3D Printing of Living Responsive Materials and Devices

Abstract

3D printing has been intensively explored to fabricate customized structures of responsive materials including hydrogels, liquid-crystal elastomers, shape-memory polymers, and aqueous droplets. Herein, a new method and material system capable of 3D-printing hydrogel inks with programed bacterial cells as responsive components into large-scale (3 cm), high-resolution (30 μm) living materials, where the cells can communicate and process signals in a programmable manner, are reported. The design of 3D-printed living materials is guided by quantitative models that account for the responses of programed cells in printed microstructures of hydrogels. Novel living devices are further demonstrated, enabled by 3D printing of programed cells, including logic gates, spatiotemporally responsive patterning, and wearable devices.

A new paradigm in 3D printing is reported by using genetically programed cells as active components to print living materials and devices. The design principle and general method are provided to fabricate large-scale, high-resolution living materials, which are capable of integrating engineered cells into hydrogel constructs that maintain high viability of cells and respond to signaling chemicals in programed manners.

http://ift.tt/2Bz8ghC

Post-operative telephone review is safe and effective: prospective study – Monash outpatient review by phone trial

Introduction

Studies have shown that post-operative telephone follow-up is satisfactory and effective. As high quality evidence is scant, we conducted a randomized controlled trial to compare it against outpatient clinic review for emergency laparoscopic appendicectomy or cholecystectomy.

Method

Patients who received emergency laparoscopic appendicectomy or cholecystectomy were eligible for this study. Once recruited, they were randomly allocated to either clinic review or telephone follow-up on discharge. Participants were reviewed at 2 weeks after operation and contacted again at 4 weeks after initial follow-up for satisfaction survey.

Results

One hundred and seventy-nine participants were recruited with one withdrawn consent and six excluded. Ninety-six underwent laparoscopic appendicectomy and 76 had laparoscopic cholecystectomy. Ninety-six attended clinic review and 76 had telephone follow-up. The two groups were similar in baseline variables. Non-attendance rate was higher for clinic review cohort (24% vs 6.6%, P = 0.002). Participants who received telephone review reported higher satisfaction level (9.31 vs 8.85, P = 0.002), and most patients prefer telephone follow-up (73.1%, P < 0.0001). No difference was detected for missed complications (P = 0.354).

Conclusion

Telephone follow-up post laparoscopic appendicectomy or cholecystectomy is safe, satisfying and effective.

http://ift.tt/2Asp2Su

Association between hospitalisation for ambulatory care-sensitive conditions and primary health care physician specialisation: a cross-sectional ecological study in Curitiba (Brazil)

Introduction

Hospitalisation for ambulatory care-sensitive conditions (HACSCs) is frequently used as an indicator of the quality and effectiveness of primary healthcare (PHC) services around the world. The aim of the present study was to evaluate whether the PHC model (family health strategy (FHS) x conventional) and the availability of specialised PHC physicians is associated or not with total hospitalisation or HACSCs in the National Health System (SUS) of the municipality of Curitiba, Paraná state (PR), Brazil.

Methodology

This is a cross-sectional ecological study using multiple linear regression with socioeconomic and professional data from municipal health units (MHUs) between 1 April 2014 and 31 March 2015.

Results

After adjustment for age and sex and control of socioeconomic variables, the FHS model was associated with six fewer HACSCs a year per 10 000 inhabitants in relation to the conventional model and the availability of one family physician at each FHS model MHU per 10 000 inhabitants was associated with 1.1 fewer HACSCs for heart failure a year per 10 000 inhabitants. Basic specialists (clinicians, paediatricians and obstetrician/gynaecologists) and subspecialists showed no significant association with HACSC rates.

Conclusion

These results obtained in a major Brazilian city reinforce the role of FHS as a priority PHC model in the country and indicate the potentially significant impact of specialising in family medicine on improving the health conditions of the population.

http://ift.tt/2ByU7kz

Association between exercise and the risk of dementia: results from a nationwide longitudinal study in China

Objective

This study was conducted to examine the causal association between exercise and the risk of dementia among older Chinese adults.

Design

Longitudinal population-based study with a follow-up duration of 9 years.

Setting

Data for the Chinese Longitudinal Healthy Longevity Survey waves occurring from 2002 to 2011–2012 were extracted from the survey database.

Participants

In total, 7501 dementia-free subjects who were older than 65 years were included at baseline. Dementia was defined as a self-reported or proxy-reported physician's diagnosis of the disease.

Outcome measures and methods

Regular exercise and potential confounding variables were obtained via a self-report questionnaire. We generated longitudinal logistic regression models based on time-lagged generalised estimating equation to examine the causal association between exercise and dementia risk.

Results

Of the 7501 older Chinese people included in this study, 338 developed dementia during the 9-year follow-up period after excluding those who were lost to follow-up or deceased. People who regularly exercised had lower odds of developing dementia (OR=0.53, 95% CI 0.33 to 0.85) than those who did not exercise regularly.

Conclusion

Regular exercise was associated with decreased risk of dementia. Policy-makers should develop effective public health programmes and build exercise-friendly environments for the general public.

http://ift.tt/2jffAZb

Impact of electronic clinical decision support on adherence to guideline-recommended treatment for hyperlipidaemia, atrial fibrillation and heart failure: protocol for a cluster randomised trial

Introduction

Clinical practice guidelines facilitate optimal clinical practice. Point of care access, interpretation and application of such guidelines, however, is inconsistent. Informatics-based tools may help clinicians apply guidelines more consistently. We have developed a novel clinical decision support tool that presents guideline-relevant information and actionable items to clinicians at the point of care. We aim to test whether this tool improves the management of hyperlipidaemia, atrial fibrillation and heart failure by primary care clinicians.

Methods/analysis

Clinician care teams were cluster randomised to receive access to the clinical decision support tool or passive access to institutional guidelines on 16 May 2016. The trial began on 1 June 2016 when access to the tool was granted to the intervention clinicians. The trial will be run for 6 months to ensure a sufficient number of patient encounters to achieve 80% power to detect a twofold increase in the primary outcome at the 0.05 level of significance. The primary outcome measure will be the percentage of guideline-based recommendations acted on by clinicians for hyperlipidaemia, atrial fibrillation and heart failure. We hypothesise care teams with access to the clinical decision support tool will act on recommendations at a higher rate than care teams in the standard of care arm.

Ethics and dissemination

The Mayo Clinic Institutional Review Board approved all study procedures. Informed consent was obtained from clinicians. A waiver of informed consent and of Health Insurance Portability and Accountability Act (HIPAA) authorisation for patients managed by clinicians in the study was granted. In addition to publication, results will be disseminated via meetings and newsletters.

Trial registration number

NCT02742545.

http://ift.tt/2ByWns2

Encouraging translation and assessing impact of the Centre for Research Excellence in Integrated Quality Improvement: rationale and protocol for a research impact assessment

Introduction

There is growing recognition among health researchers and funders that the wider benefits of research such as economic, social and health impacts ought to be assessed and valued alongside academic outputs such as peer-reviewed papers. Research translation needs to increase and the pathways to impact ought to be more transparent. These processes are particularly pertinent to the Indigenous health sector given continued concerns that Indigenous communities are over-researched with little corresponding improvement in health outcomes. This paper describes the research protocol of a mixed methods study to apply FAIT (Framework to Assess the Impact from Translational health research) to the Centre for Research Excellence in Integrated Quality Improvement (CRE-IQI). FAIT will be applied to five selected CRE-IQI Flagship projects to encourage research translation and assess the wider impact of that research.

Methods and analysis

Phase I will develop a modified programme logic model for each Flagship project including identifying process, output and impact metrics so progress can be monitored. A scoping review will inform potential benefits. In phase II, programme logic models will be updated to account for changes in the research pathways over time. Audit and feedback will be used to encourage research translation and collect evidence of achievement of any process, output and interim impacts. In phase III, three proven methodologies for measuring research impact—Payback, economic assessment and narratives—will be applied. Data on the application of FAIT will be collected and analysed to inform and improve FAIT's performance.

Ethics and dissemination

This study is funded by a nationally competitive grant (ID 1078927) from the Australian National Health and Medical Research Council. Ethics approval was obtained from the University of Newcastle's Human Research Ethics Committee (ID: H-2017–0026). The results from the study will be presented in several peer-reviewed publications, through conference presentations and via social media.

http://ift.tt/2jdRL3O

Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol

Introduction

Fatigue is a frequent and troublesome manifestation of chronic sarcoidosis. This symptom can be debilitating and difficult to treat, with poor response to the treatment. Symptomatic management with neurostimulants, such as methylphenidate, is a possible treatment option. The use of such treatment strategies is not without precedent and has been trialled in cancer-related fatigue. Their use in sarcoidosis requires further evaluation before it can be recommended for clinical practice.

Methods and analysis

The Fatigue and Sarcoidosis—Treatment with Methylphenidate study is a randomised, controlled, parallel-arm and feasibility trial of methylphenidate for the treatment of sarcoidosis-associated fatigue. Patients are eligible if they have a diagnosis of sarcoidosis, significant fatigue (measured using the Fatigue Assessment Scale) and have stable disease. Up to 30 participants will be randomly assigned to either methylphenidate (20 mg two times per day) or identical placebo in a 3:2 ratio for 24 weeks. The primary objective is to collect data determining the feasibility of a future study powered to determine the clinical efficacy of methylphenidate for sarcoidosis-associated fatigue. The trial is presently open and will continue until July 2018.

Ethics and dissemination

Ethical approval for the study was granted by the Cambridge Central Research Ethics Committee on 21 June 2016 (reference 16/EE/0087) and was approved and sponsored by the Norfolk and Norwich University Hospital (reference 190280). Clinical Trial Authorisation (EudraCT number 2016-000342-60) from the Medicines and Healthcare products Regulatory Agency (MHRA) was granted on 19 April 2016. Results will be presented at relevant conferences and submitted to appropriate journals following trial closure and analysis.

