist use, without an apparent increase in side effects, particularly in school-aged children and adolescents.

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Advancing the Science of Children's Positive Health in the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) Research Program

Launched by the National Institutes of Health in 2016, the Environmental influences on Child Health Outcomes (ECHO) Program is a 7-year initiative designed to advance knowledge of environmental exposure effects on the health of the nation's children (for more information, see www.echochildren.org). ECHO includes 84 individual cohort studies, with an anticipated combined sample of more than 50 000 children. These studies will contribute existing and newly collected data on a broad array of environmental exposures, which are measured from before birth to 5 years of age, and outcome data in four domains assessed from birth through adolescence: airways (eg, asthma); obesity; pre-, peri-, and postnatal outcomes (eg, low birth weight, small for gestational age); and, neurodevelopment (eg, autism, cognition).

http://ift.tt/2FVryk2

HIV Incidence, HIV Prevalence, and Undiagnosed HIV Infections in Men Who Have Sex With Men, United States

Background:

HIV infection is a persistent health concern in the United States, and men who have sex with men (MSM) continue to be the most affected population.

Objective:

To estimate HIV incidence and prevalence and the percentage of undiagnosed HIV infections overall and among MSM.

Design:

Cross-sectional analysis.

Setting:

National HIV Surveillance System.

Participants:

Persons aged 13 years and older with diagnosed HIV infection.

Measurements:

Data on HIV diagnoses and the first CD4 test result after diagnosis were used to model HIV incidence and prevalence and the percentage of undiagnosed HIV infections from 2008 to 2014 on the basis of a well-characterized CD4 depletion model.

Results:

Modeled HIV incidence decreased 14.8% overall, from 45 200 infections in 2008 to 38 500 in 2015, and among all transmission risk groups except MSM. The incidence of HIV increased 3.1% (95% CI, 1.6% to 4.5%) per year among Hispanic/Latino MSM (6300 infections in 2008, 7900 in 2015), decreased 2.7% (CI, −3.8% to −1.5%) per year among white MSM (8800 infections in 2008, 7100 in 2015), and remained stable among black MSM at about 10 000 infections. The incidence decreased by 3.0% (CI, −4.2% to −1.8%) per year among MSM aged 13 to 24 years and by 4.7% (CI, −6.2% to −3.1%) per year among those aged 35 to 44 years. Among MSM aged 25 to 34 years, HIV incidence increased 5.7% (CI, 4.4% to 7.0%) per year, from 6900 infections in 2008 to 10 000 in 2015. The percentage of undiagnosed HIV infections was higher among black, Hispanic/Latino, and younger MSM than white and older MSM, respectively.

Limitation:

Assumptions of the CD4 depletion model and variability of CD4 values.

Conclusion:

Expansion of HIV screening to reduce undiagnosed infections and increased access to care and treatment to achieve viral suppression are critical to reduce HIV transmission. Access to prevention methods, such as condoms and preexposure prophylaxis, also is needed, particularly among MSM of color and young MSM.

Primary Funding Source:

None.

http://ift.tt/2FPxSxh

The Black–White Cardiovascular Health Disparity Is Narrowing, But Not for the Reason You Think

Disparities in cardiovascular health remain pervasive in the United States, with higher mortality in blacks than whites. Within this context, the report from Brown and colleagues showing a narrowing of the black–white gap in cardiovascular health would seem encouraging—but the devil is in the detail. In fact, the report adds an unexpected but important wrinkle to the health disparities saga.

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Editors' Note: Call for Articles on Firearm-Related Harm

Annals of Internal Medicine is committed to helping to end the public health emergency of firearm-related harm and is working to do so by publishing high-quality research in this understudied area, as well as influential reviews, commentaries, and position papers.

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Cautions as Regulators Move to End Exclusive Reliance on Intention to Treat

Intention-to-treat (ITT) analyses of randomized trials have been favored because they alleviate concerns about baseline confounding, but ITT analyses estimate the effect of being assigned to an intervention rather than that of actually receiving it. Regulators, pharmaceutical companies, and academics are advocating approaches to complement ITT analyses. This commentary presents specifications to consider for such approaches.

