18 F–FDG-PET/CT for systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer

Abstract

Objectives

This study assesses ¹⁸F–FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer.

Methods

In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent ¹⁸F–FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.¹⁸F–FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI).

Results

A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, ¹⁸F–FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, ¹⁸F–FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9–20%).

Conclusions

¹⁸F–FDG-PET/CT revealed distant metastases in 14% (95% CI: 9–20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9–24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with ¹⁸F–FDG-PET/CT at the time of initial diagnosis.

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Diffuse 18 F-FDG uptake throughout the spinal cord in the acute phase of Neuromyelitis Optica Spectrum disorder

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The impact of repeated cycles of radioligand therapy using [ 177 Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer

Abstract

Background

[¹⁷⁷Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring.

Methods

Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [¹⁷⁷Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson's correlation coefficient and the corresponding p values.

Results

None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1° or 2°. There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C.

Conclusion

Renal toxicity in patients treated with [¹⁷⁷Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity.

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Fibrous dysplasia mimicking bone metastasis on 68 GA-PSMA PET/MRI

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Comparison of PSMA-HBED and PSMA-I&T as diagnostic agents in prostate carcinoma

Abstract

Purpose

Gallium(68)-labelled prostate-specific membrane antigen (PSMA) radiopharmaceuticals can be used to detect prostate cancer (PCa) cells due the their over expression of PSMA. The ⁶⁸Ga HBED-PSMA (PSMA-HBED) ligand has been most widely used and can be considered the current gold standard agent. Further PSMA ligands based on the DOTAGA and DOTA conjugates have more recently been developed. These agents (PSMA-I&T and PSMA-617) have potential theranostic capabilities as they can be conjugated with therapeutic radioisotopes. In this study, we examine whether PSMA-I&T has comparative efficacy, such that it could replace PSMA-HBED as a diagnostic agent in prostate carcinoma.

Methods

19 patients with PCa referred for ⁶⁸Ga-PSMA imaging were imaged with PSMA-HBED and PSMA-I&T PET-CT imaging within a 2-week period. The two pharmaceuticals were synthesised using click chemistry. Imaging was performed using the same standardised methodology on a Siemens Biograph mCT. All sites of PSMA binding thought to represent PCa (probable or definite) were included in a lesion analysis that examined lesion concordance and lesional binding efficiency (SUV_peak) between the two radiopharmaceuticals. For each patient, SUV_mean of the LV cavity blood pool, bone, muscle and liver were determined as image background measures.

Results

Across all patients, PSMA uptake was observed in 47 lesions (10 bone lesions, 19 nodal lesions, 18 high-grade intraprostatic binding). Lesions were concordant between the agents in all except for two small (<4 mm) nodal lesions which were not visualised with PSMA-I&T. SUV_peak assessment showed significantly greater overall lesion binding with HBED (paired t test, p = 0.0001). LV blood pool and bone marrow SUV_mean were significantly higher for I&T than HBED (paired t test, blood pool p < 1 × 10–5, bone marrow p < 0.005).

Conclusion

Intra-patient comparative imaging demonstrates higher lesional PSMA-HBED binding than PSMA-I&T and that the HBED agent is likely to have better lesion contrast. While there was concordance in 96% of lesions, 2 small nodal lesions were appreciated with PSMA-HBED imaging while considered normal with PSMA-I&T. These findings suggest that HBED-PSMA has a slightly higher diagnostic accuracy in comparison to PSMA-I&T.

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Microsurgery guided by sequential preoperative lymphography using 68 Ga-NEB PET and MRI in patients with lower-limb lymphedema

Abstract

Objective

The popularity of contemporary microsurgical techniques in treatment of lower-limb lymphedema calls for better visualization of the lymphatic system, both preoperatively and intra-operatively. The aim of this prospective study was to investigate the feasibility of a novel combination of ⁶⁸Ga-NEB positron emission tomography (PET) with magnetic resonance lymphography (MRL) in evaluating lymphedema and guiding surgical intervention.

Methods

A total of 11 patients (F 9, M 2, age range 29–69 y) with lower-limb lymphedema classified into stage I to III were recruited. PET acquisition was performed at 30, 60 and 90 min after subcutaneous injection of the albumin-binding radiotracer ⁶⁸Ga-NEB into the bilateral first web spaces of the feet. All the patients were also subjected to ^99mTc-sulfur colloid (SC) lymphoscintigraphy for comparison. Gd-DTPA-enhanced magnetic resonance imaging (MRI) was performed using sequences specialized for lymphatic vessel scans. All the patients underwent surgical interventions within a week. The surgical approach includes the use of a linear marker for edema localization and indocyanine green (ICG) lymphography with a near-infrared surgical navigation system intra-operatively.

Results

Lymph transport in lymphatic channels was clearly observed by visualization of ⁶⁸Ga-NEB activity in the lymphatic vessels and within lymph nodes for all 11 patients as well as the visualization of the edema section plane with dermal backflow (DB), abnormally increased and disconnected uptake along the lymphatic channels. Preoperative ⁶⁸Ga-NEB PET combined with MRL provides advantageous three-dimensional images, higher temporal resolution, significantly shorter time lapse before image acquisition after tracer injection and more accurate pathological lymphatic vessel distribution than ^99mTc-SC lymphoscintigraphy combined with MRI.

Conclusion

This study documented an effective imaging pattern to combine ⁶⁸Ga-NEB PET and MRL in patients with lower-limb lymphedema. This strategy demonstrated significant advantage over ^99mTc-SC lymphoscintigraphy/MRL in the evaluation of lymphedema severity, staging and pathological location of lymph vessels to make an individualized treatment plan. Dual ⁶⁸Ga-NEB PET/MRL is thus recommended before the operation for staging and therapy planning.

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FDG PET for therapy monitoring in Hodgkin’s and non-Hodgkin’s lymphomas: qPET versus rPET

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Sentinel lymph node mapping using SPECT/CT and gamma probe in endometrial cancer: an analysis of parameters affecting detection rate

Abstract

Purpose

SPECT/CT after pericervical injection of technetium-99 m-nanocolloid was shown to be suitable for sentinel lymph node (SLN) mapping in endometrial cancer (EC). The aim of this study was to analyze factors affecting successful SLN detection by means of SPECT/CT such as imaging findings, patient characteristics and tumor biology in a large cohort of patients.

Methods

One hundred and forty-five consecutive patients suffering from EC who received pre-surgical SLN mapping at our institution between 2011 and 2016 were included in this analysis. SPECT/CT data of abdomen and pelvis (mean 4:20 ± 1:20 h p.i.) were acquired after pericervical injection of technetium-99 m-nanocolloid (mean 230 ± 45 MBq) in all patients. Surgical staging was performed on the day after. Acquisition parameters, patient characteristics, SPECT/CT findings as well as histopathological results were collected.

Results

A total of 282 SLNs were identified by means of SPECT/CT. Overall, preoperative and intraoperative SLN detection rates were 86%, 76% and 74% respectively. The most important factor associated with failure to detect SLNs was the presence of high bone marrow on SPECT/CT (p = 0.005). Peritoneal/abdominal radioactivity was also associated with missed SLN detection in SPECT/CT (p = 0.02). However, the presence of liver/spleen uptake on its own was not predictive for detection failure. Low numbers of detected SLNs in SPECT/CT were slightly related with older age and lower injected activity. No significant influence was found for the parameters of tumor histology and stage, lymph node involvement and the time gap between injection and imaging.

Conclusions

Venous drainage as indicated by bone marrow uptake is the most important factor associated with scintigraphic SLN detection failure. Moreover, high peritoneal and abdominal activity was also associated with detection failure. Thus, meticulous application of the radiotracer is crucial in EC.

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Quantification of temporal changes in calcium score in active atherosclerotic plaque in major vessels by 18 F-sodium fluoride PET/CT

Abstract

Purpose

Our aim was to assess whether ¹⁸F-NaF PET/CT is able to predict progression of the CT calcium score.

Methods

Between August 2007 and November 2015, 34 patients (18 women, 16 men; age, mean ± standard deviation, 57.5 ± 13.9 years; age range 19–78 years) with malignancy or orthopaedic disease were enrolled in this study, with approximately 1-year follow-up data. Baseline and follow-up CT images were retrospectively evaluated for the presence of calcification sites in major vessel walls. The maximum and mean CT values (CTmax and CTmean, in Hounsfield units), calcification volumetric score (CVS, in cubic millimetres) and Agatston units score (AU) were evaluated for each site. Subsequent changes in CTmax, CTmean, CVS and AU were calculated and expressed as ΔCTmax, ΔCTmean, ΔCVS and ΔAU, respectively. We then evaluated the relationship between ¹⁸F-NaF uptake (using the maximum target-to-background ratio, TBRmax, and the maximum blood-subtracted ¹⁸F-NaF activity, bsNaFmax, which was obtained by subtracting the SUVmax of each calcified plaque lesion and NaF-avid site from the SUVmean in the right atrium blood pool) and the change in calcified plaque volume and characteristics obtained after 1 year.

Results

We detected and analysed 182 calcified plaque sites and 96 hot spots on major vessel walls. ¹⁸F-NaF uptake showed very weak correlations with CTmax, CTmean, CVS, CVS after 1 year, AU and AU after 1 year on both baseline and follow-up PET/CT scans for each site. ¹⁸F-NaF uptake showed no correlation with ΔCTmax or ΔCTmean. However, there was a significant correlation between the intensity of ¹⁸F-NaF uptake and ΔCVS and ΔAU.

Conclusion

¹⁸F-NaF uptake has a strong correlation with calcium score progression which was a predictor of future cardiovascular disease risk. PET/CT using ¹⁸F-NaF may be able to predict calcium score progression which is known to be the major characteristic of atherosclerosis.

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FDG-PET/CT for systemic staging of patients with newly diagnosed breast cancer

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Comments on ‘Area and power efficient DCT architecture for image compression’ by Dhandapani and Ramachandran

In [Dhandapani and Ramachandran, "Area and power efficient DCT architecture for image compression", EURASIP Journal on Advances in Signal Processing 2014, 2014:180] the authors claim to have introduced an appr...

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Robust depth enhancement and optimization based on advanced multilateral filters

Stereo matching of two distanced cameras and structured-light RGB-D cameras are the two common ways to capture the depth map, which conveys the per-pixel depth information of the image. However, the results wi...

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Binaural noise reduction via cue-preserving MMSE filter and adaptive-blocking-based noise PSD estimation

Binaural noise reduction, with applications for instance in hearing aids, has been a very significant challenge. This task relates to the optimal utilization of the available microphone signals for the estimat...