Trial registration number

NCT02643732; Pre-results.

http://ift.tt/2BzrROF

Retrospective, multicohort analysis of the Clinical Practice Research Datalink (CPRD) to determine differences in the cost of medication wastage, dispensing fees and prescriber time of issuing either short (=60 days) prescription lengths in primary care for common, chronic conditions in the UK

Objectives

To investigate patterns of early repeat prescriptions and treatment switching over an 11-year period to estimate differences in the cost of medication wastage, dispensing fees and prescriber time for short (<60 days) and long (≥60 days) prescription lengths from the perspective of the National Health Service in the UK.

Setting

Retrospective, multiple cohort study of primary care prescriptions from the Clinical Practice Research Datalink.

Participants

Five random samples of 50 000 patients each prescribed oral drugs for (1) glucose control in type 2 diabetes mellitus (T2DM); (2) hypertension in T2DM; (3) statins (lipid management) in T2DM; (4) secondary prevention of myocardial infarction; and (5) depression.

Primary and secondary outcome measures

The volume of medication wastage from early repeat prescriptions and three other types of treatment switches was quantified and costed. Dispensing fees and prescriber time were also determined. Total unnecessary costs (TUC; cost of medication wastage, dispensing fees and prescriber time) associated with <60 day and ≥60 day prescriptions, standardised to a 120-day period, were then compared.

Results

Longer prescription lengths were associated with more medication waste per prescription. However, when including dispensing fees and prescriber time, longer prescription lengths resulted in lower TUC. This finding was consistent across all five cohorts. Savings ranged from £8.38 to £12.06 per prescription per 120 days if a single long prescription was issued instead of multiple short prescriptions. Prescriber time costs accounted for the largest component of TUC.

Conclusions

Shorter prescription lengths could potentially reduce medication wastage, but they may also increase dispensing fees and/or the time burden of issuing prescriptions.

http://ift.tt/2Bycjus

Copanlisib Produces Prolonged Responses in Lymphoma [News in Brief]

A phase II trial of the pan-class I PI3K inhibitor copanlisib demonstrated that it induces objective responses in 59% of patients with relapsed or refractory indolent lymphoma. The responses lasted a median of 22.6 months. Although the drugs weren't compared head to head, researchers suspect that the side effects of copanlisib may be less severe than those of idelalisib, another PI3K inhibitor.

http://ift.tt/2ApDJFA

BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia [Leukemia]

The small-molecule BAX activator BTSA1 promotes apoptosis of AML cells in vitro and in vivo.

http://ift.tt/2AvKWlE

Obinutuzumab Effective in Follicular Lymphoma, but at a Cost [News in Brief]

In a phase III trial involving more than 1,200 patients with follicular lymphoma, obinutuzumab plus chemotherapy reduced the risk of disease progression, relapse, or death by 34% compared with rituximab plus chemotherapy. However, patients receiving obinutuzumab experienced more serious side effects than those receiving rituximab.

http://ift.tt/2ArtmRC

A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors [Research Articles]

Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway–dependent cancers, the scope of mechanisms enabling resistance to SMO inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to SMO inhibitors and maintains a "persister" state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

Significance: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a "persister" state or evolve and progress rapidly in an "aggressive" state. Cancer Discov; 7(12); 1436–49. ©2017 AACR.

See related commentary by Goranci-Buzhala et al., p. 1374.

This article is highlighted in the In This Issue feature, p. 1355

http://ift.tt/2AwNrUK

NIH Funds Pediatric Data Resource Center [News in Brief]

Children's Hospital of Philadelphia will lead a collaborative effort—funded with $14.8 million from the NIH—to pool genomic and phenotypic data from tens of thousands of patients to study the causes of pediatric cancer and structural birth defects.

http://ift.tt/2AsnRT4

Identified Selective USP7 Inhibitors Compete with Ubiquitin Binding [Ubiquitination]

Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.

http://ift.tt/2AvDqHt

Trastuzumab Deruxtecan Is Safe and Active in HER2-Expressing Tumors [Clinical Trials]

Trastuzumab deruxtecan achieved responses in patients with breast, gastric, and gastroesophageal tumors.

http://ift.tt/2Ar059H

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax [Review]

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax.

Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376–93. ©2017 AACR.

http://ift.tt/2AvNT5P

FDA Disperses $22 Million for Rare Diseases [News in Brief]

The FDA has awarded 15 grants totaling $22 million over 4 years through its Orphan Products Clinical Trials Grant Program. One third of the awards will support ongoing clinical trials of therapies for rare cancers for which there are few approved or effective treatment options.

http://ift.tt/2Avqj96

Nivolumab Induces Tumor Evolution in Patients with Melanoma [Immunotherapy]

Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.

http://ift.tt/2Art90M

Breast Cancer Cells Recycle Ammonia to Generate Amino Acids [Metabolism]

Ammonia generated from glutamate metabolism enhances the proliferation of breast cancer cells.

http://ift.tt/2AvKYdg

Keap1 Loss Drives Kras-Mutant Lung Cancer and Glutaminolysis Dependency [Lung Cancer]

Loss of Keap1 hyperactivates NRF2 to induce glutaminolysis-dependent Kras-driven lung cancer.

http://ift.tt/2AqlD6A

Adrenergic Nerves May Promote Angiogenesis in Prostate Cancer [Prostate Cancer]

Deleting Adrb2, encoding the β2-adrenergic receptor, in tumor endothelial cells suppresses angiogenesis.

http://ift.tt/2AveJuC

Glucose Indirectly Fuels the TCA Cycle in Tumors via Lactate [Metabolism]

Circulating lactate derived from glucose is preferentially used as fuel for the TCA cycle over glucose.

http://ift.tt/2Arshta

Lactate Fuels the TCA Cycle in Non-Small Cell Lung Cancer [Metabolism]

In many patients with NSCLC, lactate is a major fuel source for the tumor TCA cycle.

http://ift.tt/2A5n0bZ

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells [Research Articles]

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19⁺ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404–19. ©2017 AACR.

See related commentary by Mackall and Miklos, p. 1371.

This article is highlighted in the In This Issue feature, p. 1355

http://ift.tt/2AXNyeX

SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination [Neuroblastoma]

A neuroblastoma chick embryo xenograft model recapitulates tumor initiation and dissemination.

http://ift.tt/2A6oxi0

Effect of mother's voice on neonatal respiratory activity and EEG delta amplitude

Abstract

While the influence of the mother's voice on neonatal heart-rate response and its relevant activity on cerebral cortex and the autonomic nervous system (ANS) are well known, few studies have assessed its influence on respiratory activity. We investigated the relationship among the respiration rate, the delta wave amplitudes through electroencephalography, and the basal state of ANS through the respiratory variability index while 22 full-term neonates hear their mother's voice and an unknown voice. It was found that when respiratory variability was large, a transient (<5 s) change in respiration rates was observed in response to an unknown voice, while a greater increase in the delta wave amplitude was observed in the frontal lobe than the parietal one in response to the mother's voice. Conversely, when respiratory variability was small, a sustained increase (>10 s) in respiration rates was observed in response to the mother's voice, while a greater increase in the delta wave amplitude was found in both the frontal and parietal lobes. These results suggest that the basal state of ANS influences the latency of increases in respiration rates. Furthermore, induced by the mother's voice, transient increases in respiration rates are reduced in association with frontal lobe activity, and sustained increases in respiration rates are promoted in association with frontal and parietal lobe activities.

http://ift.tt/2ilqZ90

Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia

Abstract

Purpose

The objective of this study was to assess the pharmacokinetics of recombinant asparaginase (rASNase, Spectrila^®) in children with acute lymphoblastic leukemia using a population pharmacokinetic approach in order to explore potential dosing recommendations.

Methods

Data on serum asparaginase activities of 124 children from three clinical studies were included in the analysis, covering an age range from 3 days to 17 years. Most patients received 5000 U/m² rASNase intravenously every 3 days. The non-linear mixed effects modelling software (NONMEM^®) was utilized to identify drivers of rASNase pharmacokinetics in children. Different dose adjustments were simulated for their ability to increase rASNase trough activities in children who do not reach the threshold of 100 U/L.

Results

A two-compartment model with allometric weight scaling (0.75 on clearance [CL] and inter-compartmental clearance [Q] and 1 on central [V ₁] and peripheral [V ₂] volume of distribution) was the best model to describe the pharmacokinetics of rASNase. PK parameters for the median child (19.5 kg) were: CL = 0.0592 L/h, V ₁ = 1.18 L, Q = 0.307 L/h, V ₂ = 0.316 L. Organ functions, such as liver or kidney function and laboratory values, such as fibrinogen or antithrombin III levels, showed no influence on rASNase pharmacokinetics. In simulations, changing the administration interval from 72 to 48 h was appropriate to maintain rASNase activities above the therapeutic threshold, in patients with activities below 100 U/L 72 h after the first dose.

