Optimized Adeno-Associated Viral–Mediated Human Factor VIII Gene Therapy in Cynomolgus Macaques

Human Gene Therapy, Ahead of Print.


https://ift.tt/2OckmV5

Salmonella-Mediated Cytolethal Distending Toxin Transfer Inhibits Tumor Growth

Human Gene Therapy, Ahead of Print.


https://ift.tt/2NGo0Fw

A functional micro-electrode mapping of ventral thalamus in essential tremor

Abstract

Deep brain stimulation enables the delivery of therapeutic interventions to otherwise inaccessible areas of the brain while, at the same time, offering the unique opportunity to record from these same regions in awake patients. The posterior ventrolateral thalamus has become a reliable deep brain stimulation target for medically-refractory patients suffering from essential tremor. However, the contribution of the thalamus in essential tremor, and even whether posterior ventrolateral thalamus is the optimal target, remains a matter of ongoing debate. There are several lines of evidence supporting clusters of activity within the posterior ventrolateral thalamus that are important for tremor emergence. In this study we sought to map the functional properties of these clusters through microelectrode recordings during deep brain stimulation surgery. Data were obtained from 10 severely affected patients with essential tremor (12 hemispheres) undergoing deep brain stimulation surgery. Our results demonstrate power and coherence maxima located in the inferior posterior ventrolateral thalamus and immediate ventral region. Moreover, we identified distinct yet overlapping clusters of predominantly efferent (driving) and afferent (feedback) activity, with a preference for more efferent contributors, consistent with a net role in the driving of tremor output. Finally, we demonstrate that resolvable thalamic spiking activity directly relates to background activity and that the strength of tremor may be dictated by phase relationships between efferent and afferent pockets in the posterior ventrolateral thalamus. Taken together, these results provide important evidence for the role of the inferior posterior ventrolateral thalamus and its border region in essential tremor pathophysiology. Such results progress our mechanistic understanding and promote the adoption of next-generation therapies such as high resolution segregated deep brain stimulation electrodes.

https://ift.tt/2JODPri

Simultaneous Preclinical Positron Emission Tomography-Magnetic Resonance Imaging Study of Lymphatic Drainage of Chelator-Free 64Cu-Labeled Nanoparticles

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2mDzdv1

Review article: systemic treatment of hepatocellular carcinoma

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2uLZzj5

Community attitudes on tuberculosis in Botswana: an opportunity for improving the National Tuberculosis Programme outcomes, 2011

The Botswana tuberculosis HIV Knowledge Attitude and Practice study sought to assess knowledge, attitudes and practices of communities on TB and identify sources of their information on this disease and HIV. S...

https://ift.tt/2JPfTEB

KIM-1 as a blood-based marker for early detection of kidney cancer: a prospective nested case-control study

Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis. Experimental Design: KIM-1 concentrations were measured in pre-diagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to five years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival. Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 (95% confidence interval [CI]: 1.44-2.03, p-value = 4.1x10-23), corresponding to an IRR of 63.3 (95% CI: 16.2-246.9) comparing the 80th to the 20th percentile of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver operating characteristic curve of 0.8 compared to 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (p=0.0053). Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival.

https://ift.tt/2A6G5uC

Nilotinib as co-adjuvant treatment with doxorubicin in patients with sarcomas: A phase I trial of the Spanish Group for Research on Sarcoma.

Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as co-adjuvant of doxorubicin by inhibiting MRP-1/ P-gp efflux activity. The phase I part of the study is presented here. Experimental Design: Nilotinib 400 mg/12 h was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose-escalation levels for doxorubicin at 60 mg/m2, 65 mg/m2 and 75 mg/m2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma (LPS), leiomyosarcoma (LMS) and unresectable/ metastatic high-grade chondrosarcoma (CHO). Results: Thirteen patients were enrolled: 7 CHO, 4 LPS and 2 LMS. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were: neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose-level. As regards efficacy, there were 1 partial response (1 LPS), 9 SD (5 CHO, 2 LPS, 1 LMS) and 3 progressive diseases (2 CHO and 1 LMS). ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold respectively on day 5 of the cycle. Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as co-adjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared to doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2.

https://ift.tt/2uKkOBF

Randomized Phase II Study of Akt Blockade With or Without Ipatasertib in Abiraterone-Treated Patients With Metastatic Prostate Cancer With and Without PTEN Loss

Purpose: PI3K-Akt-mTOR and AR signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase 1b/2 study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC. Experimental Design: Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1000 mg twice daily orally. Co-primary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors. Results: rPFS was prolonged in the ipatasertib cohort vs placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors vs those without. The combination was well tolerated, with no treatment-related deaths. Conclusion: In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.

https://ift.tt/2A41hkV

Next-Generation Sequencing and Eating of the Tree of Knowledge

Clonal hematopoiesis is common, and the large-scale sequencing of patients' tumors in the clinical setting is becoming very common. The incidence of falsely reporting clonal hematopoiesis as tumor-associated in patients with solid tumors is a concern, as it may lead to unintended consequences.

https://ift.tt/2uGb8ID

Metabolic Reprogramming by Dual AKT/ERK Inhibition Through Imipridones Elicits Unique Vulnerabilities in Glioblastoma

Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma. Experimental Design: Gene set enrichment, LC/MS and extracellular flux analysis were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo. ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1h, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3b at serine 9. GSK3b promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone induced apoptosis in stem-like GBM cells in vitro and in vivo. Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo. Conclusion: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies.

https://ift.tt/2A6G0XQ

Integrated analysis of RNA and DNA from a phase III trial of trastuzumab-based neoadjuvant chemotherapy identifies response predictors in HER2-positive breast cancer

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy. Methods: We analyzed 137 pre-treatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II-III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for co-varying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from 4 independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNAs) and gene signatures. Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multi-platform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype and immune signatures. Variables predicting resistance included Luminal/ER+ features. Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer.

https://ift.tt/2uIafiu

SK3 gene Polymorphism is associated with Taxane Neurotoxicity and Cell Calcium Homeostasis

Purpose: Taxane-induced peripheral neuropathy is a common side effect induced by anticancer agents, and no drug capable of preventing its occurrence or ameliorate its long-term course has been identified. The physiology of taxane neuropathy is not clear, and diverse mechanisms have been suggested, with ion channels regulating Ca2+ homeostasis appearing good candidates. The calcium-activated potassium channel SK3 is encoded by the KCNN3 gene, which is characterized by a length polymorphism due to variable number of CAG repeats. Experimental Design: To study the influence of the polymorphism of CAG motif repeat of KCNN3 on the development of taxane-induced neuropathy, we evaluated 176 patients treated with taxanes for breast cancer. In parallel, we measured Ca2+ entry using Fura2-AM dye in HEK-cells expressing short vs long CAG alleles of KCNN3. Results: In the present study, we report that in the presence of docetaxel, Ca2+ entry was significantly increased in cells expressing short vs long CAG alleles of SK3 and that a SK3-lipid-blocker inhibits this effect. We found that patients carrying a short KCNN3 allele exhibited significantly increased incidence of taxane neuropathy compared to those carrying longer alleles. Conclusions: The clinical implication of these findings is that KCNN3 polymorphism may increase patient susceptibility to taxane neurotoxicity and that the use of SK3 blockers during taxanes administration may represent an interesting approach for the prevention of this neurotoxicity.

https://ift.tt/2LFAtZD

Roots of AML Detectable Long before Symptoms [News in Brief]

Three studies highlight potential of predictive blood test, early intervention.

https://ift.tt/2NFHb2s

Physiological Starvation Promotes Caenorhabditis elegans Vulval Induction

Studying how molecular pathways respond to ecologically relevant environmental variation is fundamental to understand organismal development and its evolution. Here we characterize how starvation modulates Caenorhabditis elegans vulval cell fate patterning-an environmentally sensitive process, with a nevertheless robust output. Past research has shown many vulval mutants affecting EGF-Ras-MAPK, Delta-Notch and Wnt pathways to be suppressed by environmental factors, such as starvation. Here we aimed to resolve previous, seemingly contradictory, observations on how starvation modulates levels of vulval induction. Using the strong starvation suppression of the Vulvaless phenotype of lin-3/egf reduction-of-function mutations as an experimental paradigm, we first tested for a possible involvement of the sensory system in relaying starvation signals to affect vulval induction: mutation of various sensory inputs, DAF-2/Insulin or DAF-7/TGF-β signaling did not abolish lin-3(rf) starvation suppression. In contrast, nutrient deprivation induced by mutation of the intestinal peptide transporter gene pept-1 or the TOR pathway component rsks-1 (the orthologue of mammalian P70S6K) very strongly suppressed lin-3(rf) mutant phenotypes. Therefore, physiologically starved animals induced by these mutations tightly recapitulated the effects of external starvation on vulval induction. While both starvation and pept-1 RNAi were sufficient to increase Ras and Notch pathway activities in vulval cells, the highly penetrant Vulvaless phenotype of a tissue-specific null allele of lin-3 was not suppressed by either condition. This and additional results indicate that partial lin-3 expression is required for starvation to affect vulval induction. These results suggest a cross-talk between nutrient deprivation, TOR-S6K and EGF-Ras-MAPK signaling during C. elegans vulval induction.

https://ift.tt/2AbPDEu

A fiducial-less tracking method for radiation therapy of liver tumors by diaphragm disparity analysis part 1: simulation study using machine learning through artificial neural network

Abstract

Objective

The large respiratory-induced motion of the liver tumors can affect treatment planning and delivery in many ways. As a result, motion management techniques are necessary to mitigate these effects. An effective approach to reducing the effects of respiratory motion of liver tumors is real-time tracking of the tumor. The Cyberknife treatment modality uses a combination of kV X-ray images, LED markers, an optic camera, and surgically implanted fiducial markers to track liver tumors. However, the use of an invasive method for implanting fiducial markers can lead to complications. We propose a tracking method that requires no fiducial markers for liver tumors by using the projected location of the diaphragm to identify the 3D location of the liver tumor. With the use of the 4D extended cardiac-torso (XCAT) phantom, this simulation study aims to investigate the feasibility of localizing liver tumors through the tracking of the diaphragm-lung border.