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Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p

Abstract

Background

The function of a new long non-coding RNA linc00673 remains unclear. While identified as an oncogenic player in non-small cell lung cancer (NSCLC), linc00673 was found to be anti-oncogenic in pancreatic ductal adenocarcinoma (PDAC). However whether linc00673 regulated malignancy and epithelial mesenchymal transition (EMT) has not been characterized.

Methods

Cell proliferation was assessed using CCK-8 and EdU assays, and cell migration and invasion were assessed using scratch assays and transwell invasion assays. Epithelial mesenchymal transition was examined using western blot, qRT-PCR and immunofluorescence staining. Interaction between miRNA and linc00673 was determined using luciferase reporter assays. In vivo experiments were performed to assess tumor formation. In addition, the expression data of NSCLC specimens of TCGA and patient survival data were utilized to explore the prognostic significance of linc00673.

Results

In the present study, we found high linc00673 expression was associated with poor prognosis of NSCLC patients. In vitro experiments showed linc00673 knockdown reversed TGF-β induced EMT, and miR-150-5p was predicted to target linc00673 through bioinformatics tools. Overexpression of miR-150-5p suppressed lin00673's expression while inhibition of miR-150-5p led to significant upregulation of lin00673, suggesting that linc00673 could be negatively regulated by miR-150-5p, which was further confirmed by the inverse correlation between linc00673 and miR-150-5p in NSCLC patients' specimen. Furthermore, we proved that miR-150-5p could directly target linc00673 through luciferase assay, so linc00673 could sponge miR-150-5p and modulate the expression of a key EMT regulator ZEB1 indirectly. In addition, miR-150-5p inhibition abrogated linc00673 silence mediated proliferation, migration, invasion and EMT suppressing effect. Moreover, the inhibition of linc00673 significantly attenuated the tumorigenesis ability of A549 cells in vivo.

Conclusions

We validated linc00673 as a novel oncogenic lncRNA and demonstrated the molecular mechanism by which it promotes NSCLC, which will advance our understanding of its clinical significance.

http://ift.tt/2v6bjLb

Clinical outcome and risk factors of neonatal sepsis among neonates in Felege Hiwot referral Hospital, Bahir Dar, Amhara Regional State, North West Ethiopia 2016: a retrospective chart review

Sepsis remains a major cause of morbidity and mortality among neonates. The risk factors and clinical outcomes of sepsis are poorly understood. Most cases of sepsis occurred mostly within the first week of new...

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Microbial pathogens associated with acute childhood diarrhoea in Kumasi, Ghana

Diarrhoeal diseases are among the most frequent causes of morbidity and mortality in children worldwide, especially in sub-Saharan Africa. This case–control study was conducted to investigate the bacterial, vi...

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Simple and fast quantification of DNA damage by real-time PCR, and its application to nuclear and mitochondrial DNA from multiple tissues of aging zebrafish

We describe a real-time (rt) PCR-based method of quantifying DNA damage, adapted from the long-run rtPCR method of DNA damage quantification (LORD-Q) developed by Lehle et al. (Nucleic Acids Res 42(6):e41, 2014)....

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Socio-demographic determinants of skilled birth attendant at delivery in rural southern Ghana

Maternal mortality is the subject of the United Nations' fifth Millennium Development Goal, which is to reduce the maternal mortality ratio by three quarters from 1990 to 2015. The giant strides made by wester...

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Successful treatment of refractory complete separation of an esophagojejunal anastomosis after laparoscopic total gastrectomy: a case report

Anastomotic leakage after total gastrectomy occurs despite improvements in surgical techniques and patient management. Although many cases of dehiscence can be managed non-operatively, major leakage requires a...

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Estimating Direct Cost of Cystic Fibrosis Care Using Irish Registry Healthcare Resource Utilisation Data, 2008–2012

Abstract

Background

Understanding the determinants of cost of cystic fibrosis (CF) care and health outcomes may be useful for financial planning for the delivery of CF services. Registries contain information otherwise unavailable to healthcare activity/cost monitoring systems. We estimated the direct medical cost of CF care using registry data and examined how cost was affected by patient characteristics and CF gene (CF Transmembrane Conductance Regulator [CFTR]) mutation.

Methods

Healthcare resource utilisation data (2008–2012) were obtained for CF patients enrolled with the Irish CF Registry by 2013 from linked registry and national hospitalisation database records. Mean annual hospitalisation and medication per-patient costs were estimated by demographic profile, CFTR mutation, clinical status, and CF co-morbidity, and were presented in 2014 euro values. A mixed-effects regression model was used to examine the effect of demographic, CFTR mutation, and clinical outcomes on the log₁₀ cost of direct medical CF care.

Results

Using 4261 observations from 1100 patients, we found that the median annual total cost per patient increased over the period 2008–2012 from €12,659 to €16,852, inpatient bed-day cost increased from €14,026 to €17,332, and medication cost increased from €5863 to €12,467. Homozygous F508-CFTR mutation (class II) cost was highest and milder mutation (class IV/V) cost was 49% lower. Baseline estimated cost in 2008 for a hypothetical underweight, homozygous F508del-CFTR 6-year-old female without chronic Pseudomonas aeruginosa/Staphylococcus aureus, CF-related diabetes (CFRD) or methicillin-resistant S. aureus (MRSA), and with a poor percent predicted forced expiratory volume in 1 s (ppFEV₁) was €10,113, and was €21,082 in a 25-year-old with the same hypothetical profile. Chronic P. aeruginosa infection increased baseline cost by 39%, CF co-morbidity diabetes by 18%, and frequency of pulmonary exacerbation by 15%. Underweight, declining ppFEV₁, chronic S. aureus colonisation, and time also influenced cost.

Conclusions

CFTR mutation is an important factor influencing the cost of CF care. Costs differ among cohorts of CF patients eligible to access new and emerging CFTR repair therapies. These findings support the evaluation of outcome-associated cost in CFTR mutation-specific CF patient groups.

http://ift.tt/2tCoFAF

Advances in Nanoparticles Vol.6,No.2 (May 2017)

Preparation, Characterization and Evaluation of Efficacy of Phosphorus and Potassium Incorporated Nano Fertilizer
Nano Fertilizer, Preparation, Efficacy, P-Efficiency, K-Efficiency
Paper Information Full Paper: PDF (Size:2295KB)
DOI: 10.4236/anp.2017.62006

A Facile Synthesis and Photoluminescence Properties of SiO₂:Tb³⁺ Spherical Nanoparticles
Silica, Sol-Gel, Photoluminescence, Terbium Doped-Silica
Paper Information Full Paper: PDF (Size:3598KB)
DOI: 10.4236/anp.2017.62002

Adsorption of Silver Nanoparticles from Aqueous Solution by Multiwalled Carbon Nanotubes
Silver Nanoparticles, Multiwalled Carbon Nanotubes, Adsorption, Water Treatment
Paper Information Full Paper: PDF (Size:1697KB)
DOI: 10.4236/anp.2017.62003

In-Situ XAFS Characterization of PtPd Nanoparticles Synthesized by Galvanic Replacement
Platinum, Palladium, Nanoparticles, Oxygen Reduction Reaction, In-Situ XAFS, ITFA
Paper Information Full Paper: PDF (Size:3573KB)
DOI: 10.4236/anp.2017.62007

Effect of Lithium Chloride on the Fibre Length Distribution, Processing Temperature and the Rheological Properties of High-Yield-Pulp-Fibre-Reinforced Modified Bio-Based Polyamide 11 Composite
HYP/PA11, Melting Temperature of Nylon 11, Inorganic Salt Chloride Lithium (Licl), Fibre Aspect Ratio and Length Distribution, Rheological Characteristic
Paper Information Full Paper: PDF (Size:988KB)
DOI: 10.4236/anp.2017.62005

Electrospinning Synthesis and Photoluminescence Properties of One-Dimensional SiO₂:Tb³⁺ Nanofibers and Nanobelts
Silica, Electrospinning, Photoluminescence, Terbium Doped-Silica
Paper Information Full Paper: PDF (Size:3065KB)
DOI: 10.4236/anp.2017.62004

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Using a pregnancy decision support program for women choosing birth after a previous caesarean in Japan: A mixed methods study

Publication date: Available online 10 July 2017
Source:Women and Birth
Author(s): Ikuyo Torigoe, Allison Shorten




http://ift.tt/2u7isNY

JMJD2A promotes the Warburg effect and nasopharyngeal carcinoma progression by transactivating LDHA expression

Abstract

Background

Jumonji C domain 2A (JMJD2A), as a histone demethylases, plays a vital role in tumorigenesis and progression. But, its functions and underlying mechanisms of JMJD2A in nasopharyngeal carcinoma (NPC) metabolism are remained to be clarified. In this study, we investigated glycolysis regulation by JMJD2A in NPC and the possible mechanism.

Methods

JMJD2A expression was detected by Western blotting and Reverse transcription quantitative real-time PCR analysis. Then, we knocked down and ectopically expressed JMJD2A to detect changes in glycolytic enzymes. We also evaluated the impacts of JMJD2A-lactate dehydrogenase A (LDHA) signaling on NPC cell proliferation, migration and invasion. ChIP assays were used to test whether JMJD2A bound to the LDHA promoter. Finally, IHC was used to verify JMJD2A and LDHA expression in NPC tissue samples and analyze their correlation between expression and clinical features.

Results

JMJD2A was expressed at high levels in NPC tumor tissues and cell lines. Both JMJD2A and LDHA expression were positively correlated with the tumor stage, metastasis and clinical stage. Additionally, the level of JMJD2A was positively correlated with LDHA expression in NPC patients, and higher JMJD2A and LDHA expression predicted a worse prognosis. JMJD2A alteration did not influence most of glycolytic enzymes expression, with the exception of PFK-L, PGAM-1, LDHB and LDHA, and LDHA exhibited the greatest decrease in expression. JMJD2A silencing decreased LDHA expression and the intracellular ATP level and increased LDH activity, lactate production and glucose utilization, while JMJD2A overexpression produced the opposite results. Furthermore, JMJD2A could combine to LDHA promoter region and regulate LDHA expression at the level of transcription. Activated JMJD2A-LDHA signaling pathway promoted NPC cell proliferation, migration and invasion.

Conclusions

JMJD2A regulated aerobic glycolysis by regulating LDHA expression. Therefore, the novel JMJD2A-LDHA signaling pathway could contribute to the Warburg effects in NPC progression.

http://ift.tt/2v6fg2q

High cancer mortality for US-born Latinos: evidence from California and Texas

Abstract

Background

Latinos born in the US, 36 million, comprise 65% of all US Latinos. Yet their cancer experience is nearly always analyzed together with their foreign-born counterparts, 19 million, who constitute a steady influx of truly lower-risk populations from abroad. To highlight specific cancer vulnerabilities for US-born Latinos, we compare their cancer mortality to the majority non-Latino white (NLW) population, foreign-born Latinos, and non-Latino blacks.