Conclusions

Drug monitoring is recommended to identify patients with insufficient ASNase trough activities in serum and to modify the treatment schedule, if necessary. Shortening of the treatment interval might be preferable over increasing the rASNase dose.

http://ift.tt/2jhelJ5

Salvage stereotactic radiosurgery for recurrent gliomas with prior radiation therapy

Future Oncology, Ahead of Print.


http://ift.tt/2zP8rFh

The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy

Future Oncology, Ahead of Print.


http://ift.tt/2ntFPzB

The influence of Osmunda regalis root extract on head and neck cancer cell proliferation, invasion and gene expression

According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of t...

http://ift.tt/2zMbI87

The treatment of migraine patients within chiropractic: analysis of a nationally representative survey of 1869 chiropractors

While the clinical role of manual therapies in migraine management is unclear, the use of chiropractors for this condition is considerable. The aim of this study is to evaluate the prevalence and characteristi...

http://ift.tt/2nuRLkm

Nam Dia long, a Vietnamese folk formula, induces apoptosis in MCF-7 cells through various mechanisms of action

The holistic approach of traditional medicine renders the identification of its mechanisms of action difficult. Microarray technology provides an efficient way to analyze the complex genome-wide gene expressio...

http://ift.tt/2zNpyqI

Antibacterial activity and effects of Colla corii asini on Salmonella typhimurium invasion in vitro and in vivo

Salmonella enterica serovar Typhimurium is a foodborne pathogen that triggers inflammatory responses in the intestines of humans and livestock. Colla corii asini is a traditional medic...

http://ift.tt/2nrWPGv

Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer

Purpose: Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human NSCLC. Experimental Design: Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1 and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin+ tumor epithelial cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells, CD20+ B-lymphocytes and CD68+ tumor-associated macrophages. We determined the association between the targets, clinico-pathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA was also performed. Results: VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8+ T-cells and CD68+ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T-cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival. Conclusions: VISTA is frequently expressed in human NSCLC and shows association with increased TILs, PD-1 axis markers, specific genomic alterations and outcome. These results support the immuno-modulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target.

http://ift.tt/2jg1ab2

A First-in-Human Phase 1 Study of Subcutaneous Outpatient Recombinant Human IL-15 (rhIL-15) in Adults with Advanced Solid Tumors

Purpose: Preclinical data established Interleukin-15 as a homeostatic factor and powerful stimulator of NK and CD8+ T cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL-15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday - Friday) SC injections of rhIL-15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL-15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL-15 at dose levels of 0.25, 0.5, 1, 2 and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.  Conclusions: SC rhIL-15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL-15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent.

http://ift.tt/2BzAGbq

NAMPT is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and resistance to therapy through Sirt1 and PARP

Purpose: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors. Experimental Design: ectopic overexpression of nicotinamide phosphoribosil transferase (NAMPT) and shRNAs in CRC cell lines, Tumorigenic and stemness properties and transcription measurement in culture and in vivo. Transcriptional analisis in public databases. Therapeutic approaches.Results: NAMPT, the rate-limiting enzyme responsible for the highest source of physiological NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling, thus enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of CIC-like cells in colon tumors directly extracted from patients, and transcription meta-analysis revealed that NAMPT is also a key factor that induces cancer stem pathways in CRC tumors. This effect is mediated by PARP and SIRT1. Additionally, we report a novel NAMPT-driven signature that stratifies prognosis from high to low expression groups. The NAMPT signature contained SIRT1 and PARP1 levels as well as other CSC-related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Conclusions: NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers.

http://ift.tt/2jhceVF

Lymph Node Metastases in Colon Cancer are Polyclonal

Purpose:  Recent studies have highlighted the existence of sub-clones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors including colorectal cancer (CRC). We sought to understand the genetic origin of lymph node metastasis in CRC by evaluating the relationship between CRC tumor sub-clones present in primary tumors and lymph nodes. Experimental Design:  A total of 33 samples from seven CRC's, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of LN metastases. The computational method PyClone was used to define sub-clones within each tumor. The method Citup was subsequently used to infer phylogenetic relationships among sub-clones. Results:  We found there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor. Conclusions: Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time.

http://ift.tt/2BzgJRT

Prevention of tick bites: an evaluation of a smartphone app

Lyme borreliosis (LB) is the most common reported tick-borne infection in Europe, and involves transmission of Borrelia by ticks. As long as a vaccine is not available and effective measures for controlling tick ...

http://ift.tt/2zM5xkr

Epidemiology of influenza in West Africa after the 2009 influenza A(H1N1) pandemic, 2010–2012

Over the last decade, capacity for influenza surveillance and research in West Africa has strengthened. Data from these surveillance systems showed influenza A(H1N1)pdm09 circulated in West Africa later than i...

http://ift.tt/2nrptY7

Eradication of P. aeruginosa biofilm in endotracheal tubes based on lock therapy: results from an in vitro study

Despite the several strategies available for the management of biofilm-associated ventilator-associated pneumonia, data regarding the efficacy of applying antibiotics to the subglottic space (SS) are scarce. W...

http://ift.tt/2zMBMjE

Distribution and molecular characterization of Acinetobacter baumannii international clone II lineage in Japan [PublishAheadOfPrint]

Multidrug-resistant (MDR) Acinetobacter spp. have been globally disseminated in association with successful clonal lineage Acinetobacter baumannii international clone II (IC II). Because the prevalence of MDR Acinetobacter spp. in Japan remains very low, we characterized all Acinetobacter spp. (n=866) from 76 hospitals between October 2012 and March 2013 to describe the entire molecular epidemiology of Acinetobacter spp. The most prevalent species was A. baumannii (n = 645; 74.5%), with A. baumannii IC II (n = 245) accounting for 28.3% of total. Meropenem-resistant isolates accounted for 2.0% (n = 17) and carried ISAba1-bla_OXA-23-like (n = 10), bla_IMP (n = 4), or ISAba1-bla_OXA-51-like (n = 3). Multilocus sequence typing of 110 representative A. baumannii revealed the considerable prevalence of domestic STs. A. baumannii IC II isolates were divided into domestic ST469 (n = 18) and globally disseminated ST208 (n = 14) and ST219 (n = 4). ST469 isolates were susceptible to more antimicrobial agents, while ST208 and ST219 overproduced intrinsic AmpC β-lactamase. A. baumannii IC II and some A. baumannii non-IC II STs (e.g. ST149 and ST246) were associated with fluoroquinolone resistance. This study revealed carbapenem-susceptible A. baumannii IC II was moderately disseminated in Japan. The low prevalence of acquired carbapenemase genes and presence of domestic STs could contribute to the low prevalence of MDR A. baumannii. A similar epidemiology might have appeared before the global dissemination of MDR epidemic lineages. In addition, fluoroquinolone resistance associated with A. baumannii IC II may provide insight into the significance of A. baumannii epidemic clones.

http://ift.tt/2BIClfu

Extreme drug tolerance of Mycobacterium tuberculosis in caseum [PublishAheadOfPrint]

Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence and drug tolerance are among the factors driving the long therapy duration. Assays to measure in situ drug susceptibility of Mycobacterium tuberculosis (Mtb) bacteria in pulmonary lesions are needed if we are to discover new fast acting regimens and address the global TB threat. Here we take a first step towards this goal and describe an ex vivo assay developed to measure the cidal activity of anti-TB drugs against Mtb bacilli present in cavity caseum, obtained from rabbits with active TB. We show that caseum Mtb bacilli are largely non-replicating while maintaining viability over the course of the assay, and exhibit extreme tolerance to many 1^st and 2^nd line TB drugs. Among the drugs tested, only the rifamycins fully sterilized caseum. A similar trend of phenotypic drug resistance was observed in the hypoxia and starvation induced non-replicating models, but with notable qualitative and quantitative differences: (i) caseum Mtb exhibits higher drug tolerance than non-replicating Mtb in the Wayne and Loebel models, and (ii) pyrazinamide is cidal in caseum but has no detectable activity in these classic non-replicating assays. Thus, ex vivo caseum constitutes a unique tool to evaluate drug potency against slow- or non-replicating bacilli in their native caseous environment. Intra-caseum cidal concentrations can now be related to concentrations achieved in the necrotic foci of granulomas and cavities, to establish correlations between clinical outcome and lesion-centric PK-PD parameters.

http://ift.tt/2kjOenV

In vitro, in silico and in vivo analysis of novel aromatic amidines against Trypanosoma cruzi [PublishAheadOfPrint]

Five bis-arylimidamides were assayed as anti-T.cruzi agents using in vitro, in silico and in vivo approaches. All were considered no PAINS, have favorable pharmacokinetic landscape, were active against trypomastigotes and intracellular forms but combined with benznidazole gave no interaction. The most selective (28SMB032) moved to in vivo led to 40% parasitemia reduction (0.1mg/kg/5 days by ip) but without mortality protection. In silico target fishing suggested DNA as main target, but ultrastructural data did not match.

http://ift.tt/2BIf2CI

A prospective trial on the use of trough concentration versus area under the curve (AUC) to determine therapeutic vancomycin dosing [PublishAheadOfPrint]

We hypothesized that dosing vancomycin to achieve trough concentrations >15 mg/L overdoses many adults compared to AUC-guided dosing. We conducted a 3-year, prospective study of vancomycin dosing, plasma concentrations, and outcomes. In year 1, non-study clinicians targeted trough concentrations of 10-20 mg/L (infection dependent) and controlled dosing. In years 2 and 3, the study team controlled vancomycin dosing with the BestDose Bayesian software to achieve a daily, steady-state AUC:MIC≥400, with maximum AUC 800 mg*h/L, regardless of trough concentration. For Bayesian estimation of AUCs, we used trough samples in years 1-2 and optimally timed samples in year 3. We enrolled 252 adults ≥18 years old with ≥1 available vancomycin concentration. Only 19% of all trough concentrations were therapeutic vs. 70% of AUCs (P<0.0001). After enrollment, median trough concentrations by year were 14.4, 9.7, and 10.9 mg/L (P=0.005), with 36%, 7%, and 6% over 15 mg/L (P<0.0001). Bayesian AUC-guided dosing in years 2 and 3 was associated with fewer additional blood samples per subject (3.6, 2.0, 2.4, P=0.003), shorter therapy (8.2, 5.4, 4.7 days, P=0.03), and reduced nephrotoxicity (8%, 0% and 2%, P=0.01). Among nephrotoxic patients, the median inpatient stay was 20 vs. 6 days (P=0.002). There was no difference in efficacy by year, with 42% having microbiologically proven infections. Compared to trough concentration targets, AUC-guided, Bayesian-assisted vancomycin dosing was associated with decreased nephrotoxicity, reduced per-patient blood sampling, and shorter length of therapy, without compromising efficacy. These benefits have the potential for substantial cost savings.

http://ift.tt/2kjOaVd

Mutations in Genes Encoding Penicillin-Binding Proteins and Efflux Pumps Play a Role in {beta}-Lactam Resistance in Helicobacter cinaedi [PublishAheadOfPrint]