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Trends in Racial/Ethnic and Nativity Disparities in Cardiovascular Health Among Adults Without Prevalent Cardiovascular Disease in the United States, 1988 to 2014

Background:

Trends in cardiovascular disparities are poorly understood, even as diversity increases in the United States.

Objective:

To examine U.S. trends in racial/ethnic and nativity disparities in cardiovascular health.

Design:

Repeated cross-sectional study.

Setting:

NHANES (National Health and Nutrition Examination Survey), 1988 to 2014.

Participants:

Adults aged 25 years or older who did not report cardiovascular disease.

Measurements:

Racial/ethnic, nativity, and period differences in Life's Simple 7 (LS7) health factors and behaviors (blood pressure, cholesterol, hemoglobin A_1c, body mass index, physical activity, diet, and smoking) and optimal composite scores for cardiovascular health (LS7 score ≥10).

Results:

Rates of optimal cardiovascular health remain below 40% among whites, 25% among Mexican Americans, and 15% among African Americans. Disparities in optimal cardiovascular health between whites and African Americans persisted but decreased over time. In 1988 to 1994, the percentage of African Americans with optimal LS7 scores was 22.8 percentage points (95% CI, 19.3 to 26.4 percentage points) lower than that of whites in persons aged 25 to 44 years and 8.0 percentage points (CI, 6.4 to 9.7 percentage points) lower in those aged 65 years or older. By 2011 to 2014, differences decreased to 10.6 percentage points (CI, 7.4 to 13.9 percentage points) and 3.8 percentage points (CI, 2.5 to 5.0 percentage points), respectively. Disparities in optimal LS7 scores between whites and Mexican Americans were smaller but also decreased. These decreases were due to reductions in optimal cardiovascular health among whites over all age groups and periods: Between 1988 to 1994 and 2011 to 2014, the percentage of whites with optimal cardiovascular health decreased 15.3 percentage points (CI, 11.1 to 19.4 percentage points) for those aged 25 to 44 years and 4.6 percentage points (CI, 2.7 to 6.5 percentage points) for those aged 65 years or older.

Limitation:

Only whites, African Americans, and Mexican Americans were studied.

Conclusion:

Cardiovascular health has declined in the United States, racial/ethnic and nativity disparities persist, and decreased disparities seem to be due to worsening cardiovascular health among whites rather than gains among African Americans and Mexican Americans. Multifaceted interventions are needed to address declining population health and persistent health disparities.

Primary Funding Source:

National Institute of Neurological Disorders and Stroke and National Center for Advancing Translational Science of the National Institutes of Health.

http://ift.tt/2FT6o64

An Innovative Program to Support Gender Equity and Success in Academic Medicine: Early Experiences From the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists

http://ift.tt/2G5DeUp

The Safety and Quality of Abortion Services in the United States: What Does the Evidence Indicate?

Since the Institute of Medicine last evaluated abortion services in 1975, there have been many advances. The National Academies of Sciences, Engineering, and Medicine was asked to answer a series of questions on the appropriate use of different types of abortion services, associated health risks, safety and quality of care, necessary facility requirements, health care provider skills, safeguards for different interventions, safe provision of pain management, and the research gaps. This paper provides a synopsis of the report

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Public Health Research on Gun Violence: Long Overdue

Firearm violence is a defining public health challenge of our time. Effective public health strategies have reduced other threats to public health and are built on research to identify patterns of risk, illuminate productive targets for intervention, and assess the effectiveness of interventions. The authors discuss priorities for a research agenda developed by the Institute of Medicine and the National Research Council to reduce the threat of firearm-related violence.

http://ift.tt/2G7XXao

Review: Atraumatic lumbar puncture needles reduce postdural puncture headache compared with conventional needles

http://ift.tt/2prKiRR

Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases A Nested Case–Control Study

Background:

Although certain opioid analgesics have immunosuppressive properties and increase the risk for infections in animals, the clinical effects of prescription opioid use on infection risk among humans are unknown.