Methods

We analyzed 465,751 cancer deaths from 2008 to 2012 occurring among residents of California and Texas, the two most populous states, accounting for 47% of US Latinos. This cross-sectional analysis, based on granular data obtained from death certificates on cause of death, age, race, ethnicity and birthplace, makes use of normal standardization techniques and negative binomial regression models.

Results

While Latinos overall have lower all-cancers-combined mortality rates than NLWs, these numbers were largely driven by low rates among the foreign born while mortality rates for US-born Latinos approach those of NLWs. Among Texas males, rates were 210 per 100,000 for NLWs and 166 for Latinos combined, but 201 per 100,000 for US-born Latinos and 125 for foreign-born Latinos. Compared to NLWs, US-born Latino males in California had mortality rate ratios of 2.83 (95% CI: 2.52–3.18) for liver cancer, 1.44 (95% CI: 1.30–1.61) for kidney cancer, and 1.25 (95% CI: 1.17–1.34) for colorectal cancer (CRC). Texas results showed a similar site-specific pattern.

Conclusions

Specific cancer patterns for US-born Latinos, who have relatively high cancer mortality, similar overall to NLWs, are masked by aggregation of all Latinos, US-born and foreign-born. While NLWs had high mortality for lung cancer, US-born Latinos had high mortality for liver, kidney and male colorectal cancers. HCV testing and reinforcement of the need for CRC screening should be a priority in this specific and understudied population. The unprecedented proximity of overall rates between NLWs and US-born Latino populations runs counter to the prevailing narrative of Latinos having significantly lower cancer risk and mortality. Birthplace data are critical in detecting meaningful differences among Latinos; these findings merit not only clinical but also public health attention.

http://ift.tt/2u7lQbr

Joint quantitative measurement of hTERT mRNA in both peripheral blood and circulating tumor cells of patients with nasopharyngeal carcinoma and its clinical significance

Abstract

Background

The study was aimed to quantitatively detect mRNA levels of the catalytic subunit of telomerase (hTERT) in both peripheral blood and circulating tumor cells (CTCs) of patients with nasopharyngeal carcinoma (NPC) and explore its significance in early diagnosis and treatment of NPC.

Methods

hTERT mRNA levels in peripheral blood and CTCs of 33 NPC patients before and after treatment with intensity-modulated radiation therapy (IMRT) or/and chemotherapy and 24 healthy controls were measured using real-time quantitative PCR (qPCR) and their correlations to clinic pathological factors of NPC were analyzed.

Results

Peripheral hTERT mRNA content was 10.75 ± 4.29 in NPC patients and 0.95 ± 0.37 in control subjects (P < 0.05), and had a significant correlation with patients' clinical stage, T stage, and N stage (P < 0.05). Treatment of NPC patients at stages I and II with simple IMRT significantly reduced hTERT mRNA level from 5.60 ± 2.33 to 3.43 ± 1.42 (P < 0.05) and treatment of patients at advanced stage (III and IV) with induction chemotherapy followed by IMRT significantly reduced hTERT mRNA levels from 12.68 ± 3.08 to 10.68 ± 2.48 to 3.13 ± 1.69 (P < 0.05), respectively. In addition, the study also showed that hTERT mRNA content in CTCs of NPC patients was 10.65 ± 4.28, evidently higher than that of 1.09 ± 0.40 in control subjects (P < 0.05) and hTERT mRNA level in CTCs of NPC patients was obviously correlated to patients' clinical stage, T stage and N stage (P < 0.05). After treatment, hTERT mRNA level in CTCs of NPC patients lowered from 10.65 ± 4.28 to 5.59 ± 2.32 (P < 0.05). The correlation analysis found that hTERT mRNA level in peripheral blood and CTCs of NPC patients were highly correlated with a correlation coefficient of 0.981.

Conclusions

hTERT mRNA levels in peripheral blood and CTCs of NPC patients were significantly enhanced compared to that in healthy controls and highly correlated. Changes in hTERT mRNA level was closely correlated to patients' clinical stage and T stage. Radiochemotherapy could effectively reduce hTERT mRNA level in peripheral blood and CTCs. Thus, it is possible using the joint detection of hTERT mRNA level in peripheral blood and CTCs as a new biomarker for early diagnosis, treatment efficacy and prognosis of NPC.

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Ruptured varicose veins and fatal hemorrhage

http://ift.tt/2t7EJak

Rare bacterial isolates causing bloodstream infections in Ethiopian patients with cancer

Abstract

Background

In recent years, saprophytic bacteria have been emerging as potential human pathogens causing life-threatening infections in patients with malignancies. However, evidence is lacking concerning such bacteria, particularly in sub-Saharan countries. This study was designed to determine the spectrum and drug resistance profile of the rare bacterial pathogens causing bloodstream infections (BSIs) in febrile cancer patients at a referral hospital in Ethiopia.

Methods

Between December 2011 and June 2012, blood samples were collected from 107 patients with cancer in Tikur Anbessa hospital. Culturing was performed using the blood culture bottles and solid media and the microorganisms were identified using the gram staining and APINE identification kits (Biomerieux, France). The disk diffusion method was used for the antimicrobial susceptibility testing.

Results

Overall, 13 (12.2%) rare human pathogens were isolated from 107 adult febrile cancer patients investigated. Aeromonas hydrophilia species (a fermentative gram-negative rod) was the predominant isolate, 30.8% (4/13), followed by Chryseomonas luteola 15.4% (2/13), Sphignomonas poucimobilis 15.4% (2/13), and Pseudomonas fluorescens 15.4% (2/13). Of the nine isolates tested for a nine set of antibiotics, 89% were resistant to amoxicillin-clavulanic acid, ampicillin, and trimethoprim-sulphamethoxazole.

Conclusions

This study revealed the emergence of saprophytic bacteria as potential drug-resistant nosocomial pathogens in Ethiopian patients with cancer. As these pathogens are ubiquitous in the environment, infection prevention actions should be strengthened in the hospital and early diagnosis and treatment with appropriate antibiotics are warranted for those already infected.

http://ift.tt/2sYm99m

Implementing the compassion intervention, a model for integrated care for people with advanced dementia towards the end of life in nursing homes: a naturalistic feasibility study

Background

Many people with dementia die in nursing homes, but quality of care may be suboptimal. We developed the theory-driven 'Compassion Intervention' to enhance end-of-life care in advanced dementia.

Objectives

To (1) understand how the Intervention operated in nursing homes in different health economies; (2) collect preliminary outcome data and costs of an interdisciplinary care leader (ICL) to facilitate the Intervention; (3) check the Intervention caused no harm.

Design

A naturalistic feasibility study of Intervention implementation for 6 months.

Settings

Two nursing homes in northern London, UK.

Participants

Thirty residents with advanced dementia were assessed of whom nine were recruited for data collection; four of these residents' family members were interviewed. Twenty-eight nursing home and external healthcare professionals participated in interviews at 7 (n=19), 11 (n=19) and 15 months (n=10).

Intervention

An ICL led two core Intervention components: (1) integrated, interdisciplinary assessment and care; (2) education and support for paid and family carers.

Data collected

Process and outcome data were collected. Symptoms were recorded monthly for recruited residents. Semistructured interviews were conducted at 7, 11 and 15 months with nursing home staff and external healthcare professionals and at 7 months with family carers. ICL hours were costed using Department of Health and Health Education England tariffs.

Results

Contextual differences were identified between sites: nursing home 2 had lower involvement with external healthcare services. Core components were implemented at both sites but multidisciplinary meetings were only established in nursing home 1. The Intervention prompted improvements in advance care planning, pain management and person-centred care; we observed no harm. Six-month ICL costs were £18 255.

Conclusions

Implementation was feasible to differing degrees across sites, dependent on context. Our data inform future testing to identify the Intervention's effectiveness in improving end-of-life care in advanced dementia.

Trial registration

ClinicalTrials.gov:NCT02840318: Results

http://ift.tt/2v6bTIC

Patient benefit of dog-assisted interventions in health care: a systematic review

Dogs are the most common companion animal, and therefore not surprisingly a popular choice for animal-assisted interventions. Dog-assisted interventions are increasingly used in healthcare. The aim of the revi...

http://ift.tt/2t7KFQE

Biochemical characterization and 1H NMR based metabolomics revealed Melicope lunu-ankenda leaf extract a potent anti-diabetic agent in rats

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by continuous hyperglycemia associated with insulin resistance and /or reduced insulin secretion. There is an emerging trend regarding the ...

http://ift.tt/2tCeexa

Ethambutol partitioning in tuberculous pulmonary lesions explains its clinical efficacy [PublishAheadOfPrint]

Clinical trials and practice have shown that ethambutol is an important component of the first line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against non-growing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions. We then employed mass spectrometry imaging and laser capture microdissection coupled to liquid chromatography and tandem mass spectrometry (LCM/LCMS) to show that ethambutol indeed accumulates in diseased tissues and penetrates the major human-like lesion types represented in the rabbit model of TB disease with a lesion-to-plasma exposure ratio ranging from 9 to 12. In addition, ethambutol exhibits slow but sustained passive diffusion into caseum to reach concentrations markedly higher than measured in plasma at steady state. The results explain why ethambutol has retained its place in the first line regimen, validate our in vitro lesion penetration assays and demonstrate the critical importance of effective lesion penetration for anti-TB drugs. Our findings suggest that in vitro and in vivo lesion penetration evaluation should be included in TB drug discovery programs. Finally, this is the first time that LCM/LCMS is used to quantify a small molecule at high spatial resolution in infected tissues, a method that can easily be extended to other infectious diseases.

http://ift.tt/2uLbrAr

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells in Healthy Adult Subjects [PublishAheadOfPrint]

The steady-state concentrations of omadacycline and tigecycline in plasma, epithelial lining fluid (ELF), and alveolar cells (AC) concentrations were obtained in 58 healthy adult subjects. Subjects were administered either omadacycline as 100 mg intravenously (IV) every 12 hours for two doses followed by 100 mg IV every 24 hours for three doses or tigecycline as an initial dose of 100 mg IV followed by 50 mg IV every 12 hours for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 hours, and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 hours. The AUC_0-24 value (based on mean concentrations) in ELF and the ratio of ELF to total plasma omadacycline based on AUC_0-24 values were 17.23 mg·h/L and 1.47, respectively. The AUC_0-24 value in AC was 302.46 mg·h/L and the ratio of AC to total plasma omadacycline concentrations was 25.8. In comparison, AUC_0-12 values based on mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg·h/L, respectively. The ratio of ELF and AC to total plasma concentrations of tigecycline based on AUC_0-12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline in plasma, ELF, and AC compared to tigecycline suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

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Characterization of the complete nucleotide sequence of IncA/C2 plasmids carrying In809-like integrons from Enterobacteriaceae of wildlife origin [PublishAheadOfPrint]

A total of 18 Enterobacteriaceae (seventeen from gulls, and one from a clinical sample), carrying IncA/C plasmids with the IMP-encoding In809-like integrons, collected from Australia were studied. Seven plasmids being representatives of different origins, plasmid sizes, replicon combinations and resistance genes, were completely sequenced. Plasmid pEc158, identified in a clinical ST752 Escherichia coli isolate, showed extensive similarity to type 2 IncA/C₂ plasmids. pEc158 carried none of the bla_CMY-2-like region, ARI-B and ARI-A regions, while it contained a hybrid transposon structure. The six remaining plasmids, which were of wildlife origin, were highly similar to each other and probably were fusion derivatives of type 1 and type 2 A/C₂ plasmids. The latter plasmids contained an ARI-B region and hybrid transposon structures. In all plasmids, hybrid transposon structures containing In809-like integrons were inserted 3434 bp downstream the rhs2 start codon. In all cases, the one outermost 38 bp IR of the transposon was associated with the Tn1696 tnp module, while the other outermost 38 bp IR of the transposon was associated with either a Tn6317-like module or a Tn21 mer module. However, the internal structure of the transposon and the resistance genes were different in each plasmid. These findings indicated that, for the specific periods of time and settings, different IncA/C₂ plasmid types carrying In809-like elements circulated among isolates of wildlife and clinical origin. Additionally, they provided the basis for speculations regarding the reshuffling of IncA/C₂ plasmids with In809-like integrons and confirmed the rapid evolution of IncA/C₂ plasmid lineages.