Methods

An abdominal 4DCT dataset containing 20 phases of one breathing cycle was created by using the male model of the 4D XCAT phantom. One set of orthogonal DRR images (+ 45°) was generated for each phase. On each DRR image, an outline of the lung-diaphragm border was detected using an edge detection algorithm. The simulated tumor's gravity center was identified for each phase of the breathing cycle. Using artificial neural networks (ANNs), two respiratory scenarios correlating the diaphragm's location with the corresponding 3D location of the tumor were compared: (1) lung-defined tumor motion (TL) and (2) user-defined tumor motion (TA). Additionally, using the user-defined tumor motion, we also examined the accuracy of using ANN to track the tumor under the mismatched conditions during 4DCT reconstruction.

Results

Evaluation of the ANN model was quantified by the root mean square error (RMSE) values through the leave-one-out (LOO) validation technique. The RMSE for the TL motion was 0.67 mm and for the TA motion was 0.32 mm. When the ANN model was applied to the mismatched data, it generated the RMSE of 1.63 mm, whereas applied to the ground-truth data, the RMSE is 0.88 mm.

Conclusion

This simulation study shows that the diaphragm and tumor position are closely related. The developed diaphragm disparity-analysis approach, featuring tracking capability and verified with clinically acceptable errors, has the potential to replace fiducial markers for clinical application. The tracking method will be further investigated in clinical datasets from patients.

https://ift.tt/2mCZppG

Pseudohyperkalemia: Hyperkalemia Cocktail or Alternative Diagnosis

Introduction. Hyperkalemia is a commonly encountered clinical problem. Pseudohyperkalemia is believed to be an in vitro phenomenon that does not reflect in vivo serum potassium and therefore should not be treated. Here, we present a case who unfortunately underwent unnecessary treatment because of failure to detect the common lab abnormality of pseudohyperkalemia. Case Presentation. A 91-year-old female with a history of chronic lymphocytic leukemia presented to the emergency with nausea and vomiting 24 hours after her first chemotherapy with chlorambucil. Physical examination was overall unremarkable. She had a leukocytosis of 210 × 103/µL with 96% lymphocytes along with chronic anemia with hemoglobin of 8.1 g/dL. Her initial sodium and potassium levels were normal. During the clinical course, her potassium progressively worsened and failed to improve despite standard medical treatment. Patient ultimately underwent dialysis. Conclusions. Differentiating true hyperkalemia from pseudohyperkalemia is very important in selected group of patients to avoid unnecessary medications, higher level of care, and unnecessary procedure including dialysis. We want to emphasize the importance of simple yet profound knowledge of technique of blood draws and basic metabolic panel processing for every clinician in day-to-day practice.

https://ift.tt/2Oe5RA3

Cardiac Involvement by HIV-Associated DLBCL

Non-Hodgkin's lymphoma (NHL) is a common AIDS-defining malignancy among people living with HIV. Of the different types of NHLs, diffuse large B-cell lymphoma (DLBCL) is the most common. Prognosis of DLBCL has improved over the years in the general population but remains relatively poor in HIV-positive individuals. Almost any organ system can be affected by DLBCL; however, cardiac involvement remains rare and suggests aggressive disease. We present a case of DLBCL in an HIV-positive patient, who had cardiac involvement, with the only clue to cardiac involvement being symptom being tachycardia and dysphagia.

https://ift.tt/2NBaT8C

Medical Organizations Must Address Sexual Harassment

MONDAY, July 23, 2018 -- Medical institutions and organizations need to ensure there are proactive interventions to transform the workplace in order to address sexual harassment and discrimination, according to an article published in the American...

https://ift.tt/2A32fOe

Walmart Generic Drug Discounts Often Offer More Patient Savings

MONDAY, July 23 2018 -- Walmart's Generic Drug Discount Program (GDDP), which sells many commonly used generic medications for $4 per 30-day supply, offers savings over Medicare for some generic cardiovascular medications, according to a research...

https://ift.tt/2uIPinO

Monthly Vitamin D Supplement May Not Cut Cancer Risk

MONDAY, July 23, 2018 -- Monthly high-dose vitamin D supplementation may not prevent the risk of cancer among adults aged 50 to 84 years, according to a study published online July 19 in JAMA Oncology. Robert Scragg, M.B.B.S., Ph.D., from the...

https://ift.tt/2LIbCUY

FDA Approves Tibsovo for Acute Myeloid Leukemia

MONDAY, July 23, 2018 -- Tibsovo (ivosidenib) tablets have been approved by the U.S. Food and Drug Administration to treat relapsed or refractory acute myeloid leukemia (AML) among people with a defective IDH1 gene. Tibsovo's effectiveness was...

https://ift.tt/2uIPhjK

Salmonella Spurs Recall of Ritz Crackers

MONDAY, July 23, 2018 -- A number of Ritz Crackers products are being recalled due to possible Salmonella risk, according to the U.S. Food and Drug Administration. Sixteen varieties of Ritz Cracker Sandwiches and Ritz Bits products in the United...

https://ift.tt/2LIclWc

Anorectal Malignant Melanoma—Defining the Optimal Surgical Treatment and Prognostic Factors

Abstract

Patients with anorectal malignant melanoma (ARMM) have a poor prognosis. Optimal surgical treatment is not defined. The aim of the study was to define the surgical treatment for ARMM, to compare the overall survival (OS) of abdomino-perineal resection (APR) and wide local excision (WLE) and to study various prognostic factors. Thirty patients of ARMM were managed, 20 with locoregional disease, 10 metastatic. Of the 20 patients with locoregional disease, 15 underwent APR and 5 WLE. The 1-, 2-, 3-, and 4-year overall survival rates (by Kaplan–Meier survival analysis) in the APR group were 67, 40, 40, and 32%, and in WLE group were 100, 100, 67, and 67% respectively. Median survival for APR and WLE groups were 13 and 36 months and were not significant (p 0.48). Node-negative patients had better survival than node positive in the APR group (56 vs. 13 months) (p 0.017). Patients with tumor size < 2cm, lymphovascular invasion and perineural invasion negative, and margin-negative and with superficial infiltration had a trend toward better survival than their counterparts. WLE gives an equivalent oncological outcome and can be offered for patients with smaller ARMM and APR for locally advanced, larger tumors or as a salvage following recurrence after WLE.

https://ift.tt/2uFZmhp

Does the quality of preoperative closed reduction of displaced ankle fractures affect wound complications after surgical fixation?

Publication date: Available online 23 July 2018

Source: Injury

Author(s): Bonnie Y. Chien, Kristen L. Stupay, Christopher P. Miller, Jeremy T. Smith, Jorge Briceno, John Y. Kwon

ABSTRACT

Background

Displaced ankle fractures are initially closed reduced and splinted with the goal of restoring gross ankle alignment. The benefits of an exact closed reduction are unclear and possibly detrimental and unnecessary if multiple attempts are made. The purpose of this study was to determine whether the quality of preoperative closed reduction in patients with operative ankle fractures affects post-operative wound complications.

Methods

A retrospective analysis was performed of patients with isolated, closed, operative ankle fractures treated at two level 1 trauma centers who had an initial closed reduction performed on presentation. Patient demographics, fracture characteristics, data pertinent to the reduction, and post-operative wound complications were collected. A novel grading system to assess reduction quality was developed, applied, and evaluated for inter- and intra-observer agreement.

Results

161 patients met inclusion criteria for analysis. 17% (27/161) sustained a post-operative wound complication. There was no statistically significant association between wound complications and quality of preoperative closed reduction (p = 0.17) nor with multiple reduction attempts (p = 0.887). However, patients with poor initial reductions had a decreased mean time to surgery (1.4 +/- 2.9 versus 4.7 +/- 6.3 days, p = 0.03), which may have been protective. Interclass correlation coefficients for inter- and intra-rater reliability of the classification schema was 0.942 and 0.922, respectively, demonstrating excellent agreement.

Conclusion

There was no association between preoperative closed reduction quality and incidence of post-surgical wound complications in patients with operative ankle fractures when analyzing the variables assessed in this investigation. While initial ankle reduction is still recommended, multiple attempts to achieve a perfect reduction are likely unnecessary.

https://ift.tt/2LiWj9j

Is manager support related to workplace productivity for people with depression: a secondary analysis of a cross-sectional survey from 15 countries

Objectives

To examine variations in manager reactions and support for people with depression and to investigate how these reactions are related to (1) absenteeism and (2) presenteeism due to depression among employees with self-reported depression across 15 diverse countries.

Design

Secondary data analysis of cross-sectional survey data.

Setting

15 countries, diverse in geographical region and gross domestic product (GDP): Brazil, Canada, China, Denmark, France, Germany, Great Britain, Italy, Japan, Mexico, Spain, South Africa, South Korea, Turkey and the USA.

Participants

16 018 employees and managers (approximately 1000 per country).

Primary and secondary outcome measures

We assessed level of absenteeism as measured by number of days taken off work because of depression and presenteeism score.

Results

On average, living in a country with a greater prevalence of managers saying that they avoided talking to the employee about depression was associated with employees with depression taking more days off work (B 4.13, 95% CI 1.68 to 6.57). On average, living in a country with a higher GDP was marginally associated with employees with depression taking more days off of work (p=0.09). On average, living in a country with a greater prevalence of managers actively offering help to employees with depression was associated with higher levels of presenteeism (B 7.08, 95% CI 6.59 to 7.58). Higher country GDP was associated with greater presenteeism among employees with depression (B 3.09, 95% CI 2.31 to 3.88).