Objective:

To test the hypothesis that prescription opioid use is an independent risk factor for invasive pneumococcal disease (IPD).

Design:

Nested case–control study.

Setting:

Tennessee Medicaid database linked to Medicare and Active Bacterial Core surveillance system databases (1995 to 2014).

Patients:

1233 case patients with IPD aged 5 years and older matched to 24 399 control participants by diagnosis date, age, and county of residence.

Measurements:

Opioid use was measured on the basis of pharmacy prescription fills. Invasive pneumococcal disease was defined by the isolation of Streptococcus pneumoniae from a normally sterile site. The odds of current opioid use were compared between the case and control groups, accounting for known IPD risk factors. Secondary analyses categorized opioid use by opioid characteristics, applied an IPD risk score to assure comparability between exposure groups, and analyzed pneumonia and nonpneumonia IPD cases separately.

Results:

Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately.

Limitations:

Unmeasured confounding and measurement error, although sensitivity analyses suggested that neither was likely to affect results. Actual opioid use and other nonprescription use (such as illicit opioid use) were not measured.

Conclusion:

Opioid use is associated with an increased risk for IPD and represents a novel risk factor for these diseases.

Primary Funding Source:

National Institutes of Health.

http://ift.tt/2o0VT95

Guideline: USPSTF recommends against menopausal estrogen for primary prevention of chronic conditions

http://ift.tt/2pooq9W

Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis A Randomized Trial

Background:

Synovitis is believed to play a role in producing symptoms in persons with hand osteoarthritis, but data on slow-acting anti-inflammatory treatments are sparse.

Objective:

To determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis.

Design:

Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104)

Setting:

13 primary and secondary care centers in England.

Participants:

Of 316 patients screened, 248 participants (82% women; mean age, 62.7 years) with symptomatic (pain ≥4 on a 0- to 10-point visual analogue scale) and radiographic hand osteoarthritis were randomly assigned and 210 (84.7%) completed the 6-month primary end point.

Intervention:

Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care.

Measurements:

The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months. Secondary end points included self-reported pain and function, grip strength, quality of life, radiographic structural change, and adverse events. Baseline ultrasonography was done.

Results:

At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of −0.16 point (95% CI, −0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group).

Limitation:

Hydroxychloroquine dosage restrictions may have reduced efficacy.

Conclusion:

Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis.

Primary Funding Source:

Arthritis Research UK.

http://ift.tt/2EUntiu

Benefits and Harms of Cranial Electrical Stimulation for Chronic Painful Conditions, Depression, Anxiety, and Insomnia A Systematic Review

Background:

Cranial electrical stimulation (CES) is increasingly popular as a treatment, yet its clinical benefit is unclear.

Purpose:

To review evidence about the benefits and harms of CES for adult patients with chronic painful conditions, depression, anxiety, and insomnia.

Data Sources:

Several databases from inception to 10 October 2017 without language restrictions and references from experts, prior reviews, and manufacturers.

Study Selection:

Randomized controlled trials of CES versus usual care or sham CES that reported pain, depression, anxiety, or sleep outcomes in any language.

Data Extraction:

Single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion.

Data Synthesis:

Twenty-eight articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively. Fourteen trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results. Four trials done more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES does not cause serious side effects.

Limitation:

Most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding.

Conclusion:

Evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggests modest benefit in patients with anxiety and depression.

Primary Funding Source:

Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42016023951)

http://ift.tt/2nUKAjs

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update

Description:

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD) is a selective update of the prior CKD–MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis.

Methods:

Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations.

Recommendations:

The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD–MBD and treatment of CKD–MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

http://ift.tt/2sFWimS

Pharmaceutical Benefit Managers, Brand-Name Drug Prices, and Patient Cost Sharing

The prices patients pay for brand-name medications are rising faster than many other medical care costs. Some observers claim that the business practices of pharmaceutical benefit managers are partly responsible. How the process works is complicated, and this article explains what is happening.