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The sterilizing effect of ertapenem-clavulanate in a hollow fiber model of tuberculosis and implications on clinical dosing [PublishAheadOfPrint]

Carbapenems are now being explored for treatment of multi-drug resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day, and lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once a day dose for clinical use. We utilized the hollow fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time-points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid E_max modeling was used to identify the relationship between total bacterial burden and the drug exposure, and identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose-fractionation hollow fiber study, efficacy was linked to percentage of the 24 hour dosing interval of ertapenem concentration persisting above MIC (%T_MIC). We performed a 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed %T_MIC ≥40%. We identified an intravenous dose of 2 grams once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC 2 mg/L was identified for that dose. An ertapenem dose of 2g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.

http://ift.tt/2uL8ujc

Evaluation of Combination Drug Therapy for Treatment of Antibiotic Resistant Inhalation Anthrax in a Murine Model [PublishAheadOfPrint]

Bacillus anthracis is considered a likely agent to be used as a bioweapon and use of a strain resistance to the first-line antimicrobial treatments is a concern. We determined treatment efficacy against a ciprofloxacin-resistant (C^r) strain of B. anthracis (C^r Ames) in a murine inhalational anthrax model. Ten groups of 46 BALB/c mice were exposed by inhalation to 7-35 LD₅₀ of B. anthracis C^r Ames spores. Commencing at 36 hours (h) post-exposure, groups were administered intraperitoneal doses of sterile water for injections (SWI) and ciprofloxacinalone (control groups), or ciprofloxacin combined with two antimicrobials including meropenem/linezolid, meropenem/clindamycin, meropenem/rifampin, meropenem/doxycycline, penicillin/linezolid, penicillin/doxycycline, rifampin/linezolid, or rifampin/clindamycin at appropriate dosing intervals(6 or 12 hours) for the respective antibiotics. Ten mice per group were treated for 14 days and observed until day 28. Remaining animals were euthanized every 6-12h and blood, lungs, and spleens collected for lethal factor (LF) and/or bacterial load determinations. All combination groups showed significant survival over the SWI and ciprofloxacin controls: meropenem/linezolid (p=0.004), meropenem/clindamycin (p=0.005), meropenem/rifampin (p=0.012), meropenem/doxycycline (p=0.032), penicillin/doxycycline (p=0.012), penicillin/linezolid (p=0.026), rifampin/linezolid (p=0.001), and rifampin/clindamycin (p=0.032). In controls, blood, lung, and spleen bacterial counts increased to terminal endpoints. In combination treatment groups, blood and spleen bacterial counts showed low/no colonies after 24 hours treatment. LF fell below detection limits for all combination groups, yet remained elevated in control groups. Combinations with linezolid had the greatest inhibitory effect on mean LF levels.

http://ift.tt/2uctSAT

Biofilms formed by isolates from recurrent vulvovaginal candidiasis patients are heterogeneous and insensitive to fluconazole [PublishAheadOfPrint]

Vulvovaginal candidiasis (VVC) is a global health problem affecting ~75% of women at least once in their lifetime. Here we examined the epidemiology of VVC from a patient cohort to identify the causative organisms associated with VVC. Biofilm forming capacity and antifungal sensitivity profiles were also assessed. We report a shifting prevalence of Candida species with heterogeneous biofilm forming capacity, both of which are associated with altered antifungal drug sensitivity.

http://ift.tt/2ucoYUA

Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects [PublishAheadOfPrint]

Nafithromycin concentrations in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin 800 mg once daily for three days. Noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-hour interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24 or 48 hours after the third dose of nafithromycin. Mean (± SD) plasma PK parameters after the first and third dose included C_max of 1.02 ± 0.31 and 1.39 ± 0.36 μg/mL, t_max of 3.97 ± 1.30 h and 3.69 ± 1.28 h, CL/F of 67.3 ± 21.3 L/h and 52.4 ± 18.5 L/h, and elimination t1/2 of 7.7 ± 1.1 and 9.1 ± 1.7 h. AUC_0-24 values of nafithromycin based on mean or median total plasma concentrations at BAL sampling times were 16.2 μg·h/mL. For ELF, the respective AUC_0-24 values based on mean and median concentrations were 224.1 and 176.3 μg·h/mL, whereas AUC_0-24 values for AM were 8538 and 5894 μg·hr/mL. Penetration ratios based on ELF and total plasma AUC_0-24 values based on mean and median concentrations were 13.8 and 10.9, whereas ratios of AM to total plasma concentrations were 527 and 364. The sustained ELF and AM concentrations for 48 hours after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections.

http://ift.tt/2uLkPUC

MDR1 and BCRP transporter-mediated drug-drug interaction between rilpivirine and abacavir; effect on intestinal absorption [PublishAheadOfPrint]

Rilpivirine (TMC278) is a highly potent second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo.

Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2 or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.

http://ift.tt/2ucp8v8

Persistent Loss of HBV Markers in Serum without Cellular Immunity by Combination of PEG-IFN Plus ETV Therapy in Humanized Mice [PublishAheadOfPrint]

Nucleot(s)ide analogues and peg-interferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for six weeks. High dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B core-related antigen (HBcrAg) continued to decrease and eventually became negative 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G to A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.

http://ift.tt/2uKEnrX

Role of daptomycin on wound healing in a MRSA burn infected animal model [PublishAheadOfPrint]

Prolonged hospitalization and antibiotic therapy are risk factors for the development of methicillin-resistant S. aureus (MRSA) infections in thermal burn patients. We used a rat model to study the in vivo efficacy of daptomycin in the treatment of burn wound infections by S. aureus and we evaluated the wound healing process through morphological and immunohistochemical analysis. A copper bar heated in boiling water was applied on paraspinal site of each rat resulting in two full thickness burns. A small gauze was placed over each burn and inoculated with 5x10⁷ cfu of S. aureus ATCC 43300. The study included two control not infected groups, with and without daptomycin treatment, a control infected group that did not receive any treatment and two infected groups treated, respectively, with intraperitoneal daptomycin and teicoplanin. The main outcome measures were quantitative culture, histological evaluation of tissue repair and immunohistochemical expression of wound healing markers: Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor 2 (FGF-2). The highest inhibition of infection was achieved in the group that received daptomycin reducing the bacterial load from 10⁷ cfu/mL to about 10³ cfu/g (P<0.01). The groups treated with daptomycin showed better overall healing with epithelialization and significantly higher collagen scores than the other groups, also confirmed by immunohistochemical data.

In conclusion, our results support the hypothesis that daptomycin, is an important modulator of wound repair by, possibly, reducing hypertrophic burn scar formation.

http://ift.tt/2ucwCyj

Metallo-{beta}-lactamases (DIM-1, NDM-1, VIM-2) and a 16S rRNA methyltransferase (RmtB4, RmtF2) producing Pseudomonas aeruginosa in Nepal [PublishAheadOfPrint]

A total of 11 multidrug-resistant Pseudomonas aeruginosa clinical isolates were obtained in Nepal. Four of these isolates harbored genes encoding one or more carbapenemases (DIM-1_, NDM-1 and/or VIM-2), and five harbored genes encoding a 16S rRNA methyltransferase (RmtB4 or RmtF2). A novel RmtF variant, RmtF2, had a substitution (K65E) compared with RmtF. To our knowledge, this is the first report describing carbapenemase- and 16S rRNA methyltransferase-co-producing P. aeruginosa clinical isolates in Nepal.

http://ift.tt/2uLtoyv

Implications of antimicrobial combinations in complex wound biofilms containing fungi [PublishAheadOfPrint]

Diabetic foot ulcer treatment currently focuses on targeting bacterial biofilms, while dismissing fungi. To investigate this we used an in vitro biofilm model containing bacteria and fungi, reflective of the wound environment, to test the impact of antimicrobials. Here we showed that while mono-treatment approaches influenced biofilm composition it had no discernible effect on overall quantity. Only by combining bacterial and fungal specific antibiotics were we able to decrease the biofilm bioburden, irrespective of composition.

http://ift.tt/2uceqo9

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis [PublishAheadOfPrint]

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1->3)-β-D-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole and the echinocandin micafungin, may result in improved outcome in experimental IPA in persistently neutropenic rabbits. Treatment groups included isavuconazole (ISA) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day, micafungin at 2 mg/kg/day (MFG2), or combinations of (ISA20+MFG2), (ISA40+MFG2), (ISA60+MFG2), and untreated rabbits (UC). Galactomannan index (GMI) and (1->3)-β-D-glucan levels were measured in serum. Residual fungal burden (CFU/g) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20+MFG2-, ISA40+MFG2-, and ISA60+MFG2-treated rabbits vs that of MFG2-treated or UC (p<0.01). Measures of organism-mediated pulmonary injury, lung weights and pulmonary infarct score, were lower in ISA40+MFG2-treated rabbits in comparison to those of ISA40 or MFG2 alone (p<0.01). Survival in ISA40+MFG2-treated rabbits was prolonged in comparison to those treated with ISA40 or MFG2 alone (p<0.01). These outcome variables correlated directly with a significant decline of GMI and serum (1->3)-β-D-glucan levels during therapy. GMI correlated with measures of organism-mediated pulmonary injury, lung weights (r=0.764; p<0.001) and pulmonary infarct score (r=0.911; p<0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMI and serum (1->3)-β-D-glucan levels in comparison to that of single agent isavuconazole or micafungin.

http://ift.tt/2uLkOQy

Community composition determines activity of antibiotics against multispecies biofilms [PublishAheadOfPrint]

In young cystic fibrosis (CF) patients, Staphylococcus aureus is typically the most prevalent organism, while in adults, Pseudomonas aeruginosa is the major pathogen. More recently, it was observed that also Streptococcus anginosus plays an important role in exacerbations of respiratory symptoms. These species are often co-isolated from CF lungs, yet little is known about whether antibiotic killing of one species is influenced by the presence of others. In the present study, we compared the activity of various antibiotics against S. anginosus, S. aureus and P. aeruginosa when grown in monospecies biofilms, with the activity observed in a multispecies biofilm. Our results show that differences in antibiotic activity against species grown in mono- and multispecies biofilms are species- and antibiotic-dependent. Less S. anginosus cells are killed by antibiotics that interfere with cell wall synthesis (amoxicillin+sulbactam, cefepime, imipenem, meropenem, and vancomycin) in presence of S. aureus and P. aeruginosa, while for ciprofloxacin, levofloxacin, and tobramycin, no difference was observed. In addition, we observed that the cell-free supernatant of S. aureus, but not that of P. aeruginosa biofilms, also caused this decrease in killing. Overall, S. aureus was more affected by antibiotic treatment in a multispecies biofilm, while for P. aeruginosa, no differences were observed between growth in mono- or multispecies biofilms.