Conclusions

Manager reactions were at least as important as country financial resources. When controlling for country GDP, working in an environment where managers felt comfortable to offer help and support to the employee rather than avoid them was independently associated with less absenteeism and more presenteeism.

https://ift.tt/2JNZujv

Exosome-packaged miR-1246 contributes to bystander DNA damage by targeting LIG4

https://ift.tt/2uKzVv7

Impact of the second reader on screening outcome at blinded double reading of digital screening mammograms

https://ift.tt/2A1sMvC

Small oral tongue cancers (≤ 4 cm in diameter) with clinically negative neck: from the 7th to the 8th edition of the American Joint Committee on Cancer

Abstract

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (≤ 4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12–4.99) and disease-free survival (HR 2.12, 95% CI 1.09–4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27–7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.

https://ift.tt/2mDOVGN

Incidental diagnosis of appendiceal ascariasis during colonoscopy

https://ift.tt/2A6uZG4

Recurrent jejunal metastasis from occult lung cancer

https://ift.tt/2uFR0Gz

Feasibility trial of an early therapy in perinatal stroke (eTIPS)

Perinatal stroke (PS) affects up to 1/2300 infants and frequently leads to unilateral cerebral palsy (UCP). Preterm-born infants affected by unilateral haemorrhagic parenchymal infarction (HPI) are also at ris...

https://ift.tt/2mB5d2S

A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation

A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation

A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation, Published online: 23 July 2018; doi:10.1038/s41419-018-0821-5

A lincRNA-p21/miR-181 family feedback loop regulates microglial activation during systemic LPS- and MPTP- induced neuroinflammation

https://ift.tt/2NGVFz9

Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis

Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis

Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis, Published online: 23 July 2018; doi:10.1038/s41419-018-0851-z

Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis

https://ift.tt/2OdyEof

METTL3 regulates WTAP protein homeostasis

METTL3 regulates WTAP protein homeostasis

METTL3 regulates WTAP protein homeostasis, Published online: 23 July 2018; doi:10.1038/s41419-018-0843-z

METTL3 regulates WTAP protein homeostasis

https://ift.tt/2NGVDHx

Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis

Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis

Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis, Published online: 23 July 2018; doi:10.1038/s41419-018-0815-3

Loss of DDHD2, whose mutation causes spastic paraplegia, promotes reactive oxygen species generation and apoptosis

https://ift.tt/2OcTZhZ

Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer

Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer

Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer, Published online: 23 July 2018; doi:10.1038/s41419-018-0810-8

Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer

https://ift.tt/2NGVzHN

ZDHHC8 critically regulates seizure susceptibility in epilepsy

ZDHHC8 critically regulates seizure susceptibility in epilepsy

ZDHHC8 critically regulates seizure susceptibility in epilepsy, Published online: 23 July 2018; doi:10.1038/s41419-018-0842-0

ZDHHC8 critically regulates seizure susceptibility in epilepsy

https://ift.tt/2OcnIHN

Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model

Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model

Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model, Published online: 23 July 2018; doi:10.1038/s41419-018-0820-6

Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model

https://ift.tt/2NBphOo

Long noncoding RNA Sox2ot and transcription factor YY1 co-regulate the differentiation of cortical neural progenitors by repressing Sox2

Long noncoding RNA Sox2ot and transcription factor YY1 co-regulate the differentiation of cortical neural progenitors by repressing Sox2

Long noncoding RNA <i>Sox2ot</i> and transcription factor YY1 co-regulate the differentiation of cortical neural progenitors by repressing <i>Sox2</i>, Published online: 23 July 2018; doi:10.1038/s41419-018-0840-2

Long noncoding RNA Sox2ot and transcription factor YY1 co-regulate the differentiation of cortical neural progenitors by repressing Sox2

https://ift.tt/2OcCf6k

Caring for Those Who Serve: Potential Implications of the Veterans Affairs Maintaining Internal Systems and Strengthening Integrated Outside Networks Act of 2018

Congress recently passed the Veterans Affairs Maintaining Internal Systems and Strengthening Integrated Outside Networks Act of 2018. This act removes barriers to veterans' access to community-based health care providers and permanently establishes the commercial health care marketplace as another provider of health care to veterans. The authors of this commentary discuss the implications of expanding private sector health care for veterans on veterans' health care experiences and outcomes and on the Veterans Affairs health system.

https://ift.tt/2NFhTl2

Expanding Goals of Care Conversations across a Health System: The Mapping the Future Program

Clinician failure to discuss goals of care (GOC) with seriously ill patients remains prevalent. Small-scale educational interventions have demonstrated improvement in physician communication skills, but it is unknown if these results translate into practice changes.

https://ift.tt/2NzevrC

Deriving Real-World Insights From Real-World Data: Biostatistics to the Rescue

Experts and regulators have called for methods used in traditional trials to be adapted to "real-world" settings. This article describes 3 promising approaches that meld rigorous methodology with real-world data.

https://ift.tt/2NGUmjJ

Medicare Beneficiary Out-of-Pocket Costs for Generic Cardiovascular Medications Available Through $4 Generic Drug Discount Programs

https://ift.tt/2Obd3wX

Risks and Benefits of Marijuana Use A National Survey of U.S. Adults

Background:

Despite insufficient evidence regarding its risks and benefits, marijuana is increasingly available and aggressively marketed to the public.

Objective:

To understand the public's views on the risks and benefits of marijuana use.

Design:

Probability-based online survey.

Setting:

United States, 2017.

Participants:

16 280 U.S. adults.

Measurements:

Proportion of U.S. adults who agreed with a statement.

Results:

The response rate was 55.3% (n = 9003). Approximately 14.6% of U.S. adults reported using marijuana in the past year. About 81% of U.S. adults believe marijuana has at least 1 benefit, whereas 17% believe it has no benefit. The most common benefit cited was pain management (66%), followed by treatment of diseases, such as epilepsy and multiple sclerosis (48%), and relief from anxiety, stress, and depression (47%). About 91% of U.S. adults believe marijuana has at least 1 risk, whereas 9% believe it has no risks. The most common risk identified by the public was legal problems (51.8%), followed by addiction (50%) and impaired memory (42%). Among U.S. adults, 29.2% agree that smoking marijuana prevents health problems. About 18% believe exposure to secondhand marijuana smoke is somewhat or completely safe for adults, whereas 7.6% indicated that it is somewhat or completely safe for children. Of the respondents, 7.3% agree that marijuana use is somewhat or completely safe during pregnancy. About 22.4% of U.S. adults believe that marijuana is not at all addictive.

Limitation:

Wording of the questions may have affected interpretation.

Conclusion:

Americans' view of marijuana use is more favorable than existing evidence supports.

Primary Funding Source:

National Heart, Lung, and Blood Institute.

https://ift.tt/2uZUgf0

The co-identification of mcr-4.6 and blaNDM-1 in a clinical Enterobacter cloacae isolate from China [PublishAheadOfPrint]

Here we describe the first report of a clinical colistin-resistant ST84 Enterobacter cloacae isolate co-harboring mcr-4.6 (previously named mcr-4.2) and bla_NDM-1 from a patient in China. The bla_NDM-1-harboring IncX3 plasmid and the novel mcr-4.6-harboring ColE plasmid were completely sequenced. Although this isolate showed high level resistance to colistin, mcr-4.6 plasmid transformation, gene subcloning, susceptibility testing and lipid A matrix-assisted laser desorption ionization mass spectrometry analysis indicate that mcr-4.6 itself doesn't confer resistance to colistin.

https://ift.tt/2mC9CTl

Various sequence types of Enterobacteriaceae carrying blaNDM-5 gene from commercial chicken farms in China [PublishAheadOfPrint]

A total of 108 meropenem-resistant Enterobacteriaceae isolates were obtained from 1658 rectal swabs collected from 15 unrelated commercial chicken farms in China between 2014 and 2016. These samples yielded sixteen Escherichia coli and two Klebsiella pneumoniae isolates of diverse sequence types carrying a bla_NDM-5-bearing IncX3 plasmid. Klebsiella pneumoniae strain sequence type 709 (ST709) has two bla_NDM-5-carrying plasmids that were transferred together to E.coli.

https://ift.tt/2A6k9Qo

Relative Contribution of the ABC Transporters Cdr1, Pdh1, and Snq2 to Azole Resistance in Candida glabrata [PublishAheadOfPrint]

The utility of the azole antifungals for the treatment of invasive candidiasis is severely hampered by azole resistance in Candida glabrata. This resistance is mediated almost exclusively by activating mutations in the zinc cluster transcription factor Pdr1, which controls the genes encoding the multidrug resistance transporters Cdr1, Pdh1, and Snq2. However, the specific relative contribution of these transporters to resistance is not known. To address this question, the SAT1 flipper method was used to delete CDR1, PDH1, and SNQ2 in a strain of C. glabrata engineered to carry a clinically relevant activating mutation in PDR1. Susceptibility testing was performed according to the CLSI guidelines with minor modifications and confirmed with Etest strips. Of the single transporter deletion strains, only CDR1 deletion resulted in decreased azole MIC. Deletion of PDH1 in combination with CDR1 resulted in a moderate decrease in MIC from that observed with deletion of CDR1 alone. SNQ2 deletion only decreased the MIC in the triple deletion strain in the absence of both CDR1 and PDH1. Deletion of all three transporters in combination decreased the MIC to the level observed in the PDR1 deletion strains for some, but not all azoles tested, which indicates additional Pdr1 targets likely play a minor role in this process. These results indicate that while Cdr1 is the most important Pdr1-mediated multidrug resistance transporter for azole resistance in this clinical isolate, all three of these transporters contribute to its high-level resistance to the azole antifungals.

https://ift.tt/2mC9xz1

Lysostaphin lysibody leads to effective opsonization and killing of methicillin resistant Staphylococcus aureus in a murine model [PublishAheadOfPrint]

The cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a poor immune response resulting primarily in low-affinity IgM antibodies. In a previous publication we introduced the lysibody approach to address this shortcoming. Lysibodies are engineered molecules that combine a high-affinity carbohydrate-binding domain from bacterial or bacteriophage origin and an Fc effector portion of a human IgG antibody, thus directing effective immunity to conserved bacterial surface carbohydrates. Here, we describe the first example of a lysibody containing the binding domain from a bacteriocin – lysostaphin. We also describe the creation of five lysibodies with binding domains derived from phage lysins, directed against Staphylococcus aureus. The lysostaphin and LysK lysibodies showed the most promise and were further characterized. Both lysibodies bound a range of clinically important staphylococcal strains, fixed complement on the staphylococcal surface, and induced phagocytosis of S. aureus by macrophages and human neutrophils. The lysostaphin lysibody had superior in vitro activity compared to the LysK lysibody as well as the previously characterized ClyS lysibody, and effectively protected mice in a kidney abscess/bacteremia model. These results further demonstrate that the lysibody approach is a reproducible means of creating anti-bacterial antibodies that cannot be produced by conventional means. Lysibodies therefore are a promising solution for opsonic antibodies that may be used passively to both treat and prevent infection by drug-resistant pathogens.

https://ift.tt/2uYRuHc

No Resistance to Tenofovir Alafenamide Detected Through 96 Weeks of Treatment in Patients with Chronic Hepatitis B [PublishAheadOfPrint]

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In 2 clinical trials, 1298 HBeAg-positive and HBeAg-negative patients with CHB were randomized 2:1 and treated with TAF (n=866) or TDF (n=432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (pol/RT) were assessed using INNO-LiPA Multi DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥69IU/mL) by HBV pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to study drug. At baseline, the majority of patients harbored virus with wild type pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF 11.1%, TDF 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF: 2.8%, TDF: 3.2%) that was often associated with drug nonadherence (TAF: 30%, TDF: 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96 with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA <69 IU/mL) was similar across treatment groups and no substitutions associated with resistance to TAF or TDF were detected.

https://ift.tt/2mC9ovt

Effects of phage endolysin SAL200 combined with antibiotics on Staphylococcus aureus infection [PublishAheadOfPrint]

Phages and its derivatives are increasingly reconsidered for the treatment of bacterial infections, due to rising antibiotic resistance. We assessed the anti-staphylococcal effect of the endolysin SAL200 in combination with standard-of-care (SOC) antibiotics. SAL200 activity combined with SOC antibiotics was assessed in vitro by checkerboard and time-kill assays, and in vivo with murine bacteremia and Galleria mellonella infection models. SAL200 reduced SOC antibiotic MICs and showed a ≥3-log₁₀CFU/mL reduction of S. aureus within 30 minutes in time-kill assays. Combinations of SAL200 and SOC antibiotics achieved a sustained decrease of >2-log₁₀CFU/mL. SAL200 significantly lowered blood bacterial density within 1 hour by > 1 log₁₀CFU/mL in bacteremic mice (P<0.05 vs untreated mice), and SAL200 and SOC antibiotic combinations achieved the lowest levels of bacteremia. Bacterial density in splenic tissue at 72 h post-infection was lowest in mice treated with SAL200 and SOC antibiotic combinations. SAL200 combined with SOC antibiotics also improved Galleria mellonella larvae survival at 96 h post-infection.

The combination of phage endolysin SAL200 with SOC anti-staphylococcal antibiotics showed synergistic effects in vitro and in vivo. The combination of SAL200 with SOC antibiotics could help in the treatment of difficult S. aureus infections.

https://ift.tt/2A0ug96

In Vitro Activity of LYS228, a Novel Monobactam Antibiotic, against Multidrug-resistant Enterobacteriaceae [PublishAheadOfPrint]

LYS228 is a novel monobactam with potent activity against Enterobacteriaceae. LYS228 is stable to metallo-β-lactamases (MBLs) and serine carbapenemases, including Klebsiella pneumoniae carbapenemases (KPCs), resulting in potency against the majority of extended spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE) strains tested. Overall, LYS228 demonstrated potent activity against 271 Enterobacteriaceae strains, including multidrug-resistant isolates. Based upon MIC₉₀ values, LYS228 (MIC₉₀= 1 μg/mL) was ≥32-fold more active against these strains than were aztreonam, ceftazidime, ceftazidime/avibactam, cefepime, and meropenem. The MIC₉₀ value for tigecyline was 4 μg/mL against the strains tested. Against Enterobacteriaceae isolates expressing ESBLs (N=37) or displaying carbapenem resistance (N=77), LYS228 had MIC₉₀ values of 1 and 4 μg/mL, respectively.

LYS228 exhibited potent bactericidal activity as indicated by low MBC to MIC ratios (≤4) against 97.4% (264/271) of the Enterobacteriaceae strains tested. In time-kill studies, LYS228 consistently achieved 3-log₁₀ reduction in colony-forming units (CFU)/mL (≥99.9% killing) at concentrations ≥4X the MIC for E. coli and K. pneumoniae reference strains as well as isolates encoding TEM-1, SHV-1, CTX-M-14, CTX-M-15, KPC-2, KPC-3 and NDM-1 β-lactamases.

https://ift.tt/2mByjiF

Population Pharmacokinetics of the Antimalarial Amodiaquine: A Pooled Analysis to Optimize Dosing [PublishAheadOfPrint]

Amodiaquine plus artesunate is the recommended antimalarial treatment in many malaria-endemic countries. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over three days. Plasma concentration-time profiles for both parent drug and metabolite were characterized using nonlinear mixed-effects modelling. Amodiaquine pharmacokinetics was adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 (95% CI: 1.5 – 3.7) and 3.9 (95% CI: 2.6 – 5.3) months after birth, assuming a baby born at term. Bioavailability was 22.4% (15.6 – 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither drug formulation nor hemoglobin had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 – 17 kg, 33 – 35 kg, and in patients > 62 kg compared to a typical 50 kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

https://ift.tt/2Abjkpc

Tolerability of prosthetic joint infection empirical antimicrobial therapy: a prospective cohort study [PublishAheadOfPrint]

Objectives: The empirical use of vancomycin in combination with a broad-spectrum betalactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known.

Patient and methods: Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011-2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis.

Results: The EAT of the 333 included patients (median age, 69.8 (IQR, 59.3-79.1)) mostly relies on vancomycin (n=229, 68.8%), piperacillin/tazobactam (n=131, 39.3%) and/or 3^rdGC (n=50, 15%). Forty-two (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥3). The use of vancomycin (OR, 6.9; 95%CI, 2.1-22.9), piperacillin/tazobactam (OR, 3.7; 95%CI, 1.8-7.2) or the combination of both (OR, 4.1; 95%CI, 2.1-8.2) were the only AE predictors. Acute kidney injury (AKI) was the most frequent AE (n=25; 51.0% of AE), and was also associated with the use of the vancomycin and piperacillin/tazobactam combination (OR, 6.7; 95%CI, 2.6-17.3). A vancomycin plasma overexposure was noted in 9 (37.5%) of the vancomycin-related AKI, only. Other vancomycin-based therapies were significantly less at risk of AE and AKI.

Conclusions: The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and piperacillin/tazobactam combination. These results corroborate recent finding suggesting a synergic toxicity of these drugs in comparison with vancomycin-cefepime, which remain to be evaluated in PJI.

https://ift.tt/2mC9cwf

The retrievable puncture anchor traction method for EUS-guided gallbladder drainage: a porcine study

EUS-guided gallbladder drainage (EUS-GBD) is a challenging technique for endoscopists that requires a high level of skill. A very important reason why EUS-GBD is challenging is that the gallbladder can be easily collapsed. In order to resolve this concern, we aimed to develop a retrievable puncture anchor traction (RPAT) method for EUS-GBD. We evaluated and compared the success rate, safety, and outcomes of the RPAT method for EUS-GBD against EUS-GBD without retrievable puncture anchor using a porcine model.

https://ift.tt/2LHR8ff

Impact of water exchange colonoscopy on endoscopy room efficiency: a systematic review and meta-analysis

Separate randomized controlled trials (RCTs) showed water exchange (WE) colonoscopy outperformed other techniques in minimizing insertion pain and optimizing adenoma detection rate. Longer insertion time required for removal of infused water, residual air and feces might have hampered its wider adoption. We evaluate the impact of WE compared with air or carbon dioxide insufflation (GAS) on room turnaround efficiency measured by cecal intubation, withdrawal and total procedure time.

https://ift.tt/2LmhGGQ

EMCrit Wee – The Mock Trial Verdict and a Discussion with Mike Weinstock

The verdict is in...

EMCrit Project by Scott Weingart.

https://ift.tt/2OcOsbd

Bladder Invasion in Patients with Advanced Colorectal Carcinoma

Abstract

Involvement of the bladder by colorectal cancer is sufficiently rare to be encountered by an individual surgeon on an infrequent basis. Extirpative procedures for advanced colorectal cancers can involve partial/total bladder resections. In patients without evidence of distant metastatic disease, a reasonable therapeutic effect can be expected when negative surgical margins are obtained. The decision to perform a bladder-sparing procedure or a total pelvic exenteration (TPE) will be based on the extent of the primary lesion as well as patient characteristics. In this study, we report our experience in the management of operable locally advanced colorectal carcinomas involving the urinary bladder. We retrospectively reviewed the hospital records of all patients with advanced colorectal cancer invading the urinary bladder. The age, gender, clinical presentation, physical examination findings, and imaging records were noted. Colonoscopy reports and images were noted and biopsy findings recorded. Similarly, cystoscopy findings and biopsy reports were noted and analyzed. Eight (88%) patients had a primary sigmoid tumor and one (11%) had primary rectal tumor. The clinical staging of the primary tumor was T3 in three (33%) and T4 in six (66%). A biopsy taken during cystoscopy confirmed the malignant lesion in all the nine patients. Four (44%) patients received neoadjuvant chemotherapy with 5-fluorouracil. Eight (88%) patients underwent bladder-sparing resection and the remaining one underwent total pelvic exenteration with ileal conduit for urinary drainage. The mean overall survival was 44 months. The wide spectrum of possible bladder involvement by colorectal cancer requires individual patient-specific and disease-specific approaches. En bloc bladder resection for adherent or invading colorectal cancers achieves good local control and prognosis. The potential for cure in completely excised, node-negative tumors is good. Bladder reconstruction is achievable in most patients.

https://ift.tt/2uZcNZ8

Rising Incidence of Breast Cancer in the Young Fertile Indian Population—a Reality Check