β-Lactams are often used to treat Helicobacter cinaedi infections; however, the mechanism underlying β-lactam resistance is unknown. In this study, we investigated β-lactam resistance in a H. cinaedi strain, MRY12-0051 (MIC of AMX and CRO: 32 and 128 μg/ml; obtained from human feces). Based on a comparative whole genome analysis of MRY12-0051 and the CRO-susceptible H. cinaedi strain MRY08-1234 (MIC of AMX and CRO: 1 and 4 μg/ml; obtained from human blood), we identified five mutations in genes encoding penicillin-binding proteins (PBPs), including two in pbpA, one in pbp2, and two in ftsI. Transformation and penicillin-binding assays indicated that CRO resistance was mainly associated with mutations in pbpA; mutations in ftsI also led to increased resistance to AMX. Knocking out cmeB and cmeD, which encode resistance-nodulation-division-type efflux pump components, in H. cinaedi type strain CCUG18818 (AMX MIC: 4--8 μg/ml) resulted in an 8- and 64-fold decrease, respectively, in the AMX MIC. Hence, MICs of AMX in H. cinaedi become similar to those of H. pylori isolates in the absence of cmeD. In conclusion, the difference in susceptibility to β-lactams between H. pylori and H. cinaedi is explained by differences in efflux pump components. Mutations in pbpA are the primary determinant of high resistance to β-lactams in H. cinaedi.

http://ift.tt/2BIeZa0

Role of smeU1VWU2X Operon in the Alleviation of Oxidative Stresses and the Occurrence of Sulfamethoxazole/trimethoprim-resistant Mutants in Stenotrophomonas maltophilia [PublishAheadOfPrint]

Overexpression of resistance-nodulation-division (RND)-type efflux pumps is an important mechanism for bacteria to combat antimicrobials. RND efflux pumps are also critical for bacterial physiology such as oxidative stress tolerance. Stenotrophomonas maltophilia, a multi-drug resistant opportunistic pathogen, harbors eight RND-type efflux pump operons. Of them, smeU1VWU2X operon is unique for its possession of two additional genes, smeU1 and smeU2, which encode proteins of short-chain dehydrogenase/reductase (SDR) family. Overexpression of the SmeVWX pump is known to contribute to the acquired resistance to chloramphenicol, quinolone, and tetracycline; however, SmeU1 and SmeU2 are little involved in this phenotype. In this article, we further linked smeU1VWU2X operon to oxidative stress alleviation and sulfamethoxazole/trimethoprim (SXT)-resistant mutants occurrence. SmeU1VWU2X operon was inducibly expressed upon the challenge of menadione (MD), plumbagin (PL), and hydrogen peroxide (H₂O₂), verified by chromosomal smeU1VWU2X-xylE transcriptional fusion construct and quantitative real-time PCR (qRT-PCR). The MD-mediated smeU1VWU2X upexpression was totally dependent on SoxR, partially relied on SmeRv, but was less relevant to OxyR. SmeRv, but not SoxR and OxyR, played a regulatory role in the H₂O₂-mediated smeU1VWU2X upexpression. The significance of smeU1VWU2X upexpression was investigated in respect of oxidative stress alleviation and SXT-resistant mutants occurrence. Overexpression of smeU1VWU2X operon contributed to the alleviation of MD-mediated oxidative stress. Of the encoded proteins, SmeVWX pump and SmeU2, rather than SmeU1, participated in the MD tolerance. Furthermore, we also demonstrated that MD-mediated expression of smeU1VWU2X operon decreased SXT resistance frequency when S. maltophilia was grown in the reactive oxygen species (ROS)-rich environment.

http://ift.tt/2kjO3Jh

Epidemiology of carbapenem-resistant Enterobacteriaceae infections: report from China CRE Network [PublishAheadOfPrint]

Carbapenem-resistant Enterobacteriaceae (CRE) infection is highly endemic in China, but estimates of infection burden are lacking. We established incidence of CRE infection from a multicenter study that covered 25 tertiary hospitals in 14 provinces. CRE cases defined as carbapenem non-susceptible C. freundii, E. coli, E. cloacae, or K. pneumoniae infections during January to December 2015 were collected and reviewed from medical records. Antimicrobial susceptibility testing and carbapenemase genes identification were performed. Among 664 CRE cases, most were caused by K. pneumoniae (73.9%), followed by E. coli (16.6%), and E. cloacae (7.1%). The overall CRE infection incidence per 10,000 discharges was 4.0, and differed significantly by region, with the highest in Jiangsu (14.97), and the lowest in Qinghai (0.34). 83.8% of patients had underlying co-morbidities; the median age was 62 years (range, 45–74) and 450 (67.8%) were male. Lower respiratory tract infections (65.4%) were most common, followed by urinary-tract infection (16.6%), intra-abdominal infection (7.7%), and bacteremia (7.7%). The overall hospital mortality rate was 33.5%. All isolates showed non-susceptibility to carbapenems and cephalosporins. Susceptibility rate of Polymyxin B was >90%. Tigecycline demonstrated higher susceptibility rate against E. coli, compared with K. pneumoniae (90.9% vs. 40.2%). Of 155 clinical isolates analyzed, 89% produced carbapenemases with a majority of isolates producing KPC (50%) and/or NDM (33.5%)-type beta-lactamases among K. pneumoniae and E. coli. Incidence of CRE infection in China was 4.0 per 10,000 discharges. The patient-based disease burden in tertiary hospitals in China is severe, suggesting an urgent need to enhance infection control.

http://ift.tt/2kjNYFt

Chemogenomic profiling of the fungal pathogen Candida albicans [PublishAheadOfPrint]

There are currently a small number of classes of antifungal drugs, and these drugs are known to target a very limited set of cellular functions. We derived a set of approximately 900 non-essential, transactivator-defective disruption strains from the tetracycline regulated GRACE strain collection of the fungal pathogen Candida albicans. This strain set was screened against classic antifungal drugs to identify gene inactivations that conferred either enhanced sensitivity or increased resistance to the compounds. We examined two azoles, fluconazole and posaconazole; two echinochandins, caspofungin and anidulafungin; as well as the polyene amphotericin B. Overall, the chemogenomic profiles within drug classes were highly similar, but there was little overlap between classes, suggesting the different drug classes were interacting with discrete networks of genes in C. albicans. We also tested two pyridine amides, designated GPI-LY7 and GPI-C107; these drugs gave very similar profiles that were distinct from the echinochandins, azoles or polyenes, supporting the idea they target a distinct cellular function. Intriguingly, where these gene sets can be compared to genetic disruptions conferring drug sensitivity in other fungi, we find very little correspondence in genes. Thus even though the drug targets are the same in the different species, the specific genetic profiles that can lead to drug sensitivity are distinct. This implies that chemogenomic screens in one organism may be poorly predictive of the profiles found in other organisms, and that drug sensitivity and resistance profiles can differ significantly among organisms even when the apparent target of the drug is the same.

http://ift.tt/2BHsLtf

PA5470 Counteracts Antimicrobial Effect of Azithromycin by Releasing Stalled Ribosome in Pseudomonas aeruginosa [PublishAheadOfPrint]

Pseudomonas aeruginosa causes various acute and chronic infections in human. Treatment with azithromycin (AZM) has been shown to benefit patients with chronic P. aeruginosa infections. By binding to the exit tunnel of 50S ribosome, AZM causes ribosome stalling and depletion of intracellular tRNA pool. It has been shown that AZM is able to kill stationary-phase P. aeruginosa cells and repress quorum sensing regulated virulence factors as well as swarming motility. In P. aeruginosa, PA5470 encodes a putative peptide chain release factor, whose expression is highly induced by macrolide antibiotics. However, its function remains unknown. Here we found that overexpression of PA5470 increased bacterial tolerance against AZM and alleviated the repression of swarming motility. Ribosome pull-down assays revealed that PA5470 contributes to the release of ribosome stalled by the AZM. We further demonstrate that overexpression of PA5470 counteracts AZM mediated repression on the translation of the quorum sensing regulator RhlR. Overall, our results revealed a novel role of PA5470 in bacterial response to AZM.

http://ift.tt/2kmgKW0

Limited Effect of Later-generation Fluoroquinolones in the Treatment of Ofloxacin-resistant and Moxifloxacin-susceptible Multidrug-resistant Tuberculosis [PublishAheadOfPrint]

Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant/moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used in all patients. Overall, 171 patients (82%) had ofloxacin-susceptible/moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group) and 37 (18%) had ofloxacin-resistant/moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a previous history of MDR-TB treatment (P < 0.001) and cavitary lesions on chest radiography (P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have drug resistance to pyrazinamide (P = 0.003), streptomycin (P = 0.015), prothionamide (P < 0.001), and para-aminosalicylic acid (P < 0.001). Favorable outcomes were more frequently achieved in the ofloxacin-susceptible group than in the ofloxacin-resistant group [91% (156/171) vs. 57% (21/37), respectively; P < 0.001]. In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval = 1.55-18.53) times more likely than the ofloxacin-resistant group (P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, favorable treatment outcomes for ofloxacin-resistant MDR-TB were significantly lower than for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more aggressive therapies may be needed for ofloxacin-resistant MDR-TB.

http://ift.tt/2BIW3Ie

Pharmacodynamics of the Long Acting Echinocandin, CD101, in the Neutropenic Invasive Candidiasis Murine Model Using an Extended Interval Dosing Design [PublishAheadOfPrint]

Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans making it possible to design once-weekly dosing strategies. The current study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select C. albicans (n=4), C. glabrata (n=3), and C. parapsilosis (n=3) strains. The CD101 MIC ranged from 0.03 -- 1 mg/L. Plasma pharmacokinetic measurements were performed from uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 -- 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days at which time organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The PK/PD index AUC/MIC correlated well with efficacy (R² 0.74 -- 0.93). The median stasis 24-h free drug AUC/MIC targets were: C. albicans 2.92, C. glabrata 0.07, and C. parapsilosis 2.61. The PK/PD targets for 1-log₁₀ kill endpoint were 2-4--fold higher. Interestingly, the aforementioned PK/PD targets were numerically lower for all three species compared to other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

http://ift.tt/2BICjnS

Presence of mcr-3 variant in Aeromonas caviae, Proteus mirabilis, and Escherichia coli from one domestic duck [PublishAheadOfPrint]

The rapid rise and dissemination of MDR bacteria is a major threat to public health worldwide, and has narrowed the treatment options for infections caused by these bacteria (1)....

http://ift.tt/2klaWfF

Novel treatment of Staphylococcus aureus device-related infections using fibrinolytic agents [PublishAheadOfPrint]

Objective: Staphylococcal infections involving biofilms represent a significant challenge in the treatment of patients with device-related infections. Staphylococcus aureus biofilms have been shown to be SaeRS-regulated and dependent on coagulase-catalysed conversion of fibrinogen into fibrin on surfaces coated with human plasma. Here we investigated the treatment of staphylococcal biofilm device-related infections by digesting the fibrin biofilm matrix with and without existing antimicrobials.