The results of the present study suggest that it is important to take the community composition into account when evaluating the effect of antimicrobial treatments against certain species in mixed biofilms.

http://ift.tt/2uc1U8c

The adverse effects and choice of injectable agents in MDR-TB: amikacin or capreomycin [PublishAheadOfPrint]

Background: The prolonged use of injectable agents in an MDR-TB regimen is recommended by the WHO despite association with ototoxicity and nephrotoxicity.

Objective: We undertook this study to look at the relative adverse effects of capreomycin and amikacin.

Methods: We reviewed the case notes of 100 consecutive patients treated at 4 MDR-TB treatment centres in the UK.

Results: The median total duration of treatment with an injectable agent was 178 (IQR 109-192, n=73) days for those with MDR-TB, 179 (104-192, n=12) days for those with MDR-TB plus fluoroquinolone resistance and 558 (324-735, n=8) days for those with XDR-TB. Injectable use was longer for those started with capreomycin at 183 (IQR 123-197) days compared to 119 (IQR 83-177) days with amikacin (p=0.002). Excluding XDR-TB, 51 (51/85, 60%) patients were treated with an injectable for over 6 months and 12 (12/85, 14%) for over 8 months. 40 % of all patients discontinued the injectable due to hearing loss. 55% of patients experienced ototoxicity: 5 times (hazard ratio (HR) 5.2, CI 1.2-22.6, p=0.03) more likely in those started on amikacin compared to treatment with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (Odds ratios: 0.28 (0.11-0.72)), with 5 (5/37, 14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number experiencing a creatinine rise of > 1.5 times baseline.

Conclusion: Hearing loss is frequent in this cohort, though significantly lower in those starting capreomycin which should be given greater consideration as a first line agent.

http://ift.tt/2uLah7E

Habitat Predicts Levels of Genetic Admixture in Saccharomyces cerevisiae

Genetic admixture can provide material for populations to adapt to local environments, and this process has played a crucial role in the domestication of plants and animals. The model yeast, Saccharomyces cerevisiae, has been domesticated multiple times for the production of wine, sake, beer and bread, but the high rate of admixture between yeast lineages has so far been treated as a complication for population genomic analysis. Here we make use of the low recombination rate at centromeres to investigate admixture in yeast using a classic Bayesian approach and a locus by locus phylogenetic approach. Using both approaches, we find that S. cerevisiae from stable oak woodland habitats are less likely to show recent genetic admixture compared with those isolated from transient habitats such as fruits, wine or human infections. When woodland yeast strains do show recent genetic admixture, the degree of admixture is lower than in strains from other habitats. Furthermore, S. cerevisiae populations from oak woodlands are genetically isolated from each other, with only occasional migration between woodlands and local fruit habitats. Application of the phylogenetic approach suggests that there is a previously undetected population in North Africa that is the closest outgroup to the European S. cerevisiae, including the domesticatedWine population. Careful testing for admixture in S. cerevisiae leads to a better understanding of the underlying population structure of the species and will be important for understanding the selective processes underlying domestication in this economically important species.

http://ift.tt/2u2JPct

Mouse Chromosome 4 Is Associated with the Baseline and Allergic IgE Phenotypes

Regulation of IgE concentration in the blood is a complex trait, with high concentrations associated with parasitic infections as well as allergic diseases. A/J strain mice have significantly higher plasma concentrations of IgE both at baseline and after ovalbumin antigen exposure when compared to C57BL/6J strain mice. Our objective was to determine the genomic regions associated with this difference in phenotype. To achieve this, we used a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J strains. We measured IgE in the RCS panel at baseline and following allergen exposure. Using marker by marker analysis of the RCS genotype and phenotype data, we identified multiple regions associated with the IgE phenotype. A single region was identified to be associated with baseline IgE level, while multiple regions were associated with the phenotype after allergen exposure. The most significant region was found on Chromosome 4 from 81.46 - 86.17 Mbp. Chromosome 4 substitution strain mice had significantly higher concentration of IgE than their background parental strain mice, C57BL/6J. Our data presents multiple candidate regions associated with plasma IgE concentration at baseline and following allergen exposure, with the most significant one located on Chromosome 4.

http://ift.tt/2sJVQzu

The SEK-1 p38 MAP Kinase Pathway Modulates Gq Signaling in Caenorhabditis elegans

Gq is a heterotrimeric G protein that is widely expressed in neurons and regulates neuronal activity. To identify pathways regulating neuronal Gq signaling we performed a forward genetic screen in Caenorhabditis elegans for suppressors of activated Gq. One of the suppressors is an allele of sek-1, which encodes a mitogen-activated protein kinase kinase (MAPKK) in the p38 MAPK pathway. Here we show that sek-1 mutants have a slow locomotion rate and that sek-1 acts in acetylcholine neurons to modulate both locomotion rate and Gq signaling. Furthermore, we find that sek-1 acts in mature neurons to modulate locomotion. Using genetic and behavioral approaches we demonstrate that other components of the p38 MAPK pathway also play a positive role in modulating locomotion and Gq signaling. Finally, we find that mutants in the SEK-1 p38 MAPK pathway partially suppress an activated mutant of the sodium leak channel NCA-1/NALCN, a downstream target of Gq signaling. Our results suggest that the SEK-1 p38 pathway may modulate the output of Gq signaling through NCA-1.

http://ift.tt/2u2o4t6

Functional Profiling of Transcription Factor Genes in Neurospora crassa

Regulation of gene expression by DNA-binding transcription factors is essential for proper control of growth and development in all organisms. In this study, we annotate and characterize growth and developmental phenotypes for transcription factor genes in the model filamentous fungus Neurospora crassa. We identified 312 transcription factor genes, corresponding to 3.2% of the protein coding genes in the genome. The largest class was the fungal-specific Zn2Cys6 (C6) binuclear cluster, with 135 members, followed by the highly conserved C2H2 zinc finger group, with 61 genes. Viable knockout mutants were produced for 273 genes and complete growth and developmental phenotypic data is available for 242 strains, with 64% possessing at least one defect. The most prominent defect observed was in growth of basal hyphae (43% of mutants analyzed), followed by asexual sporulation (38%) and the various stages of sexual development (19%). Two growth or developmental defects were observed for 21% of the mutants, while 8% were defective in all three major phenotypes tested. Analysis of available mRNA expression data for a time course of sexual development revealed mutants with sexual phenotypes that correlate with transcription factor transcript abundance in wild type. Inspection of this data also implicated cryptic roles in sexual development for several co-transcribed transcription factor genes that do not produce a phenotype when mutated.

http://ift.tt/2sJKEmk

Whole Genome Sequence of the Heterozygous Clinical Isolate Candida krusei 81-B-5

Candida krusei is a diploid, heterozygous yeast that is an opportunistic fungal pathogen in immunocompromised patients. This species also is utilized for fermenting cocoa beans during chocolate production. One major concern in the clinical setting is the innate resistance of this species to the most commonly used antifungal drug fluconazole. Here we report a high-quality genome sequence and assembly for the first clinical isolate of C. krusei, strain 81-B-5, into 11 scaffolds generated with PacBio sequencing technology. Gene annotation and comparative analysis revealed a unique profile of transporters that could play a role in drug resistance or adaptation to different environments. In addition, we show that while 82% of the genome is highly heterozygous, a 2.0 Mb region of the largest scaffold has undergone loss of heterozygosity. This genome will serve as a reference for further genetic studies of this pathogen.

http://ift.tt/2u2fb2K

ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy

Allele-specific siRNAs (ASP-siRNAs) have emerged as promising therapeutic molecules owing to their selectivity to inhibit the mutant allele or associated single nucleotide polymorphisms (SNPs) sparing the expression of the wild-type counterpart. Thus, a dedicated bioinformatics platform encompassing updated ASP-siRNAs and an algorithm for the prediction of their inhibitory efficacy will be helpful in tackling currently intractable genetic disorders. In the present study, we have developed the ASPsiRNA resource (http://ift.tt/2u2r5cV) covering three components viz (i) ASPsiDb (ii) ASPsiPred and (iii) analysis tools like ASP-siOffTar. ASPsiDb is a manually curated database harboring 4543 (including 422 chemically modified) ASP-siRNAs targeting 78 unique genes involved in 51 different diseases. It furnishes comprehensive information from experimental studies on ASP-siRNAs along with multidimensional genetic and clinical information for numerous mutations. ASPsiPred is a two-layered algorithm to predict efficacy of ASP-siRNAs for fully complementary mutant (Eff^mut) and wild-type allele (Eff^wild) with one mismatch by ASPsiPred^SVM and ASPsiPred^matrix respectively. In ASPsiPred^SVM, 922 unique ASP-siRNAs with experimentally validated quantitative Eff^mut were used. During 10-fold cross-validation (10nCV) employing various sequence features on training/testing dataset (T737), the best predictive model achieved a maximum Pearson's correlation coefficient (PCC) of 0.71. Further, the accuracy of the classifier to predict Eff^mut against novel genes was assessed by leave one target out cross-validation approach (LOTOCV). ASPsiPred^matrix was constructed from rule-based studies describing the effect of single siRNA:mRNA mismatches on the efficacy at 19-different locations of siRNA. Thus, ASPsiRNA encompasses the first database, prediction algorithm and off-target analysis tool that is expected to accelerate research in the field of RNAi based therapeutics for human genetic diseases.

http://ift.tt/2sK3hGW

Pharmacoeconomic analysis of antifungal therapy for primary treatment of invasive candidiasis caused by Candida albicans and non-albicans Candida species

Cost-effectiveness studies of echinocandins for the treatment of invasive candidiasis, including candidemia, are rare in Asia. No study has determined whether echinocandins are cost-effective for both Candida alb...

http://ift.tt/2u76JPw

Measuring Resilience in the Adolescent Population: A Succinct Tool for Outpatient Adolescent Health

To create a valid tool to measure adolescent resilience, and to determine if this tool correlates with current participation in risk behaviors and prior adverse childhood events.

http://ift.tt/2uKTB08

Pediatric Anticoagulation: Time for a New Paradigm?