Abstract

Breast cancer in India appears to be diagnosed more in the young women, but whether this is an actual higher incidence, and hence a matter of concern, needs more clarity, and the extent to which correctable measures can be taken to reduce or overcome this additional disease burden, if any, has to be better understood. The article analyzes these and more in a systematic manner and highlights the important issues in the very young women which makes the clinical management of breast cancer more complex.

https://ift.tt/2mEHmj3

Renal Refugees

In front of us lies a drowsy young woman. Her breathing is labored; she frequently rouses to vomit into the plastic container by her bedside. She stares out into the sterile surroundings, groaning, begging for relief from her distress. Her husband and children look on cautiously. We infuse her with furosemide, anti-emetics, and other temporizing therapies. But her potassium level remains dangerously high. She needs dialysis.

https://ift.tt/2NH53mq

In Reply to ‘The Use of Estimated GFR–Based Staging in Children With CKD: Proceed With Care’

We appreciate the opportunity to respond to the correspondence from Dr Choy1 regarding our article.2 Although caution regarding creatinine measurement is an important discussion, there are a number of factually incorrect points in the letter. The author states that the CKiD study was conducted from 1998 to 2001; it was initiated in 2003, enrollment began in 2005, and follow-up is ongoing. ESCAPE was published in 2009, not 2006. The letter states that the CKiD cohort used creatinine measurements by high-performance liquid chromatography (HPLC).

https://ift.tt/2Ob94Av

Initial Evaluation of the Patient with Waldenström Macroglobulinemia

The initial evaluation of the patient with Waldenström macroglobulinemia can be challenging. Not only is it a rare disease, but the clinical features can vary greatly from patient to patient. In this article, we aim at providing concise and practical recommendations for the initial evaluation of patients with Waldenström macroglobulinemia, specifically regarding history taking, physical examination, laboratory testing, bone marrow aspiration, and biopsy evaluation and imaging studies. We then review the most common special clinical situations seen in patients with Waldenström macroglobulinemia, especially anemia, hyperviscosity, cryoglobulinemia, peripheral neuropathy, extramedullary disease, Bing-Neel syndrome, and amyloidosis.

https://ift.tt/2A65TXU

Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) among travellers to Africa: destination-specific data pooled from three European prospective studies

One third of travellers to low- and middle-income regions of the tropics and subtropics become colonized by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). The risk varies by destination ...

https://ift.tt/2LC98dU

A 0.8-cm clear cell neuroendocrine tumor G1 of the gallbladder with lymph node metastasis: a case report

Abstract

Background

Neuroendocrine tumors (NETs) of the gallbladder are rare and generally considered low-grade malignancies. We herein describe a case of a patient with a 0.8-cm clear cell NET G1 of the gallbladder with nodal involvement.

Case presentation

A 65-year-old man with no medical history indicative of von Hippel-Lindau (VHL) disease underwent laparoscopic cholecystectomy for cholecystolithiasis. There was a 0.8-cm tumor in the neck of the gallbladder. Histologic examination revealed nests or trabecular growth of clear cells with small round-to-oval nuclei. Immunohistochemically, tumor cells showed positivity for chromogranin A and synaptophysin; Ki-67 index was < 1.0%. Based on the World Health Organization 2010 classification, we made a diagnosis of clear cell variant of NET G1 without VHL disease. The tumor invaded the muscular layer and had no extension to the perimuscular connective tissue but had metastasized to a cystic duct node. A radical second resection with regional lymphadenectomy of the gallbladder was performed, and there was no metastasis on histology. After the definitive surgery, he was followed up for 10 months without adjuvant therapy and is alive and well with no evidence of recurrence.

Conclusions

Our experience suggests that, even when smaller than 1 cm, NET G1 of the gallbladder can metastasize. When NET G1 is incidentally identified in the gallbladder of a surgical specimen, detailed pathologic examination of the cystic duct node, when found, should be performed to guide whether a radical second resection with regional lymphadenectomy is appropriate.

https://ift.tt/2Leld9Q

RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

Abstract

Background

Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown.

Methods

Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays.

Results

Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis.

Conclusions

Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.

https://ift.tt/2JT7XSM

Pathological bases and clinical impact of long noncoding RNAs in prostate cancer: a new budding star

Abstract

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides. Recent advances in the non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack coding protein function, termed non-coding RNA (ncRNA). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNA world. Moreover, accumulating evidence has demonstrated that many lncRNAs are dysregulated in prostate cancer (PC) and closely related to tumorigenesis, metastasis, and prognosis or diagnosis. In this review, we will briefly outline the regulation and functional role of lncRNAs in PC. Finally, we discussed the potential of lncRNAs as prospective novel targets in PC treatment and biomarkers for PC diagnosis.

https://ift.tt/2Lik0P3

CDC: More People With High Cholesterol Taking Medications

MONDAY, July 23, 2018 -- There has been a substantial increase in the percentage of patients with high cholesterol over age 60 years taking lipid-lowering medications from 2005 to 2016, but such increases have not been seen among younger patients...

https://ift.tt/2uWmF5J

Few HIV Tests Given to Black Men Who Have Sex With Men in South

MONDAY, July 23, 2018 -- Few HIV tests in the southern United States are provided for black men who have sex with men (MSM) even though they account for a substantial percentage of new diagnoses, according to research published in the July 20 issue...

https://ift.tt/2mE1JwS

Embezzlement Not Uncommon in Medical Practices

MONDAY, July 23, 2018 -- Embezzlement occurs frequently in medical practices and steps should be taken to prevent it, according to an article published in Medical Economics. Physician practices suffer from some of the highest rates of money...

https://ift.tt/2A2wKE5

Child-Targeted Gluten-Free Products No Healthier

MONDAY, July 23, 2018 -- Child-targeted gluten-free products do not appear to be healthier, with similar levels of sugar and poor nutritional quality as product equivalents, according to a study published online July 23 in Pediatrics. Charlene...

https://ift.tt/2mE1IsO

Guidelines Conflict for Long-Term Opioid Tx in Cancer Survivors

MONDAY, July 23, 2018 -- Evidence is lacking about the need for and outcomes of long-term opioid therapy in cancer survivors, and contemporary guidelines offer conflicting recommendations, according to a viewpoint article recently published online...

https://ift.tt/2A47htW

Poor Outcomes for Prefrail/Frail at Risk of Malnutrition

MONDAY, July 23, 2018 -- Prefrail/frail seniors at risk of malnutrition have poor health outcomes and increased mortality, according to a study published online July 13 in JAMA Network Open. Kai Wei, M.D., from Shanghai Jiao Tong University in...

https://ift.tt/2mzKuwC

Portable Sleep Monitoring Accurate in Heart Failure Patients

MONDAY, July 23, 2018 -- For patients hospitalized with decompensated heart failure, portable sleep monitoring with respiratory polygraphy can accurately diagnose sleep apnea, according to a study published in the July issue of CHEST. Rashmi Nisha...

https://ift.tt/2uUTmRa

Details of Montreal Cognitive Assessment Widely Publicized

MONDAY, July 23, 2018 -- Many published news articles included details of the Montreal Cognitive Assessment (MoCA) in association with President Trump, some of which invited readers to self-administer the test, according to a research letter...

https://ift.tt/2mE1EJA

Intermittent Energy Restriction Effectively Cuts HbA1c in T2DM

MONDAY, July 23, 2018 -- For patients with type 2 diabetes, intermittent energy restriction is comparable to continuous energy restriction for reduction of hemoglobin A1c (HbA1c), according to a study published online July 20 in JAMA Network...

https://ift.tt/2A2LMdb

FDA Warns Against Risks of Contaminated Synthetic Cannabis

MONDAY, July 23, 2018 -- Users of synthetic marijuana products and health care providers should be aware of the risk of bleeding associated with contamination of synthetic cannabinoid products with brodifacoum, according to the U.S. Food and Drug...

https://ift.tt/2mE1CBs

Influence of pre-transplant minimal residual disease on prognosis after Allo-SCT for patients with acute lymphoblastic leukemia: systematic review and meta-analysis

Abstract

Background

This meta-analysis was performed to explore the impact of minimal residual disease (MRD) prior to transplantation on the prognosis for patients with acute lymphoblastic leukemia (ALL).

Methods

A systematic search of PubMed, Embase, and the Cochrane Library was conducted for relevant studies from database inception to March 2016. A total of 21 studies were included.

Results

Patients with positive MRD prior to allogeneic stem cell transplantation (allo-SCT) had a significantly higher rate of relapse compared with those with negative MRD (HR = 3.26; P <  0.05). Pre-transplantation positive MRD was a significant negative predictor of relapse-free survival (RFS) (HR = 2.53; P <  0.05), event-free survival (EFS) (HR = 4.77; P < 0.05), and overall survival (OS) (HR = 1.98; P < 0.05). However, positive MRD prior to transplantation was not associated with a higher rate of nonrelapse mortality.

Conclusions

Positive MRD before allo-SCT was a predictor of poor prognosis after transplantation in ALL.

Trial registration

Not applicable.

https://ift.tt/2A3MXZx

Mass. first responders equipped with ballistic vests, helmets

The ballistic gear allows firefighters and paramedics into the "warm zone" alongside law enforcement to quickly provide life-saving first aid

https://ift.tt/2uJHe6m

2018 Hooley awards winners announced at ImageTrend Connect

LAKEVILLE, MINN. — ImageTrend, Inc. announced the winners of the 2018 Hooley™ Awards at the 10th annual ImageTrend Connect Conference. Nominees were narrowed down to a field of nine finalists – three in each of three categories – from which the winners were selected by a panel of third-party judges. Judges cast votes via secret ballot for each category. ImageTrend extends...

https://ift.tt/2uW6c1p

https://ift.tt/2mE7MS1

The application of fibular free flap with flexor hallucis longus in maxilla or mandible extensive defect: a comparison study with conventional flap

Abstract

Background

The repair and reconstruction of maxillary and mandibular extensive defects have put huge challenges to surgeons. The fibular free flap (FFF) is one of the standard treatment choices for reconstruction. The conventional FFF has deficiencies, such as forming poor oral mucosa, limited flap tissue, and perforator vessel variation. To improve the use of FFF, we add the flexor hallucis longus (FHL) in the flap (FHL-FFF). In this paper, we described the advantage and indication of FHL-FFF and conducted a retrospective study to compare FHL-FFF and FFF without FHL.