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Some Years Having Passed Since I Lost You

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Why Internists Might Want Single-Payer Health Care

Clinicians know what is wrong with U.S. health care: It costs too much. They spend too much time negotiating with insurance companies, and too much of their remaining time is spent documenting what they did to ensure payment. Today's electronic health record makes documenting worse by invading the clinician's private time outside the office. This commentary suggests a possible solution.

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IV prochlorperazine + diphenhydramine improved migraine pain relief more than IV hydromorphone in the ED

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The Health Consequences of Natural Disasters in the United States: Progress, Perils, and Opportunity

After Hurricane Katrina devastated New Orleans in 2005, the United States responded by revamping its approach to preparedness, hardening the medical infrastructure, leveraging technology, and building community resilience. These changes resulted in a health infrastructure that performed significantly better during the 2017 hurricane season. The author emphasizes that the nation must continue to strengthen its planning and response infrastructure so that the tragedy of Katrina is never repeated.

http://ift.tt/2sApyLy

Lost in Translation: Linking Biomedical Research and Clinical Practice at the National Institutes of Health, 1977 to 2013

This article examines the history and effect of the Consensus Development Program (CDP) at the National Institutes of Health (NIH). Introduced at a time when the relationship between the U.S. public and the medical profession was at a nadir, the CDP frequently placed the NIH in the middle of broader debates in medical practice and health policy during the last quarter of the 20th century. Drawing on published and archival sources, this paper sheds light on the challenges associated with collecting, assessing, and communicating evidence to medical professionals and convincing them to act on it in the name of improved health care. Administrators at the NIH sought a middle ground between changing medical practice and respecting professional autonomy, with varying degrees of success. This debate has continued implications today as tensions persist between scientific guidelines and the clinical medicine practiced by physicians and expected by patients.

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Annals for Educators - 20 March 2018

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Hydroxychloroquine: Another Battle Lost in the Campaign to Find Effective Therapies for Hand Osteoarthritis

The findings from the HERO (Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis) trial are reported in this issue. The editorialists discuss the observation of no benefit of hydroxychloroquine compared with placebo in light of the hypothesized role of inflammation in nodal hand osteoarthritis.

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Trends in U.S. Drug Overdose Deaths in Non-Hispanic Black, Hispanic, and Non-Hispanic White Persons, 2000–2015

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Five-year outcomes following hypofractionated stereotactic radiotherapy delivered in five fractions for acoustic neuromas: the mean cochlear dose may impact hearing preservation

Abstract

Background

The aim of this study was to assess the clinical outcomes of acoustic neuromas (ANs) treated with hypofractionated stereotactic radiotherapy (hypo-FSRT) prescribed at a uniform dose.

Methods

Forty-seven patients with a unilateral AN were treated consecutively with hypo-FSRT between February 2007 and March 2012. Nineteen patients maintained a serviceable hearing status at the beginning of hypo-FSRT. The prescribed dose was 25 Gy delivered in five fractions per week to the isocenter, and the planning target volume was covered by the 80% isodose line.

Results

The median follow-up and audiometric follow-up periods were 61 and 52 months, respectively. The estimated tumor control rate at 5 years was 90% (95% CI 76–96). The existence of the cystic component before hypo-FSRT had a significantly worse impact on tumor control (p = 0.02). The estimated hearing preservation rates at 1, 3 and 5 years were 68% (95% CI 42–84), 41% (95% CI 20–62) and 36% (95% CI 15–57), respectively. A borderline significant difference was identified in the mean biological effective dose with an α/β value of 3 Gy (BED₃) to the ipsilateral cochlea between the preserved hearing and hearing loss groups (19 Gy vs. 28 Gy) (p = 0.08).