In this volume of The Journal, Baker et al1 reported their experience with combined use of warfarin and aspirin in children with Kawasaki disease (KD) with giant coronary artery aneurysms (CAAs) from their computerized patient database. Not surprisingly, the patients' International Normalized Ratios remained within predetermined therapeutic range only two-thirds of the time after the initial dose stabilization. In their 9 patients followed for a median period of 7.2 years, there were 6 bleeding episodes, which were either major or clinically relevant.

http://ift.tt/2ucgeh9

Impact of Enteroviral Polymerase Chain Reaction Testing on Length of Stay for Infants 60 Days Old or Younger

To determine the impact of a cerebrospinal fluid enterovirus polymerase chain reaction (PCR) test performance on hospital length of stay (LOS) in a large multicenter cohort of infants undergoing evaluation for central nervous system infection.

http://ift.tt/2uc3Aii

Solving the Extubation Equation: Successfully Weaning Infants Born Extremely Preterm from Mechanical Ventilation

Prolonged mechanical ventilation of infants born preterm is associated with adverse neurodevelopmental outcomes and bronchopulmonary dysplasia (BPD).1,2 Limiting exposure to mechanical ventilation may be achieved by avoiding intubation and mechanical ventilation altogether; randomized trials have demonstrated that early continuous positive airway pressure (CPAP) as an alternative to routine intubation in the delivery room is feasible and effective in reducing the need for mechanical ventilation in infants born extremely preterm3-6 and that this practice may reduce rates of BPD.

http://ift.tt/2uKM4OQ

Twenty-Five Year Survival of Children with Intellectual Disability in Western Australia

To investigate survival up to early adulthood for children with intellectual disability and compare their risk of mortality with that of children without intellectual disability.

http://ift.tt/2ubNQeU

Can We Define Bronchopulmonary Dysplasia?

The progression from severe respiratory distress syndrome (RDS) to lung injury was carefully described and named bronchopulmonary dysplasia (BPD) by Northway et al 50 years ago in a seminal report.1 The context for that report was very high mortality of moderately preterm infants from RDS because supplemental oxygen was the only effective therapy available in the late 1960s. Several neonatal services were trying to ventilate infants with RDS with minimal success until Gregory et al described the use of continuous positive airway pressure in 1971.

http://ift.tt/2uKUNRj

Inhibiting 4EBP1 in glioblastoma

Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the phosphatidylinositol-3 kinase-mechanistic target of rapamycin pathway. While a number of small molecules target the PI3K-AKT-mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain, and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Clinical trials using allosteric mTOR inhibitors (rapamycin and rapalogs) to treat glioblastoma patients have also been unsuccessful or uncertain, in-part because rapamycin inefficiently blocks the mTORC1 target 4EBP1, and also feeds back to activate PI3K-AKT signaling. Inhibitors of the mTOR kinase (TORKi) such as TAK-228/MLN0128 interact orthosterically with the ATP and substrate-binding pocket of mTOR kinase, efficiently block 4EBP1 in-vitro, and are currently being investigated in the clinical trials. Preclinical studies suggest that TORKi have poor residence times of mTOR kinase, and our data suggests that this poor pharmacology translates into disappointing efficacy in glioblastoma xenografts. RapaLink-1, a TORKi linked to rapamycin, represents a drug with improved pharmacology against 4EBP1. In this review, we clarify the importance of 4EBP1 as a biomarker for the efficacy of PI3K-AKT-mTOR inhibitors in glioblastoma. We also review mechanistic data by which RapaLink-1 blocks p-4EBP1, and discuss future clinical strategies for 4EBP1 inhibition in glioblastoma.

http://ift.tt/2u29QZg

A novel sclerosing atypical lipomatous tumor/well-differentiated liposarcoma in a 7-year-old girl: Report of a case with molecular confirmation

Atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma (ALT/WDL/DDL) is a common type of liposarcoma in late adulthood. However, pediatric ALT/WDL/DDL is extremely rare, and only 3 cases have been described in children younger than 10years of age. Notably, none of these cases harbored MDM2 gene amplification. Here, we reported a sclerosing ALT/WDL in a 7-year-old Chinese girl. Histologically, in most areas, the neoplastic cells were embedded within the collagenous background and typical lipogenic areas were inconspicuous throughout the sclerotic areas.

http://ift.tt/2tBTLsn

Inflammatory myofibroblastic tumors of the lung carrying a chimeric A2M–ALK gene: report of two infantile cases and review of the differential diagnosis of infantile pulmonary lesions

We report two infantile cases of pulmonary tumor carrying a chimeric A2M–ALK gene. A2M–ALK is a newly identified anaplastic lymphoma kinase (ALK)-related chimeric gene from a tumor diagnosed as fetal lung interstitial tumor (FLIT). FLIT is a recently recognized infantile pulmonary lesion defined as a mass-like lesion that morphologically resembles the fetal lung. Grossly, FLIT characteristically appears as a well-circumscribed spongy mass, whereas the tumors in these patients were solid and firm.

http://ift.tt/2t7twXg

GATA3 as a valuable marker to distinguish clear cell papillary renal cell carcinomas from morphologic mimics

Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade, indolent neoplasm, with no reported cases of death from disease or metastasis. These lesions can show clinical, morphologic and immunophenotypic overlap with several aggressive forms of renal cell carcinoma (RCC), including clear cell (CCRCC), translocation RCC and papillary RCC (PRCC) with cytoplasmic clearing. Given the difference in behavior, it is important to reliably separate these entities.We retrospectively reviewed 47 tumors from 45 patients with morphologic features of CCPRCC.

http://ift.tt/2tCe0WY

Perineural Invasion by Prostate Cancer on MR/US Fusion Targeted Biopsy is Associated with Extraprostatic Extension and Early Biochemical Recurrence after Radical Prostatectomy

In recent years, multiparametric magnetic resonance imaging (MRI) and MR/ultrasound (US) fusion targeted biopsy (TB) have become more widely adopted to aid in prostate cancer (PCa) detection. Previously, TB has been found to increase the yield of clinically significant PCa and is more likely to sample the index tumor compared to traditional 12-core extended sextant biopsies. Currently the prognostic significance of perineural invasion (PNI) when identified on TB (PNI-TB) is unknown. We identified 95 men at two tertiary referral centers who underwent TB followed by radical prostatectomy between January 2014 and January 2017.

http://ift.tt/2t82E9y

Using P16 Immunohistochemistry to Classify Morphologic Cervical Intraepithelial Neoplasia 2: Correlation of Ambiguous Staining Patterns with HPV Subtypes and Clinical Outcome

P16INK4a immunohistochemistry (IHC) is widely used to facilitate the diagnosis of human papillomavirus (HPV)-associated cervical precancerous lesions. While most p16 results are distinctly positive or negative, certain ones are ambiguous: they meet some but not all requirements for the "block-positive" pattern. It is unclear whether ambiguous p16 immunoreactivity indicates oncogenic HPV infection or risk of progression. Herein, we compared HPV genotypes and subsequent High-grade Squamous Intraepithelial Lesion (HSIL) outcomes among 220 cervical biopsies with a differential diagnosis of Cervical Intraepithelial Neoplasia 2 (CIN 2) based on hematoxylin and eosin morphology and varying degrees of p16 immunoreactivity.

http://ift.tt/2tBSz87

Bone lesions in yaws – another potential marker of indigenous Australian remains

http://ift.tt/2sZ5um9

The gut microbiota in larvae of the housefly Musca domestica and their horizontal transfer through feeding

House fly larvae provide a prolific and sustainable source of proteins used in poultry and fish feed. Wheat bran is a superior diet for house fly larvae and has been widely investigated to exploit its potentia...

http://ift.tt/2sJogcL

The role of inorganic nitrogen in successful formation of granular biofilms for wastewater treatment that support cyanobacteria and bacteria

Recently, the use of phototrophs for wastewater treatment has been revisited because of new approaches to separate them from effluent streams. One manifestation uses oxygenic photogranules (OPGs) which are den...

http://ift.tt/2u2eYMZ

Correction of Abdominal Distension by Biofeedback-guided Control of Abdomino-thoracic Muscular Activity in a Randomized, Placebo-Controlled Trial

Abdominal distension is produced by abnormal somatic postural tone; we developed an original biofeedback technique based on electromyography-guided control of abdomino-thoracic muscular activity. We performed a randomized, placebo-controlled study demonstrate the superiority of biofeedback to placebo for the treatment of abdominal distension.

http://ift.tt/2uKIswx

Corporate Leanwashing and Consumer Beliefs About Obesity

Abstract

Purpose of Review

Caloric overconsumption, rather than lack of exercise, is the primary driver of overweight and obesity. We review people's beliefs about the causes of obesity, the origins and consequences of these beliefs, and suggest possible mechanisms for corrective action.

Recent Findings

In multiple samples across the world, approximately half of the population mistakenly believes that lack of exercise is the primary cause of obesity. These misbeliefs have consequences: people who underestimate the importance of one's diet are more likely to be overweight or obese than people who correctly believe that diet is the primary cause of obesity. Next, we discuss the systematic misrepresentation of these factors—which we call "leanwashing"—by the food and beverage industry. Corporate messaging and actions are likely contributing factors to these mistaken beliefs being so widespread, and thus corrective actions are required. These include regulation and taxation.

Summary

People's beliefs have important medical consequences, and the origins of these beliefs and misbeliefs need to be monitored and regulated.

http://ift.tt/2u6YiUj

The Role of Vitamin K Status in Cardiovascular Health: Evidence from Observational and Clinical Studies

Abstract

Purpose of Review

Vitamin K is a fat-soluble vitamin required for the activation of several vitamin K-dependent proteins to confer functioning. A growing body of evidence supports that vitamin K has beneficial effects on bone and cardiovascular health. This review summarizes key evidence on vitamin K status as measured by circulating measures and cardiovascular outcomes.