Methods

Fifty-four patients who underwent FFF were enrolled and divided into two groups: nFHL group (using FFF without FHL, 38 patients) and FHL group (using FHL-FFF, 16 patients). The perioperative clinical data of patients was collected and analyzed.

Results

The flaps all survived in two groups. We mainly used FHL to fill dead space, and the donor-site morbidity was slight. In FHL group, flap harvesting time was shorter (118.63 ± 11.76 vs 125.74 ± 11.33 min, P = 0.042), the size of flap's skin paddle was smaller (16.5 (0–96) vs 21.0(10–104) cm², P = 0.027) than nFHL group. There were no significant differences (P > 0.05) in hospital days, hospitalization expense, rate of perioperative complications, etc. between the two groups. Compared with FFF without FHL, FHL-FFF will neither affect the use of flap nor bring more problems.

Conclusion

The FHL-FFF simplifies the flap harvesting operation. The FHL can form good mucosa and make FFF rely less on skin paddle. It can be used for adding flap tissue and dealing with perforator vessel variation in reconstruction of maxillary and mandibular extensive defects.

https://ift.tt/2LrLnW7

Long-Term Risk of In-Stent Restenosis and Stent Fracture for Extracranial Vertebral Artery Stenting

Abstract

Purpose

Stenting and angioplasty of the vertebral artery (VA) is used to treat symptomatic stenosis but the long-term outcomes and complications are unclear. This study evaluated the long-term clinical outcomes and procedure-related complications in patients who underwent extracranial VA stenting and angioplasty, in particular the risks of in-stent restenosis (ISR) and stent fracture.

Methods

This was a retrospective review of consecutive patients suffering from symptomatic extracranial VA stenosis who were treated with balloon-expandable bare metal stents. The clinical and angiographical outcomes were reviewed for procedural complications, recurrent stroke, ISR and stent fracture.

Results

In this study 22 patients (17 male, 5 female) with a mean age of 63.4 years (SD 9.1 years) were included. The median follow-up was 56 months (interquartile range IQR 51.8 months). There were no periprocedural complications. The cumulative ISR risk was 45% with 6 cases detected at 1 year and 3 cases detected at 3 years post operation. The cumulative stent fracture rate at 1 year, 3 years, 5 years and the entire follow-up period were 5%, 15%, 25%, and 30%, respectively. Posterior circulation stroke occurred in 1 patient (4.5%), and 3 patients died of non-cerebrovascular causes during follow-up. Of the patients 2 with ISR and stent fracture required additional treatment.

Conclusion

The long-term ISR and stent fracture risks were high in extracranial VA stenosis treated with balloon-expandable bare metal stents. The risk of stent fracture increased over time during the follow-up period. Further studies should be conducted to clarify the long-term safety and efficacy of extracranial VA stenting.

https://ift.tt/2LGwFr6

Improved Brachial Plexus Visualization Using an Adiabatic iMSDE-Prepared STIR 3D TSE

Abstract

Purpose

The close proximity of blood vessels to the brachial plexus nerves can confound nerve visualization in conventional fat-suppressed 3D T2-weighted sequences. Vessel suppression can be accomplished by means of motion-sensitizing preparation. The aim of this study was to qualitatively and semi-quantitatively evaluate short tau inversion recovery (STIR) 3D turbo spin echo (TSE) in conjunction with an adiabatic T2 preparation incorporating motion sensitization for magnetic resonance neurography (MRN) of the brachial plexus in a clinical routine setting.

Methods

The MRN of the brachial plexus was performed in 22 patients (age 45.5 ± 20.3 years) with different clinical implications using the proposed improved motion-sensitized driven equilibrium (iMSDE) STIR 3D TSE and the STIR 3D TSE. Images were evaluated regarding image quality, overall artifacts, artifacts caused by vessel signal, signal homogeneity, visibility of small nerves and signal contrast. Furthermore, signal-to-noise ratios (aSNR), nerve muscle contrast to noise ratios (aNMCNR) and nerve vessel contrast to noise ratios (aNVCNR) were calculated and compared.

Results

The incorporation of motion sensitization in the T2 preparation resulted in robust blood suppression across subjects, leading to significantly higher aNVCNRs (p < 0.001) and aNMCNRs (p < 0.05), increased conspicuousness of the nerves, better vessel suppression and image quality and less artifacts compared with STIR 3D TSE (p < 0.001).

Conclusion

The incorporation of the proposed adiabatic iMSDE-based motion sensitization was shown to provide robust blood suppression of vessels in close proximity to brachial plexus nerves. The use of STIR iMSDE 3D TSE can be considered for clinical MRN examinations of the brachial plexus.

https://ift.tt/2uL2dp7

CD155 downregulation synergizes with adriamycin to induce breast cancer cell apoptosis

Abstract

CD155 has been implicated in migration, invasion, proliferation and apoptosis of human cancer cells, and DNA damage response caused by chemotherapeutic agents or reactive oxygen species has been shown to attribute to CD155 induction. Adriamycin (Adr) is one of the most common chemotherapeutic drugs used to treat breast cancer. Here we reported that treatment with Adr upregulated CD155 expression on several in vitro cultured breast cancer cells and in breast cancer cell 4T1 xenografts. We also found that CD155 knockdown or Adr treatment induced apoptosis of in vitro cultured cancer cells and cancer cells in 4T1 xenografts, and a combination of CD155 knockdown with Adr treatment induced more cell death than either of them. Furthermore, we revealed that the combination of CD155 knockdown with Adr treatment suppressed the growth of 4T1 xenografts more significantly than them alone. In summary, our results demonstrate that CD155 downregulation synergizes with Adr to induce breast cancer cell apoptosis, thereby to suppress tumor growth. Our results also suggest that CD155 upregulation may be a mechanism underlying Adr resistance by breast cancer cells.

https://ift.tt/2uWVeJ7

Antimicrobial resistance in mollicutes: Known and newly emerging mechanisms

Abstract

The review is devoted to the mechanisms of antibiotic resistance in mollicutes (class Bacilli, subclass Mollicutes), the smallest self-replicating bacteria, that can cause diseases in plants, animals and humans, and also contaminate cell cultures and vaccine preparations. Research in this area has been mainly based on the 'ubiquitous mollicute' and the main contaminant of cell cultures, Acholeplasma laidlawii (A. laidlawii). The 'omics' technologies applied to this and other bacteria have yielded a complex picture of responses to antimicrobials, including their removal from the cell, the acquisition of antibiotic resistance genes and mutations that potentially allow global reprogramming of many cellular processes. The review provides a brief summary of well-known resistance mechanisms that have been demonstrated in several mollicutes species and, in more detail, novel mechanisms revealed in A. laidlawii, including the least explored vesicle-mediated transfer of short RNAs with a regulatory potency. We hope that this review highlights new avenues for further studies on antimicrobial resistance in these bacteria for both a basic science and an application perspective of infection control and management in clinical and research/production settings.

https://ift.tt/2LGR8fs

Cancers, Vol. 10, Pages 240: Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Cancers, Vol. 10, Pages 240: Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism

Cancers doi: 10.3390/cancers10070240

Authors: Nikolaos Tsesmetzis Cynthia B. J. Paulin Sean G. Rudd Nikolas Herold

Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, in combination with other chemotherapeutics, have revolutionised clinical oncology and transformed cancer into a curable disease. However, even though combination chemotherapy, together with radiation, surgery and immunotherapy, can nowadays cure almost all types of cancer, we still fail to achieve this for a substantial proportion of patients. The understanding of differences in metabolism, pharmacokinetics, pharmacodynamics, and tumour biology between patients that can be cured and patients that cannot, builds the scientific basis for rational therapy improvements. Here, we summarise current knowledge of how tumour-specific and patient-specific factors can dictate resistance to nucleobase/nucleoside analogues, and which strategies of re-sensitisation exist. We revisit well-established hurdles to treatment efficacy, like the blood-brain barrier and reduced deoxycytidine kinase activity, but will also discuss the role of novel resistance factors, such as SAMHD1. A comprehensive appreciation of the complex mechanisms that underpin the failure of chemotherapy will hopefully inform future strategies of personalised medicine.

https://ift.tt/2LL46sI

Ex vivo expanded tumour-infiltrating lymphocytes from ovarian cancer patients release anti-tumour cytokines in response to autologous primary ovarian cancer cells

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of gynaecological cancer-related death in Europe. Although most patients achieve an initial complete response with first-line treatment, recurrence occurs in more than 80% of cases. Thus, there is a clear unmet need for novel second-line treatments. EOC is frequently infiltrated with T lymphocytes, the presence of which has been shown to be associated with improved clinical outcomes. Adoptive T-cell therapy (ACT) using ex vivo-expanded tumour-infiltrating lymphocytes (TILs) has shown remarkable efficacy in other immunogenic tumours, and may represent a promising therapeutic strategy for EOC. In this preclinical study, we investigated the efficacy of using anti-CD3/anti-CD28 magnetic beads and IL-2 to expand TILs from freshly resected ovarian tumours. TILs were expanded for up to 3 weeks, and then subjected to a rapid-expansion protocol (REP) using irradiated feeder cells. Tumours were collected from 45 patients with EOC and TILs were successfully expanded from 89.7% of biopsies. Expanded CD4⁺ and CD8⁺ subsets demonstrated features associated with memory phenotypes, and had significantly higher expression of key activation and functional markers than unexpanded TILs. Expanded TILs produced anti-tumour cytokines when co-cultured with autologous tumour cells, inferring tumour cytotoxicity. Our findings demonstrate that it is possible to re-activate and expand tumour-reactive T cells from ovarian tumours. This presents a promising immunotherapy that could be used sequentially or in combination with current therapeutic strategies.