Conclusions

Hypo-FSRT delivered in five fractions for unilateral ANs may achieve excellent tumor control with no severe facial or trigeminal complications. The mean BED₃ in the cochlea may impact the hearing preservation rate. Therefore, the cochlear dose should be as low as possible.

http://ift.tt/2G5XBRl

Mercury Medical announces new agreement with Henry Schein Medical to expand the EMS market distribution of airway management product lines

CLEARWATER, Fla. — Doug Smith, Mercury's VP of Sales & Marketing, is pleased to announce that Mercury Medical has signed an agreement with Henry Schein Medical, the U.S. medical division of Henry Schein, Inc., to represent the company's Airway Management Devices in the United States' Emergency Medical Services (EMS) market. Effective January 1, 2018, the EMS business of Henry ...

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Is clove oil effective for toothache?

In this article, we look at the evidence for clove oil as a treatment for toothache, and investigate whether it has any possible side effects.

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Predicting survival for metastatic spine disease: a comparison of nine scoring systems

Publication date: Available online 19 March 2018
Source:The Spine Journal
Author(s): A. Karim Ahmed, C. Rory Goodwin, Amir Heravi, Rachel Kim, Nancy Abu-Bonsrah, Eric Sankey, Daniel Kerekes, Rafael De la Garza Ramos, Joseph Schwab, Daniel M. Sciubba
Background ContextDespite advances in spinal oncology, research into patient-based prognostic calculators for metastatic spine disease is lacking. Much of the literature in this area investigates the general predictive accuracy of scoring systems in heterogeneous populations, with few studies considering the accuracy of scoring systems based on patient specifics such as type of primary tumor.PurposeThe aim of the current study was to compare the ability of widespread scoring systems to estimate both overall survival at various time points and tumor-specific survival for patients undergoing surgical treatment for metastatic spine disease in order to provide surgeons with information to determine the most appropriate scoring system for a specific patient and timeline.Study DesignRetrospective.Patient Sample176 patients who underwent surgical resection for metastatic spine disease at a single institution were included.Outcome MeasuresSurvival. Areas under the receiver operating characteristic curves were generated from comparison of actual survival of patients and survival as predicted by application of prevalent scoring systems.MethodsA pre-operative score for all 176 patients was retrospectively calculated utilizing the SORG Classic Scoring algorithm, SORG Nomogram, Original Tokuhashi, Revised Tokuhashi, Tomita, Original Bauer, Modified Bauer, Katagiri, and van der Linden scoring systems. Univariate and multivariate cox proportional hazard models were constructed to assess the association of patient variables with survival. Receiver operating characteristic analysis (ROC) modeling was utilized to quantify the accuracy of each test at different end-points and for different primary tumor subgroups. No funds were received in support of this work. The authors have no conflicts of interest to disclose.ResultsAmong all patients surgically treated for metastatic spine disease, the SORG Nomogram demonstrated the highest accuracy at predicting 30-day (AUC 0.81), and 90-day (AUC 0.70) survival following surgery. The Original Tokuhashi was the most accurate at predicting 365-day survival (AUC 0.78). Multivariate analysis demonstrated multiple pre-operative factors strongly associated with survival following surgery for spinal metastasis. The accuracy of each scoring system in determining survival probability relative to primary tumor etiology and time elapsed since surgery was assessed.ConclusionsAmong the nine scoring systems assessed, this study determined the most accurate scoring system for short-term (30-day), intermediate (90-day), and long-term (365-day) survival, relative to primary tumor etiology. The findings of this study may be utilized by surgeons in a personalized effort to select the most appropriate scoring system for a given patient.



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Biomechanical comparative study on stability of injectable pedicle screw with 1 different lateral holes augmented with different volumes of polymethylmethacrylate in osteoporotic lumbar vertebrae