Recent Findings

Overall, observational studies indicate that low vitamin K status as measured by high dephosphorylated uncarboxylated matrix gla protein concentrations plays a potential role in cardiovascular disease development, particularly in high-risk and chronic kidney disease populations. Very few vitamin K intervention trials have been conducted with cardiovascular-related outcomes. A couple of intervention trials studied the effect of the combination of vitamin D + K supplementation, which might have synergistic effects compared to vitamin K supplementation alone.

Summary

Assessing vitamin K status in prospective studies and well-designed randomized trials would provide important insight whether vitamin K is causally related to vascular calcification and cardiovascular disease.

http://ift.tt/2v5pGPG

Case of painless thyroiditis that developed during adjuvant chemotherapy for breast cancer

Abstract

We report a case of painless thyroiditis that occurred during adjuvant chemotherapy for breast cancer. A 41-year-old woman was diagnosed with right breast cancer and underwent surgery followed by adjuvant chemotherapy, given the tumor size and relatively high ratio of Ki-67-positive cells. Three weeks after the first intravenous administration of fluorouracil (500 mg/m²), epirubicin (100 mg/m²), cyclophosphamide (500 mg/m²), and dexamethasone (6.6 mg/body), followed by 3 days of oral dexamethasone (8 mg/day), she complained of continued palpitations. Although Graves' disease was initially suspected, she was diagnosed with painless thyroiditis because of a low free T3:free T4 ratio and low thyroid uptake of iodine. The mechanism of painless thyroiditis, in this case, remains unclear, although supposed etiologic event was the use of cytotoxic drugs (including fluorouracil) or the withdrawal of short-term steroid administration. Painless thyroiditis very rarely occurs during chemotherapy. However, we should consider painless thyroiditis when a patient undergoing cytotoxic chemotherapy for breast cancer experiences continued palpitations. The appropriate diagnosis and treatment of symptoms might avoid an unnecessary dose reduction or discontinuation of chemotherapy and, moreover, may prevent adverse effects associated with the metabolism of anticancer agents.

http://ift.tt/2t7qO3P

Taking “Play-Doh” to the Kids: Using the ALPPS Approach to Prevent Postoperative Liver Failure

No abstract available

http://ift.tt/2uKUDcv

Response to “An Addition to the Technical Skills Assessment Toolbox”

No abstract available

http://ift.tt/2uc0FWP

Lateral Node Dissection in Low Rectal Cancer: Time for a Global Approach?

No abstract available

http://ift.tt/2uK5tzJ

Comparison of Surgical Resection and Radiofrequency Ablation for Hepatocellular Carcinoma: Take Care Not to Neglect Radiofrequency Technic and Device

No abstract available

http://ift.tt/2ubCuI5

Impact of Procedural Specialty on Maternity Leave and Career Satisfaction Among Female Physicians

Objective: The aim of this study was to perform a large-scale, national survey of physician mothers to define the personal, professional, and financial impact of maternity leave and its relationship to career satisfaction for female physicians in procedural and nonprocedural fields. Summary of Background Data: Little is known about the impact of maternity leave on early career female physicians or how childbearing affects career satisfaction. Methods: A nationwide sample of physician mothers completed a 45-question anonymous, secure, online questionnaire regarding the impact of pregnancy and childbearing. Results: One thousand five hundred forty-one respondents were attending physicians during their most recent pregnancy and 393 (25.5%) practiced in a procedural field. Overall, 609 (52.9%) reported losing over $10,000 in income during leave with no significant difference between procedural and nonprocedural fields. Maternity leave was included in only 28.9% of female physicians' most recent contracts. Proceduralists were more likely to report negative impact on referrals by maternity leave [odds ratio (OR) 1.78, 95% confidence interval (95% CI) 1.28–2.47, P = 0.001], a requirement to complete missed shifts (OR 3.04, 95% CI 2.12–4.36, P

http://ift.tt/2ubNkhb

The Changing Face of Surgery Today: It is Not a Women's Issue, It's a Work Force Issue

No abstract available

http://ift.tt/2uKMaGu

Response to the Letter to the Editor: Minimally Invasive Versus Open Pancreaticoduodenectomy for Cancer Is Associated With Increased 30-day Mortality

No abstract available

http://ift.tt/2ubOGsc

Surgical Performance: A Pathway to Excellence

No abstract available

http://ift.tt/2ubx2Vo

Proposals for Shortening UK Surgical Training Will Directly Impact on Patient Safety

No abstract available

http://ift.tt/2uKjVYj

Ensuring Early Mobilization Within an Enhanced Recovery Program for Colorectal Surgery: A Randomized Controlled Trial

Objective: To estimate the extent to which the addition of staff-directed facilitation of early mobilization to an Enhanced Recovery Program (ERP) impacts recovery after colorectal surgery, compared with usual care. Summary Background Data: Early mobilization is considered an important component of ERPs but, despite guidelines recommendations, adherence remains quite low. The value of dedicating specific resources (eg, staff time) to increase early mobilization is unknown. Methods: This randomized trial involved 99 colorectal surgery patients in an established ERP (median age 63, 57% male, 80% laparoscopic) randomized 1:1 to usual care (including preoperative education about early mobilization with postoperative daily targets) or facilitated mobilization [staff dedicated to assist transfers and walking from postoperative days (PODs) 0–3]. Primary outcome was the proportion of patients returning to preoperative functional walking capacity (6-min walk test) at 4 weeks after surgery. We also explored the association of the intervention with in-hospital mobilization, time to achieve discharge criteria, time to recover gastrointestinal function, 30-day comprehensive complication index, and patient-reported outcome measures. Results: In the facilitated mobilization group, adherence to mobilization targets was greater on POD0 [OR 4.7 (95% CI 1.8–11.9)], POD1 [OR 6.5 (95% CI 2.3–18.3)], and POD2 [OR 3.7 (95% CI 1.2–11.3)]. Step count was at least 2-fold greater on POD1 [mean difference 843.3 steps (95% CI 219.5–1467.1)] and POD2 [mean difference 1099.4 steps (95% CI 282.7–1916.1)] There was no between-group difference in recovery of walking capacity at 4 weeks after surgery [OR 0.77 (95% CI 0.30–1.97)]. Other outcome measures were also not different between groups. Conclusions: In an ERP for colorectal surgery, staff-directed facilitation of early mobilization increased out-of-bed activities during hospital stay but did not improve outcomes. This study does not support the value of allocating additional resources to ensure early mobilization in ERPs. Trial Registration: ClinicalTrials.gov Identifier: NCT02131844

http://ift.tt/2uKrNsT

Minimally Invasive Versus Open Esophageal Resection: Three-year Follow-up of the Previously Reported Randomized Controlled Trial: the TIME Trial

Objective: The aim of this study was to investigate 3-year survival following a randomized controlled trial comparing minimally invasive with open esophagectomy in patients with esophageal cancer. Background: Research on minimally invasive esophagectomy (MIE) has shown faster postoperative recovery and a marked decrease in pulmonary complications. Debate is ongoing as to whether the procedure is equivalent to open resection regarding oncologic outcomes. The study is a follow-up study of the TIME-trial (traditional invasive vs minimally invasive esophagectomy, a multicenter, randomized trial). Methods: Between June 2009 and March 2011, patients with a resectable intrathoracic esophageal carcinoma, including the gastroesophageal junction tumors (Siewert I), were randomized between open and MI esophagectomy with curative intent. Primary outcome was 3-year disease-free survival. Secondary outcomes include overall survival, lymph node yield, short-term morbidity, mortality, complications, radicality, local recurrence, and metastasis. Analysis was by intention-to-treat. This trial is registered with the Netherlands Trial Register, NTR TC 2452. Both trial protocol and short-term results have been published previously. Results: One hundred fifteen patients were included from 5 European hospitals and randomly assigned to open (n = 56) or MI esophagectomy (n = 59). Combined overall 3-year survival was 40.4% (SD 7.7%) in the open group versus 50.5% (SD 8%) in the minimally invasive group (P = 0.207). The hazard ratio (HR) is 0.883 (0.540 to 1.441) for MIE compared with open surgery. Disease-free 3-year survival was 35.9% (SD 6.8%) in the open versus 40.2% (SD 6.9%) in the MI group [HR 0.691 (0.389 to 1.239). Conclusions: The study presented here depicted no differences in disease-free and overall 3-year survival for open and MI esophagectomy. These results, together with short-term results, further support the use of minimally invasive surgical techniques in the treatment of esophageal cancer.

http://ift.tt/2uKtUNq

Burden of Surgical Conditions in Uganda: A Cross-sectional Nationwide Household Survey

Objective: To quantify the burden of surgical conditions in Uganda. Background: Data on the burden of disease have long served as a cornerstone to health policymaking, planning, and resource allocation. Population-based data are the gold standard, but no data on surgical burden at a national scale exist; therefore, we adapted the Surgeons OverSeas Assessment of Surgical Need survey and conducted a nation-wide, cross-sectional survey of Uganda to quantify the burden of surgically treatable conditions. Methods: The 2-stage cluster sample included 105 enumeration areas, representing 74 districts and Kampala Capital City Authority. Enumeration occurred from August 20 to September 12, 2014. In each enumeration area, 24 households were randomly selected; the head of the household provided details regarding any household deaths within the previous 12 months. Two household members were randomly selected for a head-to-toe verbal interview to determine existing untreated and treated surgical conditions. Results: In 2315 households, we surveyed 4248 individuals: 461 (10.6%) reported 1 or more conditions requiring at least surgical consultation [95% confidence interval (CI) 8.9%–12.4%]. The most frequent barrier to surgical care was the lack of financial resources for the direct cost of care. Of the 153 household deaths recalled, 53 deaths (34.2%; 95% CI 22.1%–46.3%) were associated with surgically treatable signs/symptoms. Shortage of time was the most frequently cited reason (25.8%) among the 11.6% household deaths that should have, but did not, receive surgical care (95% CI 6.4%–16.8%). Conclusions: Unmet surgical need is prevalent in Uganda. There is an urgent need to expand the surgical care delivery system starting with the district-level hospitals. Routine surgical data collection at both the health facility and household level should be implemented.

http://ift.tt/2uKU1Uy

The Global Incidence of Appendicitis: A Systematic Review of Population-based Studies