Methods: The fibrinolytic agents plasmin, streptokinase, nattokinase and the recombinant trypsin-like protease TrypLE™ were used to digest and treat S. aureus biofilms grown in vitro using in vivo like static biofilm assays with and without antimicrobials. Cytotoxicity, potential to induce a cytokine response in whole human blood and risk of induction of tolerance to fibrinolytic agents were investigated. A rat model of intravascular catheter infection was established to investigate the efficacy of selected fibrinolytic agents in vivo.

Results: Under biomimetic conditions the fibrinolytic agents effectively dispersed established S. aureus biofilms and in combination with common anti-staphylococcal antimicrobials effectively killed bacterial cells being released from the biofilm. These fibrinolytic agents were not cytotoxic and did not affect host immune response. The rat model of infection successfully demonstrated the activity of the selected fibrinolytic agents alone and in combination with antimicrobials on established biofilm in vivo.

Conclusion: TrypLE™ and nattokinase most successfully removed adherent cells from plasma-coated surfaces and significantly improved the efficacy of existing antimicrobials against S. aureus biofilms in vitro and in vivo. These biofilm dispersal agents represent a viable future treatment option for S. aureus device-related infections.

http://ift.tt/2kkgHdn

Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease [PublishAheadOfPrint]

Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of non-cavitary nodular bronchiectatic (NB) Mycobacterium avium complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent non-cavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (n = 26) or intermittent therapy (n = 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared with the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent non-cavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent non-cavitary NB MAC lung disease.

http://ift.tt/2BIesVy

Host - pathogen - treatment triad: host factors matter most in MRSA bacteremia outcomes [PublishAheadOfPrint]

Background: Previous studies have separately emphasized the importance of host, pathogen and treatment characteristics in determining short term or in-hospital mortality for patients with methicillin resistant Staphylococcus aureus (MRSA) bloodstream infections. Less is known about the relative importance of these factors and their interaction in determining short, medium and long-term mortality.

Methods: This is an observational cohort study where all patients admitted to University of New Mexico Health Sciences Center (UNM HSC) between July 2002 and August 2013 with MRSA positive blood cultures were recorded. We collected patients' demographic and treatment data along with genetic markers of the MRSA isolates. Outcomes of interest were determinants of short (30 days), medium (30-90 days) and long-term (>90 days) mortality.

Results: This study included 273 patients with MRSA bacteremia. Short, medium and long-term mortality were 18.7%, 26.4% and 48% respectively. Thirty-day mortality was influenced by host variables along with host-pathogen interaction characteristics. Pitt bacteremia score, malignancy and healthcare exposure contributed to 30 - 90-day mortality while duration of therapy longer than 4 weeks had a protective effect. Age remained a significant risk factor for greater than 90-day mortality while admission leukocytosis was protective. Infection represented the most frequent cause of death for all 3 time frames and it varied from 72.6% in the first 30 days, 60% for 30-90 days to 35.7% at more than 90 days (p= 0.003).

Conclusion: Host characteristics impact short, medium and long term mortality in MRSA bloodstream infections more than genetic pathogen markers and treatment factors.

http://ift.tt/2klZpMY

Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer [Research Articles]

Triple negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole exome sequencing (WES) and RNAseq to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expressions or oncoprotein-containing fusions, respectively, as well as frame-shift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. While the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNAseq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine guided TNBC treatment.

http://ift.tt/2AQ5SX6

Normothermia after decompressive surgery for space-occupying middle cerebral artery infarction: a protocol-based approach

Moderate hypothermia after decompressive surgery might not be beneficial for stroke patients. However, normothermia may prove to be an effective method of enhancing neurological outcomes. The study aims were t...

http://ift.tt/2AWhJU6

Atrial fibrillation is not uncommon among patients with ischemic stroke and transient ischemic stroke in China

Atrial fibrillation (AF) is reported to be a less frequent cause of ischemic stroke in China than in Europe and North America, but it is not clear whether this is due to underestimation. Our aim was to define ...

http://ift.tt/2A3pszE

Selection bias in clinical stroke trials depending on ability to consent

Clinical trials are the hallmark of evidence-based medicine, but recruitment is often challenging, especially in stroke trials investigating patients not being able to give informed consent. In some nations, e...

http://ift.tt/2AVdjg1

The Effect of Auricular Acupoint Stimulation in Overweight and Obese Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective. To investigate the effect of auricular acupoint stimulation on overweight and obese adults. Methods. We searched databases including PubMed, EMBASE, Allied and Complementary Medicine Database, National Knowledge Infrastructure, and the PerioPath Index to Taiwan Periodical Literature. The modified Jadad scale was used to assess study quality. We investigated the effect of auricular acupoint stimulation on anthropometric measurements. Results. Eighteen randomized controlled trials (RCTs) were included in our systematic review. Thirteen RCTs were pooled in a meta-analysis that revealed a significant reduction in body weight (BW) with a mean difference (MD) of 1.21 kg and a 95% confidence interval (CI) from 1.94 to 0.47 with a heterogeneity of = 88%. Significant decreases in body mass index (BMI; MD: 0.57 kg/m2; 95% CI 0.82 to 0.33; = 78%), body fat (BF; MD: 0.83%; 95% CI 1.43 to 0.24; = 0%), and waist circumference (WC; MD: 1.75 cm; 95% CI 2.95 to 0.55; = 87%) were also revealed. Conclusions. This meta-analysis shows that auricular acupoint stimulation improves physical anthropometric parameters including BW, BMI, BF, and WC in overweight and obese adults. These methods are less effective on hip circumference and waist-to-hip ratio.

http://ift.tt/2ANoGpY

Obesity prevalence among healthcare professionals in England: a cross-sectional study using the Health Survey for England

Objective

To estimate obesity prevalence among healthcare professionals in England and compare prevalence with those working outside of the health services.

Design

Cross-sectional study based on data from 5 years (2008–2012) of the nationally representative Health Survey for England.

Setting

England.

Participants

20 103 adults aged 17–65 years indicating they were economically active at the time of survey classified into four occupational groups: nurses (n=422), other healthcare professionals (n=412), unregistered care workers (n=736) and individuals employed in non-health-related occupations (n=18 533).

Outcome measure

Prevalence of obesity defined as body mass index ≥30.0 with 95% CIs and weighted to reflect the population.

Results

Obesity prevalence was high across all occupational groups including: among nurses (25.1%, 95% CI 20.9% to 29.4%); other healthcare professionals (14.4%, 95% CI 11.0% to 17.8%); non-health-related occupations (23.5%, 95% CI 22.9% to 24.1%); and unregistered care workers who had the highest prevalence of obesity (31.9%, 95% CI 28.4% to 35.3%). A logistic regression model adjusted for sociodemographic composition and survey year indicated that, compared with nurses, the odds of being obese were significantly lower for other healthcare professionals (adjusted OR (aOR) 0.52, 95% CI 0.37 to 0.75) and higher for unregistered care workers (aOR 1.46, 95% CI 1.11 to 1.93). There was no significant difference in obesity prevalence between nurses and people working in non-health-related occupations (aOR 0.94, 95% CI 0.74 to 1.18).

Conclusions

High obesity prevalence among nurses and unregistered care workers is concerning as it increases the risks of musculoskeletal conditions and mental health conditions that are the main causes of sickness absence in health services. Further research is required to better understand the reasons for high obesity prevalence among healthcare professionals in England to inform interventions to support individuals to achieve and maintain a healthy weight.

http://ift.tt/2BElPNz

Update: Topical Anesthetics for Pain Control During Repair of Dermal Laceration

The authors included 25 randomized controlled trials with a total of 3,278 adult and pediatric patients. They found that various topical cocaine-free agents provided adequate analgesia; however, comparison of specific agents was not possible because of high risk of bias among comparison studies. In 2 pooled studies, self-reported improvement in visual analog scale scores (0 to 100 mm), the improvement was greater for topical prilocaine-phenylephrine compared with topical tetracaine-epinephrine-cocaine, with a difference of 5.6 points.

http://ift.tt/2zQ168l

What Is the Utility of Coronary Computed Tomography Angiography Compared With Standard of Care for the Evaluation of Acute Chest Pain?