Publication date: Available online 19 March 2018
Source:The Spine Journal
Author(s): Da Liu, Jun Sheng, Yang Luo, Chen Huang, Hong-Hua Wu, Jiang-Jun Zhou, Xiao-Jun Zhang, Wei Zheng
Background ContextPolymethylmethacrylate (PMMA) is widely used for pedicle screw augmentation in osteoporosis. Until now, there had been no studies of the relationship between screw stability and the distribution and volume of PMMA.PurposeTo analyze the relationship between screw stability and the distribution pattern and injected volume of PMMA.Study DesignBiomechanical comparison of injectable pedicle screws with different lateral holes augmented with different volumes of PMMA in cadaveric osteoporotic lumbar vertebrae.MethodsForty-eight osteoporotic lumbar vertebrae were randomly divided into groups A, B, C with different pedicle screws (16 vertebrae in each group), and then each group was randomly divided into subgroups 0, 1, 2, 3 with different volumes of PMMA (four vertebra with eight pedicles in each subgroup). A pilot hole was prepared in advance using the same method in all samples. Type A and type B pedicle screws were directly inserted into vertebrae in groups A and B, respectively, and then different volumes of PMMA (0, 1.0, 1.5, and 2.0 mL) were injected through the screws and into vertebrae in subgroups 0, 1, 2, and 3. The pilot holes were filled with different volumes of PMMA (0, 1.0, 1.5, and 2.0 mL), and then the screws were inserted in groups C0, C1, C2 and C3. Screw position and distribution of PMMA were evaluated radiographically, and axial pull-out tests were performed to measure maximum axial pullout strength (Fmax).ResultsPMMA surrounded the anterior one-third of screws in the vertebral body in groups A1, A2, and A3; the middle one-third of screws in the junction area of the vertebral body and the pedicle in groups B1, B2, and B3; and the full length of screws evenly in both the vertebral body and the pedicle in groups C1, C2, and C3. There was no malpositioning of screws or leakage of PMMA in any sample. Two-way analysis of variance revealed that two factors—distribution and volume of PMMA—significantly influenced Fmax (p < .05) but that they were not significantly correlated (p = .088). Fmax in groups using augmentation with PMMA values were significantly improved compared with those in groups without PMMA (p < .05).ConclusionsPMMA can significantly enhance the stability of different injectable pedicle screws in osteoporotic lumbar vertebrae, and screw stability is significantly correlated with the distribution pattern and injected volume of PMMA. The closer the PMMA to the pedicle and the greater the quantity of injected PMMA, the greater pedicle screw stability is. Injection of 2.0 mL of PMMA through screws with four lateral 180° holes or of 1.0 mL of PMMA through screws with six lateral 180° holes increases the stability of pedicle screws.



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Impact of Anesthetic Regimen on Remote Ischemic Preconditioning in the Rat Heart In Vivo

Remote ischemic preconditioning (RIPC) seems to be a promising cardioprotective strategy with contradictive clinical data suggesting the anesthetic regimen influencing the favorable impact of RIPC. This study aimed to investigate whether cardio protection by RIPC is abolished by anesthetic regimens. Male Wistar rats were randomized to 6 groups. Anesthesia was either maintained by pentobarbital (Pento) alone or a combination of sevoflurane (Sevo) and remifentanil or propofol (Prop) and remifentanil in combination with and without RIPC. RIPC reduced infarct size in Pento- and Sevo-anesthetized rats (Pento-RIPC: 30% ± 9% versus Pento-control [Con]: 65% ± 6%, P

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In Response

No abstract available

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The Role of the WFSA in Reaching the Goals of the Lancet Commission on Global Surgery

No abstract available

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Safe Surgery Globally by 2030: The View From Anesthesia

No abstract available

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Higher Operating Table for Optimal Needle-Entry Angle and Less Discomfort During Spinal Anesthesia

The aim of this study was to find the optimal table height to facilitate insertion of the spinal needle at a 90° angle and to reduce the anesthesiologist's discomfort. Sixty patients were randomly allocated according to landmarks on the anesthesiologist's body: umbilicus (group U), lowest rib margin (R), xiphoid process (X), and nipple (N). The coronal insertion angle between the patient's skin and the spinal needle was obtuse in groups U and R, and 90° in group X. We demonstrated that high operating tables at the xiphoid and nipple level facilitate more optimal needle entry angles while reducing the discomfort and joint flexion of anesthesiologists during spinal anesthesia.

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