Objective: We compared the incidence of appendicitis or appendectomy across the world and evaluated temporal trends. Summary Background Data: Population-based studies reported the incidence of appendicitis. Methods: We searched MEDLINE and EMBASE databases for population-based studies reporting the incidence of appendicitis or appendectomy. Time trends were explored using Poisson regression and reported as annual percent change (APC) with 95% confidence intervals (CI). APC were stratified by time periods and pooled using random effects models. Incidence since 2000 was pooled for regions in the Western world. Results: The search retrieved 10,247 citations with 120 studies reporting on the incidence of appendicitis or appendectomy. During the 21st century the pooled incidence of appendicitis or appendectomy (in per 100,000 person-years) was 100 (95% CI: 91, 110) in Northern America, and the estimated number of cases in 2015 was 378,614. The pooled incidence ranged from 105 in Eastern Europe to 151 in Western Europe. In Western countries, the incidence of appendectomy steadily decreased since 1990 (APC after 1989=−1.54; 95% CI: −2.22, −0.86), whereas the incidence of appendicitis stabilized (APC=−0.36; 95% CI: −0.97, 0.26) for both perforated (APC=0.95; 95% CI: −0.25, 2.17) and nonperforated appendicitis (APC=0.44; 95% CI: −0.84, 1.73). In the 21st century, the incidence of appendicitis or appendectomy is high in newly industrialized countries in Asia (South Korea pooled: 206), the Middle East (Turkey pooled: 160), and Southern America (Chile: 202). Conclusions: Appendicitis is a global disease. The incidence of appendicitis is stable in most Western countries. Data from newly industrialized countries is sparse, but suggests that appendicitis is rising rapidly.

http://ift.tt/2uKxYxe

30-day Readmission After Pancreatic Resection: A Systematic Review of the Literature and Meta-analysis

Objective: The aim of this study was to identify and compare common reasons and risk factors for 30-day readmission after pancreatic resection. Background: Hospital readmission after pancreatic resection is common and costly. Many studies have evaluated this problem and numerous discrepancies exist regarding the primary reasons and risk factors for readmission. Methods: Multiple electronic databases were searched from 2002 to 2016, and 15 relevant articles identified. Overall readmission rate was calculated from individual study estimates using a random-effects model. Study data were combined and overall estimates of odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each risk factor. Multivariable data were qualitatively synthesized. Results: The overall 30-day readmission rate was 19.1% (95% CI 17.4–20.7) across all studies. Infectious complications and gastrointestinal disorders, such as failure to thrive and delayed gastric emptying, together accounted for 58.9% of all readmissions. Demographic factors did not predict readmission. Heart disease (OR 1.37, 95% CI 1.12–1.67), hypertension (OR 1.44, 95% CI 1.09–1.91), and intraoperative blood transfusion (OR 1.45, 95% CI 1.15–1.83) were weak predictors of readmission, while any postoperative complications (OR 2.22, 95% CI 1.55–3.18) or severe complications (OR 2.84, 95% CI 1.65–4.89) were stronger predictors. Conclusions: Readmission after pancreatic resection is common and can largely be attributed to infectious complications and inability to maintain adequate hydration and nutrition. Focus on outpatient resources and follow-up to address these issues will prove valuable in reducing readmissions.

http://ift.tt/2uKmN7L

Response to “RE: Escalation of Care in Surgery: A Systematic Risk Assessment to Prevent Avoidable Harm in Hospitalized Patients”

No abstract available

http://ift.tt/2ubPEEC

What Do We Know About Intraoperative Teaching?: A Systematic Review

Background: There is increasing attention on enhancing surgical trainee performance and competency. The purpose of this review is to identify characteristics and themes related to intraoperative teaching that will better inform interventions and assessment endeavors. Methods: A systematic search was carried out of the Ovid MEDLINE, Ovid MEDLINE InProcess, Ovid Embase, and the Cochrane Library databases to identify all studies that discussed teaching in the operating room for trainees at the resident and fellow level. Evidence for main outcome categories was evaluated with the Medical Education Research Study Quality Instrument (MERSQI). Results: A total of 2101 records were identified. After screening by title, abstract, and full text, 34 studies were included. We categorized these articles into 3 groups on the basis of study methodology: perceptions, best practices, and interventions to enhance operative teaching. Overall strength of evidence for each type of study was as follows: perceptions (MERSQI: 7.5–10); best practices (6.5–11.5), and interventions (8–15). Although very few studies (n = 5) examined interventions for intraoperative teaching, these studies demonstrate the efficacy of techniques designed to enhance faculty teaching behaviors. Conclusions: Interventions have a positive impact on trainee ratings of their faculty intraoperative teaching performance. There is discordance between trainee perceptions of quantity and quality of teaching, compared with faculty perceptions of their own teaching behaviors. Frameworks and paradigms designed to provide best practices for intraoperative teaching agree that effective teaching spans 3 phases that take place before, during, and after cases.

http://ift.tt/2uc4IlL

Does Participation in the ACS-NSQIP Improve Outcomes?

No abstract available

http://ift.tt/2uc4HOJ

Is Coffee Consumption Associated With Lower Risk for Death?

http://ift.tt/2uKyvPp

Sensitivity Analysis for Unmeasured Confounding: E-Values for Observational Studies

In their current article in Annals, VanderWeele and Ding introduce the "E-value" as a simple measure of the potential for bias arising from unmeasured confounders in observational studies. Using an example of an observational study of coffee intake and mortality, the editorialists discuss how the E-value can help researchers explore the possible influence of bias from unobserved factors.

http://ift.tt/2ubIYqm

Coffee Drinking and Mortality in 10 European Countries A Multinational Cohort Study

Background:

The relationship between coffee consumption and mortality in diverse European populations with variable coffee preparation methods is unclear.

Objective:

To examine whether coffee consumption is associated with all-cause and cause-specific mortality.

Design:

Prospective cohort study.

Setting:

10 European countries.

Participants:

521 330 persons enrolled in EPIC (European Prospective Investigation into Cancer and Nutrition).

Measurements:

Hazard ratios (HRs) and 95% CIs estimated using multivariable Cox proportional hazards models. The association of coffee consumption with serum biomarkers of liver function, inflammation, and metabolic health was evaluated in the EPIC Biomarkers subcohort (n = 14 800).

Results:

During a mean follow-up of 16.4 years, 41 693 deaths occurred. Compared with nonconsumers, participants in the highest quartile of coffee consumption had statistically significantly lower all-cause mortality (men: HR, 0.88 [95% CI, 0.82 to 0.95]; P for trend P for trend = 0.009). Inverse associations were also observed for digestive disease mortality for men (HR, 0.41 [CI, 0.32 to 0.54]; P for trend P for trend P for trend P for trend = 0.002) and a positive association with ovarian cancer mortality (HR, 1.31 [CI, 1.07 to 1.61]; P for trend = 0.015). In the EPIC Biomarkers subcohort, higher coffee consumption was associated with lower serum alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; γ-glutamyltransferase; and, in women, C-reactive protein, lipoprotein(a), and glycated hemoglobin levels.

Limitations:

Reverse causality may have biased the findings; however, results did not differ after exclusion of participants who died within 8 years of baseline. Coffee-drinking habits were assessed only once.

Conclusion:

Coffee drinking was associated with reduced risk for death from various causes. This relationship did not vary by country.

Primary Funding Source:

European Commission Directorate-General for Health and Consumers and International Agency for Research on Cancer.

http://ift.tt/2u6BnZh

Moderate Coffee Intake Can Be Part of a Healthy Diet

In this issue, 2 large studies provide new evidence on the association of coffee intake with mortality. The editorialists discuss these findings in light of previous evidence and conclude that coffee intake can be part of a healthy diet.

http://ift.tt/2uKjpte

Sensitivity Analysis in Observational Research: Introducing the E-Value

Sensitivity analysis is useful in assessing how robust an association is to potential unmeasured or uncontrolled confounding. This article introduces a new measure called the "E-value," which is related to the evidence for causality in observational studies that are potentially subject to confounding. The E-value is defined as the minimum strength of association, on the risk ratio scale, that an unmeasured confounder would need to have with both the treatment and the outcome to fully explain away a specific treatment–outcome association, conditional on the measured covariates. A large E-value implies that considerable unmeasured confounding would be needed to explain away an effect estimate. A small E-value implies little unmeasured confounding would be needed to explain away an effect estimate. The authors propose that in all observational studies intended to produce evidence for causality, the E-value be reported or some other sensitivity analysis be used. They suggest calculating the E-value for both the observed association estimate (after adjustments for measured confounders) and the limit of the confidence interval closest to the null. If this were to become standard practice, the ability of the scientific community to assess evidence from observational studies would improve considerably, and ultimately, science would be strengthened.

http://ift.tt/2ubuBCt

Association of Coffee Consumption With Total and Cause-Specific Mortality Among Nonwhite Populations

Background:

Coffee consumption has been associated with reduced risk for death in prospective cohort studies; however, data in nonwhites are sparse.

Objective:

To examine the association of coffee consumption with risk for total and cause-specific death.

Design:

The MEC (Multiethnic Cohort), a prospective population-based cohort study established between 1993 and 1996.

Setting:

Hawaii and Los Angeles, California.

Participants:

185 855 African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites aged 45 to 75 years at recruitment.

Measurements:

Outcomes were total and cause-specific mortality between 1993 and 2012. Coffee intake was assessed at baseline by means of a validated food-frequency questionnaire.

Results:

58 397 participants died during 3 195 484 person-years of follow-up (average follow-up, 16.2 years). Compared with drinking no coffee, coffee consumption was associated with lower total mortality after adjustment for smoking and other potential confounders (1 cup per day: hazard ratio [HR], 0.88 [95% CI, 0.85 to 0.91]; 2 to 3 cups per day: HR, 0.82 [CI, 0.79 to 0.86]; ≥4 cups per day: HR, 0.82 [CI, 0.78 to 0.87]; P for trend Limitation:

http://ift.tt/2uKu0nY

Rethinking How to Measure the Appropriateness of Cervical Cancer Screening

http://ift.tt/2ubvACu

Prophylaxis of postoperative complications after craniotomy.

Purpose of review: This review reports an update of the evidence on practices applied for the prevention and management of the most common complications after craniotomy surgery. Recent findings: Latest guidelines support the combined thromboprophylaxis with the use of both mechanical and chemical modalities, preferably applied within 24 h after craniotomy. Nevertheless, a heightened risk of minor hemorrhagic events remains an issue of concern. Postoperative nausea and vomiting (PONV) and pain constitute the complications most commonly encountered during the first 24 h postcraniotomy. Recently, neurokinin type-1 receptor antagonists have been tested as adjuncts for PONV prophylaxis with encouraging results, whereas dexmedetomidine and gabapentinoids emerge as promising alternatives for postcraniotomy pain management. The available data for seizure prophylaxis following craniotomy lacks scientific quality; thus, this remains still a debatable issue. Significantly, a growing body of evidence supports the superiority of levetiracetam over the older antiepileptic drugs (AEDs), in terms of efficacy and safety. Summary: Optimum management of postoperative complications is incorporated as an integral part of the augmented quality of care in patients undergoing craniotomy surgery, aiming to improve outcomes. This review may serve as a benchmark for neuroanesthetists for heightened clinical awareness and prompt institution of well-documented practices. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2ub3AyR