https://ift.tt/2uVFu9b

Primer set 2.0 for highly parallel qPCR array targeting antibiotic resistance genes and mobile genetic elements

Abstract

The high-throughput antibiotic resistance gene (ARG) qPCR array, initially published in 2012, is increasingly used to quantify resistance and mobile determinants in environmental matrices. Continued utility of the array; however, necessitates improvements such as removing or redesigning questionable primer sets, updating targeted genes and coverage of available sequences. Towards this goal, a new primer design tool (EcoFunPrimer) was used to aid in identification of conserved regions of diverse genes. The total number of assays used for diverse genes was reduced from 91 old primer sets to 52 new primer sets, with only a 10% loss in sequence coverage. While the old and new array both contain 384 primer sets, a reduction in old primer sets permitted 147 additional ARGs and mobile genetic elements (MGEs) to be targeted. Results of validating the updated array with a mock community of strains resulted in over 98% of tested instances incurring true positive/negative calls. Common queries related to sensitivity, quantification, and conventional data analysis (e.g. Ct cutoff value, and estimated genomic copies without standard curves) were also explored. A combined list of new and previously used primer sets is provided with a recommended set based on redesign of primer sets and results of validation.

https://ift.tt/2uIfsXB

Ex vivo expanded tumour-infiltrating lymphocytes from ovarian cancer patients release anti-tumour cytokines in response to autologous primary ovarian cancer cells

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of gynaecological cancer-related death in Europe. Although most patients achieve an initial complete response with first-line treatment, recurrence occurs in more than 80% of cases. Thus, there is a clear unmet need for novel second-line treatments. EOC is frequently infiltrated with T lymphocytes, the presence of which has been shown to be associated with improved clinical outcomes. Adoptive T-cell therapy (ACT) using ex vivo-expanded tumour-infiltrating lymphocytes (TILs) has shown remarkable efficacy in other immunogenic tumours, and may represent a promising therapeutic strategy for EOC. In this preclinical study, we investigated the efficacy of using anti-CD3/anti-CD28 magnetic beads and IL-2 to expand TILs from freshly resected ovarian tumours. TILs were expanded for up to 3 weeks, and then subjected to a rapid-expansion protocol (REP) using irradiated feeder cells. Tumours were collected from 45 patients with EOC and TILs were successfully expanded from 89.7% of biopsies. Expanded CD4⁺ and CD8⁺ subsets demonstrated features associated with memory phenotypes, and had significantly higher expression of key activation and functional markers than unexpanded TILs. Expanded TILs produced anti-tumour cytokines when co-cultured with autologous tumour cells, inferring tumour cytotoxicity. Our findings demonstrate that it is possible to re-activate and expand tumour-reactive T cells from ovarian tumours. This presents a promising immunotherapy that could be used sequentially or in combination with current therapeutic strategies.

https://ift.tt/2uVFu9b

Introduction

Publication date: Available online 23 July 2018

Source: Seminars in Spine Surgery

Author(s): Brittany E. Haws, Benjamin Khechen, Jordan A. Guntin, Kaitlyn L. Cardinal, Kern Singh

https://ift.tt/2LifuQv

Trehalose/hyaluronate eyedrop effects on ocular surface inflammatory markers and mucin expression in dry eye patients

https://ift.tt/2O9hhFj

Photodynamic therapy in combination with intravitreal ziv-aflibercept and aflibercept injection in patients with chronic or repeatedly recurrent acute central serous chorioretinopathy: a single-center retrospective study

https://ift.tt/2NCeEKZ

A prospective, observational study investigating the use of carbon monoxide screening to identify maternal smoking in a large university hospital in Ireland

Objectives

This study evaluated breath carbon monoxide (BCO) testing in identifying maternal smokers as well as the difference between disclosers and non-disclosers of smoking status. We also investigated if other extrinsic factors affected the women's BCO levels in pregnancy.

Design

A prospective observational study.

Setting

A university obstetric hospital in an urban setting in Ireland.

Participants

Women (n=250) and their partners (n=54) were recruited at their first antenatal visit. Women <18 years and those who did not understand English were excluded. A booking history, including recording of smoking status, was collected by midwives. Following this, women were recruited and completed a detailed research questionnaire on smoking and extrinsic/environmental BCO sources. A BCO test was performed on both the woman and her partner.

Primary and secondary outcome measures

The number of self-reported smokers and those that were positive on the BCO test. The characteristics of women who disclosed and did not disclose smoking status. The effect of extrinsic factors on the BCO test results.

Results

Based on the receiver-operating characteristic curve, a BCO cut-off point of ≥3 ppm was the optimal level to identify ongoing smoking. At booking history, 15% of women reported as current smokers. Based on BCO levels ≥3 ppm combined with self-reported smoking in the research questionnaire, the rate increased to 25%. Non-disclosers had similar characteristics to non-smokers. No extrinsic factors affected maternal BCO levels.

Conclusions

Based on self-report and BCO levels, a quarter of women presenting for antenatal care continued to smoke, but only 60% reported their smoking to midwives. BCO measurement is an inexpensive, practical method of improving identification of maternal smoking, and it was not effected by extrinsic sources of BCO. Improved identification means more smokers can be supported to stop smoking in early pregnancy potentially improving the short-term and long-term health of both mother and child.

https://ift.tt/2O8wfew

Quantifying nursing care delivered in Kenyan newborn units: protocol for a cross-sectional direct observational study

Introduction

In many African countries, including Kenya, a major barrier to achieving child survival goals is the slow decline in neonatal mortality that now represents 45% of the under-5 mortality. In newborn care, nurses are the primary caregivers in newborn settings and are essential in the delivery of safe and effective care. However, due to high patient workloads and limited resources, nurses may often consciously or unconsciously prioritise the care they provide resulting in some tasks being left undone or partially done (missed care). Missed care has been associated with poor patient outcomes in high-income countries. However, missed care, examined by direct observation, has not previously been the subject of research in low/middle-income countries.

Methods and analysis

The aim of this study is to quantify essential neonatal nursing care provided to newborns within newborn units. We will undertake a cross-sectional study using direct observational methods within newborn units in six health facilities in Nairobi City County across the public, private-for-profit and private-not-for-profit sectors. A total of 216 newborns will be observed between 1 September 2017 and 30 May 2018. Stratified random sampling will be used to select random 12-hour observation periods while purposive sampling will be used to identify newborns for direct observation. We will report the overall prevalence of care left undone, the common tasks that are left undone and describe any sharing of tasks with people not formally qualified to provide care.

Ethics and dissemination

Ethical approval for this study has been granted by the Kenya Medical Research Institute Scientific and Ethics Review Unit. Written informed consent will be sought from mothers and nurses. Findings from this work will be shared with the participating hospitals, an expert advisory group that comprises members involved in policy-making and more widely to the international community through conferences and peer-reviewed journals.

https://ift.tt/2NzgvAe

Sensitivity and specificity of breast cancer ICD-9-CM codes in three Italian administrative healthcare databases: a diagnostic accuracy study

Objectives

To assess the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in identifying patients diagnosed with incident carcinoma in situ and invasive breast cancer in three Italian administrative databases.

Design

A diagnostic accuracy study comparing ICD-9-CM codes for carcinoma in situ (233.0) and for invasive breast cancer (174.x) with medical chart (as a reference standard). Case definition: (1) presence of a primary nodular lesion in the breast and (2) cytological or histological documentation of cancer from a primary or metastatic site.

Setting

Administrative databases from Umbria Region, Azienda Sanitaria Locale (ASL) Napoli 3 Sud (NA) and Friuli VeneziaGiulia (FVG) Region.

Participants

Women with breast carcinoma in situ (n=246) or invasive breast cancer (n=384) diagnosed (in primary position) between 2012 and 2014.

Outcome measures

Sensitivity and specificity for codes 233.0 and 174.x.

Results

For invasive breast cancer the sensitivities were 98% (95% CI 93% to 99%) for Umbria, 96% (95% CI 91% to 99%) for NA and 100% (95% CI 97% to 100%) for FVG. Specificities were 90% (95% CI 82% to 95%) for Umbria, 91% (95% CI 83% to 96%) for NA and 91% (95% CI 84% to 96%) for FVG.

For carcinoma in situ the sensitivities were 100% (95% CI 93% to 100%) for Umbria, 100% (95% CI 95% to 100%) for NA and 100% (95% CI 96% to 100%) for FVG. Specificities were 98% (95% CI 93% to 100%) for Umbria, 86% (95% CI 78% to 92%) for NA and 90% (95% CI 82% to 95%) for FVG.

Conclusions

Administrative healthcare databases from Umbria, NA and FVG are accurate in identifying hospitalised news cases of carcinoma of the breast. The proposed case definition is a powerful tool to perform research on large populations of newly diagnosed patients with breast cancer.

https://ift.tt/2O8wc2k

Risk of rheumatoid arthritis in patients with hepatitis C virus infection receiving interferon-based therapy: a retrospective cohort study using the Taiwanese national claims database

Objectives

To illuminate the association between interferon-based therapy (IBT) and the risk of rheumatoid arthritis (RA) in patients infected with hepatitis C virus (HCV).

Design, setting, participants and interventions

This retrospective cohort study used Taiwan's Longitudinal Health Insurance Database 2005 that included 18 971 patients with HCV infection between 1 January 1997 and 31 December 2012. We identified 1966 patients with HCV infection who received IBT (treated cohort) and used 1:4 propensity score-matching to select 7864 counterpart controls who did not receive IBT (untreated cohort).

Outcome measures

All study participants were followed until the end of 2012 to calculate the incidence rate and risk of incident RA.

Results

During the study period, 305 RA events (3.1%) occurred. The incidence rate of RA was significantly lower in the treated cohort than the untreated cohort (4.0 compared with 5.5 per 1000 person-years, p<0.018), and the adjusted HR remained significant at 0.63 (95% CI 0.43 to 0.94, p=0.023) in a Cox proportional hazards regression model. Multivariate stratified analyses revealed that the attenuation in RA risk was greater in men (0.35; 0.15 to 0.81, p=0.014) and men<60 years (0.29; 0.09 to 0.93, p=0.036).