The search strategy identified 648 articles, of which 10 trials (6,285 total participants) met the inclusion criteria. The studies were published between 2007 and 2016, and none were determined to be at high risk of bias. Six studies were performed in the ED and 4 studies were performed in the inpatient setting. The mean age ranged from 50 to 60 years, and the percentage of female patients ranged from 42% to 63%. Eight studies excluded patients with known coronary artery disease. Standard of care included myocardial perfusion imaging in 8 studies, stress ECG in 5 studies, and stress echocardiogram in 2 studies.

http://ift.tt/2ntFsF1

Aldosterone-Producing Cell Clusters in Normal and Pathological States

Horm Metab Res 2017; 49: 951-956
DOI: 10.1055/s-0043-122394

Primary aldosteronism (PA) significantly increases the risk of cardiovascular complications, and early diagnosis and targeted treatment based on its pathophysiology is warranted. Next-generation sequencing (NGS) has revealed recurrent somatic mutations in aldosterone-driving genes in aldosterone-producing adenoma (APA). By applying CYP11B2 (aldosterone synthase) immunohistochemistry and NGS to adrenal glands from normal subjects and PA patients, we and others have shown that CYP11B2-positive cells make small clusters, termed aldosterone-producing cell clusters (APCC), beneath the adrenal capsule, and that APCC harbor somatic mutations in genes mutated in APA. We have shown that APCC are increased in CT-negative PA adrenals, while others showed potential progression from APCC to micro APA through mutations. These results suggest that APCC are a key factor for understanding the origin of PA, and further investigation on the relation between APCC and PA is highly needed.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2AP7TCJ

Health-Related Quality of Life and Mental Health in Primary Aldosteronism: A Systematic Review

Horm Metab Res 2017; 49: 943-950
DOI: 10.1055/s-0043-121706

The aim of this review was to determine the impact of primary aldosteronism on health-related quality of life (HRQoL) and mental health. We performed a systematic literature search up to July 2017 in six electronic databases. First, we screened the articles derived from this search based on title and abstract. Second, the selected studies were systematically reviewed and checked for our predefined inclusion criteria. The search yielded 753 articles, of which 15 studies met our inclusion criteria. Untreated patients with primary aldosteronism showed an impaired physical and mental HRQoL as compared to the general population. Multiple domains of HRQoL were affected. This applied to patients with both an aldosterone-producing adenoma and bilateral adrenal hyperplasia. Adrenalectomy improves HRQoL. Conflicting results have been reported on the extent of this improvement, the improvement after initiation of medical treatment, and whether there is a difference in HRQoL after both treatments. Similarly, psychopathological symptoms of anxiety, demoralization, stress, depression and nervousness were more frequently reported in untreated patients with primary aldosteronism than in the general population and patients with hypertension. Also an impaired sleep quality has been reported. Improvement of these symptoms was observed after treatment with both adrenalectomy and mineralocorticoid receptor antagonists. This review shows that HRQoL is impaired and psychopathology is more frequently reported in patients with primary aldosteronism. This seems to be at least partly reversible after treatment but the extent of improvement remains unknown. To assess HRQoL in these patients more precisely a primary aldosteronism-specific HRQoL questionnaire is required.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2ALwYi9

Disordered CYP11B2 Expression in Primary Aldosteronism

Horm Metab Res 2017; 49: 957-962
DOI: 10.1055/s-0043-122238

Primary aldosteronism is the most common type of secondary hypertension affecting 6–10% of patients with primary hypertension. PA is mainly caused by unilateral hyperaldosteronism due to an aldosterone-producing adenoma, unilateral hyperplasia with or without micronodules or bilateral zona glomerulosa hyperplasias with or without macro or micronodules. The development of antibodies against the terminal enzyme of aldosterone biosynthesis (CYP11B2) has permitted the further characterization of normal adrenals and resected adrenals from patients with primary aldosteronism. Normal adrenals exhibit two different patterns of cellular expression of CYP11B2: young individuals display a relatively uniform expression of the enzyme throughout the zona glomerulosa while the adrenals of older individuals have dispersed CYP11B2-expressing cells but have more groups of cells called aldosterone-producing cell clusters (APCC). APAs exhibit different patterns of CYP11B2 staining that vary from uniform to homogeneous. There are also a proportion of cells within the APA that co-express different enzymes that are not normally co-expressed in normal individuals. Approximately 30% of patients with unilateral hyperaldosteronism do not have an APA, but either have an increased number of CYP11B2 expressing micronodules or hyperplasia of the zona glomerulosa. In summary, the studies reported in this review are shedding new light on the pathophysiology of primary aldosteronism. The wide variation in histopathological features of the adenomas and concurrent presence of APCCs raises the possibility that most cases of unilateral production of aldosterone actually might represent bilateral asymmetric hyperplasia with nodules frequently due to the development of somatic aldosterone-driving mutations.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

http://ift.tt/2AP89BR

The Feasibility of Xpert MTB/RIF Testing to Detect Rifampicin Resistance among Childhood Tuberculosis for Prevalence Surveys in Northern China

Drug resistance surveillance is crucial for control of drug-resistant tuberculosis (TB). However, limited data exists on the burden of drug-resistant TB in children. The goal of this work was to generate prevalence data regarding rifampicin- (RIF-) resistant childhood TB in northern China and to test the feasibility of Xpert for surveying pediatric TB drug resistance prevalence. We enrolled 362 clinically diagnosed childhood TB patients and collected sputum, gastric lavage aspirate (GLA), bronchoalveolar lavage fluid (BALF), and cerebral spinal fluid (CSF) samples. Xpert and solid culture were utilized to detect RIF resistance. The detection rate of Xpert-positive TB among new clinically diagnosed TB cases was 38.4% (139/362), significantly higher than that of solid culture-positive TB (16.3%, 59/362, ). Notably, Xpert-positive rates differed significantly by sample type, with the highest positive rate for GLA (51.2%). The unit testing costs per RIF-resistant TB patient were $828.41 for solid culture and $761.86 for Xpert. Our data demonstrate that the prevalence of RIF resistance among childhood TB cases in our study (6.9%) is comparable to the national RIF resistance prevalence level of new cases (6.7%). In addition, Xpert is superior to the solid culture for RIF resistance survey in the childhood TB patients.

http://ift.tt/2iPQQJO

Improving Carboplatin Dosing Based on Estimated GFR

Kidney disease affects drug pharmacokinetics and pharmacodynamics, and level of kidney function is a key consideration in the use of drugs. Carboplatin, a widely used cancer chemotherapeutic agent, is excreted mainly by glomerular filtration. Maintaining efficacy and avoiding toxicity requires determination of glomerular filtration rate (GFR) for accurate dosing.1 In a recent study published in the Journal of Clinical Oncology, Janowitz et al2 evaluated the accuracy of GFR estimating equations in patients being treated with carboplatin and developed a new equation for the purpose of calculating a patient's carboplatin dose to achieve a target exposure.

http://ift.tt/2jNDaLX

Longitudinal Weight Change During CKD Progression and Its Association With Subsequent Mortality

Few studies have investigated the changes in weight that may occur over time among adults with the progression of chronic kidney disease (CKD). Whether such weight changes are independently associated with death after the onset of end-stage renal disease has also not been rigorously examined.

http://ift.tt/2igVsot

Autosomal Dominant Tubulointerstitial Kidney Disease Due to MUC1 Mutation

Mucin 1 kidney disease, previously referred to as medullary cystic kidney disease type 1, is a rare hereditary kidney disease. It is one of several diseases now termed autosomal dominant tubulointerstitial kidney disease, as proposed by a KDIGO (Kidney Disease: Improving Global Outcomes) consensus report in 2014. Autosomal dominant tubulointerstitial kidney diseases share common clinical findings, such as autosomal dominant inheritance, bland urinary sediment, absent to mild proteinuria, and progressive loss of kidney function.

http://ift.tt/2jNMVJY

The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy

Abstract

Background and purpose

To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer.

Materials and methods

Seventeen consecutive rectal cancer patients undergoing preoperative radiation were selected and setup in either the prone (N = 8) or supine (N = 9) position. All patients were treated using posteriorly-applied VMAT. Bladder and small bowel dose and cone beam CT (CBCT) reproducibility metrics were retrospectively collected.

Results

Dose metrics for bladder and small bowel did not show significant differences between the prone and supine orientations. The prone data had a trend for smaller irradiated volumes than supine for the small bowel at lower doses—V20 (prone: 135 ± 99 cm³; supine: 201 ± 162 cm³) and V30 (prone: 78 ± 71 cm³; supine: 105 ± 106 cm³). At higher doses, the trend reversed as exemplified by the small bowel V50.4 (prone: 20 ± 28 cm³; supine: 10 ± 14 cm³). CBCT data showed that rotational errors in pitch and roll were significantly larger for the prone vs. supine orientation (pitch: 2.0° ± 1.3° vs. 0.8° ± 1.1° p < 0.001; roll: 1.0° ± 0.9° vs. 0.3° ± 0.5°, p < 0.001).

Conclusions

Bladder and small bowel doses were not significantly different when comparing VMAT plans developed for the prone and supine orientations. The supine orientation demonstrated improved setup reproducibility.

http://ift.tt/2BHJDAj

Stenotic Lesions and the Maximum Diameter of Coronary Artery Aneurysms in Kawasaki Disease

To determine the prevalence of subsequent stenotic lesions based on the maximum diameter of the largest coronary artery aneurysm in patients with Kawasaki disease and the threshold value of coronary artery diameter associated with risk of developing stenotic lesion.

http://ift.tt/2jNdQ8I

Coming to Terms with Cardiovascular Morbidity after Early Term Birth

There is accumulating evidence that the consequences of even late preterm birth (34-37 weeks of gestation) reach well beyond the neonatal hospitalization into morbidities commonly seen in adulthood. The Barker hypothesis proposed that fetal adaptations to suboptimal intrauterine oxygen and nutrient supply result in changes in physiology and metabolism that subsequently predispose these individuals to an increased risk of cardiovascular diseases over their lifetime, including ischemic heart disease, stroke, diabetes, and hypertension.

http://ift.tt/2iiAo0I

Improvement of Outcomes for Children with Down Syndrome

Structured care of children with Down syndrome is highly important. Indeed, the American Academy of Pediatrics published in 2011, and reaffirmed in 2014, the clinical report, "Health Supervision for Children with Down Syndrome" to help the pediatrician provide longitudinal care for children and their families in a medical home.1 Two studies published in this volume of The Journal reinforce the value of systematic care for children with Down syndrome and illustrate how important continuing surveillance is to the outcome of these children.

http://ift.tt/2jNe4wA

Papular Purpuric Gloves and Socks Syndrome because of a Mycoplasma Infection

A 3-year-old girl presented to our clinic with mild, nonpruritic, palmar and plantar erythematous papules, and a few erythematous lesions on the oral mucosa. The lesions appeared 2-3 days before presentation and besides low-grade fever, physical examination was unremarkable. Vaccination history was according to national immunization schedules. The clinical picture was most compatible with hand-foot-and-mouth disease (most common cause coxsackievirus A16), and the child was sent home without treatment.

http://ift.tt/2jNhAHo

Clinical Indices Can Standardize and Monitor Pediatric Care: A Novel Mechanism to Improve Quality and Safety

The Cancer Care Index (CCI), a single metric that sums the number of undesirable patient events in a given time frame (either preventable harm events or missed opportunities to provide optimal care), resulted in a 42% improvement in performance. Our objective was to test the index concept in other service lines to determine whether similar performance improvement occurred.

http://ift.tt/2jNhrDQ

Intrauterine and Early Postnatal Exposure to Particulate Air Pollution and Kawasaki Disease: A Nationwide Longitudinal Survey in Japan

To examine the effects of prenatal and postnatal exposure to particulate matter on Kawasaki disease (KD) occurrence, using data from a nationwide population-based longitudinal survey in Japan that began in 2010.

http://ift.tt/2igwjdI

Childhood Corporal Punishment and Future Perpetration of Physical Dating Violence

To test whether experiencing childhood corporal punishment is linked to later perpetration of dating violence.

http://ift.tt/2ihRXy6

One-Year Outcome for Congenital Diaphragmatic Hernia: Results From the French National Register

To evaluate the status of congenital diaphragmatic hernia (CDH) management in France and to assess predictors of adverse outcomes.

http://ift.tt/2ileoTj

Re: Impact of pre-operative health-related quality of life on outcomes after heart surgery

http://ift.tt/2iPmLu4

Medicine in small doses

http://ift.tt/2AN2UT5

Issue information - TOC

http://ift.tt/2iP7MQW

Referees

http://ift.tt/2ANd3PM

Response to Re: Laboratory Risk Indicator for Necrotizing Fasciitis score for early diagnosis of necrotizing fasciitis in Darwin

http://ift.tt/2iQh9zz

Let’s make the most of the underutilized capacity of the private hospital system for educating our future surgical workforce

http://ift.tt/2ANcYeW

Acknowledging pancreaticoduodenectomy as a multi-visceral resection

http://ift.tt/2iRH0aq

25, 50 & 75 years ago

http://ift.tt/2AN2Dzx

Re: How to do it: use of the Alexis wound protector as a laparostomy device

http://ift.tt/2iQSScU

Routine reporting of mammographic density from screening mammograms

http://ift.tt/2AN2tYX

Response to Re: Impact of pre-operative health-related quality of life on outcomes after heart surgery

http://ift.tt/2iQ92TF

Re: Laboratory Risk Indicator for Necrotizing Fasciitis score for early diagnosis of necrotizing fasciitis in Darwin

http://ift.tt/2AN2jRl

The World Health Organization Surgical Safety Checklist

http://ift.tt/2iP7LfQ

Endoscopic balloon dilatation of Crohn's strictures: a safe method to defer surgery in selective cases

Background

Endoscopic balloon dilatation (EBD) provides a valuable alternative to surgery for strictures in Crohn's disease (CD). Data are lacking regarding the factors that improve the safety and effectiveness of EBD in CD. The aim of this study is to determine the safety and efficacy of EBD and the clinical variables, which are predictive of successful treatment of CD strictures with EBD.

Methods

The records of all patients with CD in whom EBD was attempted between 2008 and 2013 were reviewed. Procedures were conducted at a single tertiary referral centre using a Boston Scientific CRE® TTS balloon. Technical success was defined as the ability to traverse the stricture with the endoscope and clinical success as the resolution of obstructive symptoms at review.

Results

Forty-seven patients with a total of 58 strictures (19 primary and 39 anastomotic strictures) were treated with EBD with median follow-up of 37 months. A total of 161 dilatation procedures were performed, with technical success reported in 139/158 (88%) cases and clinical success reported in 105/137 (76.7%) cases with complete data. Complications occurred in 7/161 dilatations (4.3% dilatations, 15% patients), three patients with perforation, one with acute bleeding and three admitted with abdominal pain. Eighteen of the 47 patients required surgery (38%). Strictures of <50 mm (P = 0.04) and those dilated to a diameter of ≥15 mm (P = 0.031) were less likely to require surgical resection.

Conclusions

EBD is safe for both primary and post-surgical strictures. Stricture length and diameter of dilatation are predictive of success. In selected patients, treatment with EBD may reduce or delay the need for surgery.

http://ift.tt/1NfnEij

Outcome of bridge to surgery stenting for obstructive left colon cancer

Background

The aim of our study was to compare short- and long-term outcomes of stent insertion followed by surgery with those of emergency surgery for left colon malignant obstructions.

Methods

The medical records of patients who received curative resection due to obstructive primary left colon cancer and who were diagnosed with stage II or III from January 2004 to December 2010 in six hospitals affiliated with The Catholic University of Korea were reviewed. One hundred and twelve patients in self-expandable metallic stent (SEMS) group were matched to 56 patients in the emergency surgery (ES) group using propensity score matching method. Overall survival (OS) and disease-free survival (DFS) were compared between the groups. Perioperative outcomes and pathologic results were also compared.

Results

Baseline characteristics were comparable between the two groups after matching. The analysis of perioperative outcomes showed short-term advantages of stent insertion. Patients in the SEMS group were more likely (87.5 versus 75.0%, P = 0.049) to have a distal resection margin >5 cm. Harvesting ≥12 lymph nodes were more frequent (89.3 versus 71.4%, P = 0.007) in the SEMS group. Five-year DFS was 69.5% in the SEMS group and 73.1% in the ES group (P = 0.464). Five-year OS was not different between the groups (79.7 versus 77.7%, P = 0.989).

Conclusions

SEMS can be a reasonable therapeutic option for malignant obstruction in patients with left colon cancer until definitive conclusion about the long-term survival effect of SEMS is made from further large-scale prospective randomized trials.

http://ift.tt/1Wj8d04

USP6 gene rearrangement differentiate primary paranasal sinus solid aneurysmal bone cyst from other giant cell-rich lesions, report of a rare case

Aneurysmal bone cysts (ABCs) mostly occur in the metaphysis of long bones. Primary paranasal ABCs are extremely rare and most reported cases reveal typical histopathological features including cystic space with fibrous septa and hemorrhage. Solid variant ABCs or solid ABCs lacking cyst formation may be histologically indistinguishable from giant cell reparative granulomas (GCRGs), giant cell tumor of bone (GCTB), and brown tumor. Here we report the case of a 24-year-old female with a paranasal mass diagnosed as USP6-rearranged solid ABC, mimicking GCRG, GCTB and brown tumor.

http://ift.tt/2jPF4vM

Incidental iatrogenic form of collagenized organizing pneumonia

We read with interest the study from Dr Yousem [1] describing a cicatricial form of cryptogenic organizing pneumonia (COP) in 12 patients presenting with bilateral, nodular or reticulonodular disease. All but one were symptomatic, and none had extra-thoracic diseases. Histologically, the lesions were characterized by collagenization of the fibromyxoid polyps of OP pattern, while the underlying lung architecture was preserved. Most of the patients (10 out of 12) had a response to steroids. (See Fig.

http://ift.tt/2AOMfyt

Composite Lymphoma of Follicular B-cell and Peripheral T-cell Types with Distinct Zone Distribution in a 75-year-old Male Patient: a Case Study

Composite lymphoma (CL) of T−/B-cell type is rare, and follicular lymphoma composite with peripheral T-cell lymphoma (PTCL) has not previously been reported. We report such a case with both neoplastic components displaying a unique zone of distribution. A 75-year-old male patient presented with generalized lymphadenopathy. Sections of axillary lymph node demonstrated potentially two clonal processes, PTCL with aberrant CD20 expression and follicular lymphoma. Interestingly, the two neoplastic components were confined to their respective classic distribution zones, with PTCL occupying the interfollicular areas and follicular lymphoma residing in follicles.

http://ift.tt/2iRTpuZ

Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma

Radiation is hypothesized to augment the immunogenicity of tumor cells. We retrospectively evaluated survival outcomes, incidence of new brain metastases, and treatment-related adverse events in patients who received stereotactic radiosurgery for brain metastases with concurrent immune checkpoint inhibition, with non-concurrent immune checkpoint inhibition, and with stereotactic radiosurgery alone. Delivering SRS with concurrent ICI may be associated with decreased incidence of new BM and favorable survival outcomes without increased rates of adverse events.

http://ift.tt/2jOSRm9

The Impact of Academic Facility Type and Case Volume On Survival in Patients Undergoing Curative Radiotherapy for Muscle-Invasive Bladder Cancer

We conducted a retrospective cohort study of patients in the National Cancer Database with muscle-invasive bladder cancer undergoing curative radiotherapy to identify whether the facility type and treating facility's case volume impact survival outcomes. When controlling for disease extent and treatment characteristics, patients at academic and non-academic facilities and low and high volume facilities had similar survival outcomes. Thus bladder-sparing curative radiotherapy should be discussed and offered confidently at most centers.

http://ift.tt/2igQdFl

Functional Impairment and Decline in Middle Age A Cohort Study

Background:

Difficulties with daily functioning are common in middle-aged adults. However, little is known about the epidemiology or clinical course of these problems, including the extent to which they share common features with functional impairment in older adults.

Objective:

To determine the epidemiology and clinical course of functional impairment and decline in middle age.

Design:

Cohort study.

Setting:

The Health and Retirement Study.

Participants:

6874 community-dwelling adults aged 50 to 56 years who did not have functional impairment at enrollment.

Measurements:

Impairment in activities of daily living (ADLs), defined as self-reported difficulty performing 1 or more ADLs, assessed every 2 years for a maximum follow-up of 20 years, and impairment in instrumental ADLs (IADLs), defined similarly. Data were analyzed by using multistate models that estimate probabilities of different outcomes.

Results:

Impairment in ADLs developed in 22% of participants aged 50 to 64 years, in whom further functional transitions were common. Two years after the initial impairment, 4% (95% CI, 3% to 5%) of participants had died, 9% (CI, 8% to 11%) had further ADL decline, 50% (CI, 48% to 52%) had persistent impairment, and 37% (CI, 35% to 39%) had recovered independence. In the 10 years after the initial impairment, 16% (CI, 14% to 18%) had 1 or more episodes of functional decline and 28% (CI, 26% to 30%) recovered from their initial impairment and remained independent throughout this period. The pattern of findings was similar for IADLs.

Limitation:

Functional status was self-reported.

Conclusion:

Functional impairment and decline are common in middle age, as are transitions from impairment to independence and back again. Because functional decline in older adults has similar features, current interventions used for prevention in older adults may hold promise for those in middle age.

Primary Funding Source:

National Institute on Aging and National Center for Advancing Translational Sciences through the University of California, San Francisco, Clinical and Translational Sciences Institute.

http://ift.tt/2yzSMcc

Comparative Effectiveness of Routine Invasive Coronary Angiography for Managing Unstable Angina

http://ift.tt/2nudqsW

46-Year Trends in Systemic Lupus Erythematosus Mortality in the United States, 1968 to 2013 A Nationwide Population-Based Study

Background:

No large population-based studies have been done on systemic lupus erythematosus (SLE) mortality trends in the United States.

Objective:

To identify secular trends and population characteristics associated with SLE mortality.

Design:

Population-based study using a national mortality database and census data.

Setting:

United States.

Participants:

All U.S. residents, 1968 through 2013.

Measurements:

Joinpoint trend analysis of annual age-standardized mortality rates (ASMRs) for SLE and non-SLE causes by sex, race/ethnicity, and geographic region; multiple logistic regression analysis to determine independent associations of demographic variables and period with SLE mortality.

Results:

There were 50 249 SLE deaths and 100 851 288 non-SLE deaths from 1968 through 2013. Over this period, the SLE ASMR decreased less than the non-SLE ASMR, with a 34.6% cumulative increase in the ratio of the former to the latter. The non-SLE ASMR decreased every year starting in 1968, whereas the SLE ASMR decreased between 1968 and 1975, increased between 1975 and 1999, and decreased thereafter. Similar patterns were seen in both sexes, among black persons, and in the South. However, statistically significant increases in the SLE ASMR did not occur among white persons over the 46-year period. Females, black persons, and residents of the South had higher SLE ASMRs and larger cumulative increases in the ratio of the SLE to the non-SLE ASMR (31.4%, 62.5%, and 58.6%, respectively) than males, other racial/ethnic groups, and residents of other regions, respectively. Multiple logistic regression showed independent associations of sex, race, and region with SLE mortality risk and revealed significant racial/ethnic differences in associations of SLE mortality with sex and region.

Limitations:

Underreporting of SLE on death certificates may have resulted in underestimates of SLE ASMRs. Accuracy of coding on death certificates is difficult to ascertain.

Conclusion:

Rates of SLE mortality have decreased since 1968 but remain high relative to non-SLE mortality, and significant sex, racial, and regional disparities persist.

Primary Funding Source:

None.

http://ift.tt/2xAtvhv

Should This Patient Receive Aspirin? Grand Rounds Discussion From Beth Israel Deaconess Medical Center

Aspirin exerts antiplatelet effects through irreversible inhibition of cyclooxygenase-1, whereas its anticancer effects may be due to inhibition of cyclooxygenase-2 and other pathways. In 2009, the U.S. Preventive Services Task Force endorsed aspirin for primary prevention of cardiovascular disease. However, aspirin's role in cancer prevention is still emerging, and no groups currently recommend its use for this purpose. To help physicians balance the benefits and harms of aspirin in primary disease prevention, the Task Force issued a guideline titled, "Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer" in 2016. In the evidence review conducted for the guideline, cardiovascular disease mortality and colorectal cancer mortality were significantly reduced among persons taking aspirin. However, there was no difference in nonfatal stroke, cardiovascular disease mortality, or all-cause mortality, nor in total cancer mortality, among those taking aspirin. Aspirin users were found to be at increased risk for major gastrointestinal bleeding. In this Beyond the Guidelines, the guideline is reviewed and 2 experts discuss how they would apply it to a 57-year-old man considering starting aspirin for primary prevention. Our experts review the data on which the guideline is based, discuss how they would balance the benefits and harms of aspirin therapy, and explain how they would incorporate shared decision making into clinical practice.

http://ift.tt/2zOdCFf

Annals Graphic Medicine - Dear Doctor II

http://ift.tt/2nucSmS

Hepatitis B Vaccination, Screening, and Linkage to Care: Best Practice Advice From the American College of Physicians and the Centers for Disease Control and Prevention

Background:

Vaccination, screening, and linkage to care can reduce the burden of chronic hepatitis B virus (HBV) infection. However, recommendations vary among organizations, and their implementation has been suboptimal. The American College of Physicians' High Value Care Task Force and the Centers for Disease Control and Prevention developed this article to present best practice statements for hepatitis B vaccination, screening, and linkage to care.

Methods:

A narrative literature review of clinical guidelines, systematic reviews, randomized trials, and intervention studies on hepatitis B vaccination, screening, and linkage to care published between January 2005 and June 2017 was conducted.

Best Practice Advice 1:

Clinicians should vaccinate against hepatitis B virus (HBV) in all unvaccinated adults (including pregnant women) at risk for infection due to sexual, percutaneous, or mucosal exposure; health care and public safety workers at risk for blood exposure; adults with chronic liver disease, end-stage renal disease (including hemodialysis patients), or HIV infection; travelers to HBV-endemic regions; and adults seeking protection from HBV infection.

Best Practice Advice 2:

Clinicians should screen (hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis B surface antigen) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated alanine aminotransferase levels (≥19 IU/L for women and ≥30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers.

Best Practice Advice 3:

Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B–directed care.

http://ift.tt/2zYeMPt

Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain

http://ift.tt/2nq1l8l

Benefits of Direct-Acting Antivirals for Hepatitis C

Emerging data show that direct-acting antivirals (DAAs) improve clinical outcomes in hepatitis C virus (HCV). This commentary discusses these benefits in light of a recent systematic review suggesting that evidence is insufficient to confirm or reject an effect of DAA therapy on HCV-related illness.

http://ift.tt/2yzGNxB

Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain

http://ift.tt/2nqTUxB

Technology and Medicine: Reimagining Provider Visits as the New Tertiary Care

Technologies enabling remote monitoring and transmission of patients' data hold promise for improved care. The authors caution, however, that these developments might increase the burden on physicians if the flow of additional information is not thoughtfully channeled in a manner that decreases rather than increases the need for physician–patient interactions.

http://ift.tt/2zL8nXd

Annals for Educators - 5 December 2017

http://ift.tt/2nqTKpZ

Introducing a Patient Portal and Electronic Tablets to Inpatient Care

Although a great deal of information has been published about Web-based portals for outpatients, little is known about the use of this technology among inpatients. In this article, the authors describe their experience with patients admitted to 2 academic hospitals who were provided with electronic tablets to enable them to access their medical records, care plans, care team rosters, and other information through a Web-based portal.

http://ift.tt/2zIE9UN

Hepatitis B Vaccination, Screening, and Linkage to Care

http://ift.tt/2jdtMRk

What Recent History Has Taught Us About Responding to Emerging Infectious Disease Threats

Presidential administrations face any number of unexpected crises during their tenure, and global pandemics are among the most challenging. As of January 2017, one of the authors had served under 5 presidents as the director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. During each administration, the government faced unexpected pandemics, ranging from the HIV/AIDS pandemic, which began during the Reagan administration, to the recent Zika outbreak in the Americas, which started during the Obama administration. These experiences underscored the need to optimize preparation for and response to these threats whenever and wherever they emerge. This article recounts selected outbreaks occurring during this period and highlights lessons that were learned that can be applied to the infectious disease threats that will inevitably be faced in the current presidential administration and beyond.

http://ift.tt/2yzSL88

Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain

http://ift.tt/2ntrjb1

Do the Tenets of Late-Life Disability Apply to Middle Age?

Brown and colleagues used longitudinal data from a large, nationally representative sample of nondisabled persons aged 50 to 56 years who were interviewed every 2 years for up to 20 years to describe the cumulative rates of disability by the age of 64 years. The editorialist discusses the findings, which suggest that disability may be as complex in middle age as it is in late life.

http://ift.tt/2yzSJ00

Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain

http://ift.tt/2ntqKxV

Bringing Data to Life: Interactive Visualizations of Complex Data

The advent of large, information-rich data sets partnered with advanced computation has made it increasingly possible to inject life into data through interactive visualization. Brown and colleagues' study of midlife health trajectories includes the type of complex data that begs interactive exploration. The editorialists introduce an interactive graphic that enables readers to delve into the data reported by these investigators.

http://ift.tt/2AIEkjA

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

http://ift.tt/2jO8p9F

Whole-Exome Sequencing in Adults With Chronic Kidney Disease A Pilot Study

Background:

The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.

Objective:

To study the diagnostic utility of WES in a selected referral population of adults with CKD.

Design:

Observational cohort.

Setting:

A major academic medical center.

Patients:

92 adults with CKD of unknown cause or familial nephropathy or hypertension.

Measurements:

The diagnostic yield of WES and its potential effect on clinical management.

Results:

Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most solved cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.

Limitation:

The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.

Conclusion:

Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.

Primary Funding Source:

New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

http://ift.tt/2ik4KAj