Conclusions

This study demonstrates that IBT may reduce the risk of RA and contributes to growing evidence that HCV infection may lead to development of RA.

https://ift.tt/2NF5E7N

Drowning mortality by intent: a population-based cross-sectional study of 32 OECD countries, 2012-2014

Objective

To compare the drowning mortality rates and proportion of deaths of each intent among all drowning deaths in Organisation for Economic Co-operation and Development (OECD) countries in 2012–2014.

Design

A population-based cross-sectional study.

Setting

32 OECD countries.

Participants

Individuals in OECD countries who died from drowning.

Main outcome measures

Drowning mortality rates (deaths per 100 000 population) and proportion (%) of deaths of each intent (ie, unintentional intent, intentional self-harm, assault, undetermined intent and all intents combined) among all drowning deaths.

Results

Countries with the highest drowning mortality rates (deaths per 100 000 population) were Estonia (3.53), Japan (3.49) and Greece (2.40) for unintentional intent; Ireland (0.96), Belgium (0.96) and Korea (0.89) for intentional self-harm; Austria (0.57), Korea (0.56) and Hungary (0.44) for undetermined intent and Japan (4.35), Estonia (3.70) and Korea (2.73) for all intents combined. Korea ranked 12th and 3rd for unintentional intent and all intents combined, respectively. By contrast, Belgium ranked 2nd and 15th for intentional self-harm and all intents combined, respectively. The proportion of deaths of each intent among all drowning deaths in each country varied greatly: from 26.2% in Belgium to 96.8% in Chile for unintentional intent; 0.7% in Mexico to 57.4% in Belgium for intentional self-harm; 0.0% in nine countries to 4.9% in Mexico for assault and 0.0% in Israel and Turkey to 38.3% in Austria for undetermined intent.

Conclusions

A large variation in the practice of classifying undetermined intent in drowning deaths across countries was noted and this variation hinders valid international comparisons of intent-specific (unintentional and intentional self-harm) drowning mortality rates.

https://ift.tt/2Oe0WiK

How do Korean nursing students build knowledge? A constructivist grounded theory study

Introduction

Nursing is a knowledge-intensive profession. Therefore, to cope with the demands of the nursing role, nursing students need to become competent in managing information to build nursing knowledge. However, nursing students' knowledge building process is poorly understood. This research aimed to explore (1) nursing students' dynamics of how they process nursing information for knowledge building and (2) nursing students' learning context in South Korea for their knowledge building.

Methods

A constructivist grounded theory approach was used for this research. Data collection was achieved through four rounds of intensive individual and group interviews with 16 fourth year nursing students in South Korea. The collected data were coded by initial, focused and theoretical coding methods. Constant comparison analysis between data, codes, memos and categories was applied.

Results

This research identified knowledge building dynamics consisting of three cognitive processes: connecting with information, deciding to accept information and building knowledge. Five motivational factors, including learners' interest, necessity of information, volition to learn, utility of information and the frequency of information that influence the processes were discovered. Moreover, four knowledge stages of memorising, understanding, synthesising and applying and creating emerged.

Conclusions

This is the first empirical study on knowledge building dynamics in educational environments for healthcare professionals. The findings of this research provide nursing educators with a practical model that can be used to improve nursing curricula in facilitating students' knowledge building processes. Moreover, a deeper understanding of sociocultural influences on nursing education can assist educators to adapt and generalise the findings to their pedagogical contexts, providing a culturally sensitive and relevant approach to nursing education.

https://ift.tt/2Nz0ZV9

Tools to assess the measurement properties of quality of life instruments: a meta-review protocol

Introduction

Using specific tools to assess the measurement properties of health status instruments is recommended both to standardise the review process and to improve the methodological quality of systematic reviews. However, depending on the measurement standards on which these tools are developed, the approach to appraise the measurement properties of instruments may vary. For this reason, the present meta-review aims to: (1) identify systematic reviews assessing the measurement properties of instruments evaluating health-related quality of life (HRQoL); (2) identify the tools applied to assess the measurement properties of HRQoL instruments; (3) describe the characteristics of the tools applied to assess the measurement properties of HRQoL instruments; (4) identify the measurement standards on which these tools were developed or conform to and (5) compare the similarities and differences among the identified measurement standards.

Methods and analysis

A systematic review will be conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols Guidelines. Electronic search will be carried out on bibliographic databases, including PubMed, Cumulative Index to Nursing and Allied Health Literature, Psychological Information, SCOPUS, Web of Science, COSMIN database and ProQuest Dissertations & Theses Global, being limited by time (2008–2018) and language (English). Descriptive analyses of different aspects of tools applied to evaluate the measurement properties of HRQoL instruments will be presented; the different measurement standards will be described and some recommendations about the methodological and research applications will be made.

Ethics and dissemination

Ethical approval is not necessary for systematic review protocols. The results will be disseminated by its publication in a peer-reviewed journal and presented at a relevant conference.

PROSPERO registration number

CRD42017065232

https://ift.tt/2O4QqKB

Clinical characteristics of young adult cataract patients: a 10-year retrospective study of the Zhongshan Ophthalmic Center

Aim

To investigate the characteristics of young adult cataract (YAC) patients over a 10-year period.

Methods

This observational study included YAC patients aged 18–49 years who were treated surgically for the first time at the Zhongshan Ophthalmic Center in China. YAC patients were analysed and compared with patients with childhood cataract (CC) in January 2005 to December 2014.

Results

During the 10-year period, 515 YAC patients and 2421 inpatients with CC were enrolled. Among the YAC patients, 76.76% (109/142) of unilateral patients had a corrected distance visual acuity (CDVA) better than 20/40 in the healthy eye, whereas only 20.38% (76/373) of bilateral patients had a CDVA better than 20/40 in the eye with better visual acuity. Compared with the CC group, the YAC group had a higher proportion of rural patients (40.40% vs 31.60%, p=0.001). Furthermore, the prevalence of other ocular abnormalities in YAC patients was higher than that in patients with CC (29.71% vs 17.47%, p<0.001).

Conclusions

A large proportion coming from rural areas and a high prevalence of complicated ocular abnormalities may be the most salient characteristics of YAC patients. Strengthening the counselling and screening strategy for cataract and health education for young adults are required especially for those in rural areas.

https://ift.tt/2Nz0SJd

FODMAPs for FGIDs—just alphabet soup or therapy for real?

Functional gastrointestinal disorders (FGIDs) are characterized by persistent or recurrent gastrointestinal symptoms related to any combination of motility disturbances, visceral hypersensitivity, altered mucosal and immune function, gut microbiota, and/or central nervous system processing that cannot be attributed to another medical condition after appropriate medical evaluation. Perhaps the best known FGID is irritable bowel syndrome (IBS) with a prevalence of 8% to 12% in children across the United States.

https://ift.tt/2JLNAGJ

Prognosis in cystic kidney disorders

There are 2 inherited cystic kidney diseases that progress to kidney failure. Both are "ciliopathies," a relatively new category of disorders consequent to single gene mutations in the sensory cilia that are present on a host of epithelial cells. Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end stage kidney disease in adults; although the disorder has its onset in childhood, kidney failure in children from ADPKD is rare.

https://ift.tt/2LAHFJA

The Journal's updated policy on reporting guidelines and data sharing statements

Reporting guidelines have been developed to assist researchers in the writing of their studies in an effort to improve the reliability, transparency, and reproducibility in published health research. Additionally, reporting guideline checklists serve as a tool used by reviewers and editors to evaluate the completeness and accuracy of the research reported.

https://ift.tt/2JNoPKu

Table of Contents

https://ift.tt/2LAHxtA

Masthead

https://ift.tt/2JNoWFU

50 Years Ago in The Journal of Pediatrics

Hessel SJ, Haggerty RJ. J Pediatr 1968;73:271-9

https://ift.tt/2LuwRNo

50 Years Ago in The Journal of Pediatrics

Magenis RE, Hecht F, Milham Jr S. J Pediatr 1968;73:222-8

https://ift.tt/2uXMnH4

50 Years Ago in The Journal of Pediatrics

Lapatsanis P, Deliyanni V, Doxiadis S. J Pediatr 1968;73:195-202.

https://ift.tt/2LAHmyq

50 Years Ago in The Journal Of Pediatrics

Hustu HO, Holton C, James D, Pinkel D. J Pediatr 1968;73:249-51.

https://ift.tt/2uTM8gn

50 Years Ago in the Journal of Pediatrics

Katz M, Plotkin SA. J Pediatr 1968;73:267-70

https://ift.tt/2LvjP1W

Subjectively and Objectively Assessed Behavioral, Social, and Physical Environmental Correlates of Sedentary Behavior in Preschoolers

To investigate associations between preschoolers' objective leisure-time sedentary behavior and a comprehensive set of subjective and objective potential correlates of sedentary behavior across the behavioral, social, and physical environmental domains on both the family and community level.

https://ift.tt/2JNc2HX

How to Calculate the Risk of Shortage and Surplus of Pediatric Workforce?

In the first part of this series debating the required pediatric workforce in different European child healthcare systems, the European Paediatric Association (EPA) presented the equations for calculating the need of annual number of newly certified pediatricians in the different European national contexts, and for keeping their national pediatric workforce stable.1 This article provides further equations for calculating dynamically the risk of shortage and surplus in numbers of pediatricians, and its impact on child healthcare services.

https://ift.tt/2LveV4V

New findings in congenital cytomegalovirus infection: The spectrum from asymptomatic to symptomatic infection

Inagaki et al from the University of Mississippi Medical Center at Jackson performed a retrospective analysis of serial cross-sectional data during 4 years between 2000-2012 using the Kids' Inpatient Database (KID). They aimed to assess risk factors, geographical distribution, length of stay, and birth hospital charges for cases of symptomatic congenital cytomegalovirus infection (cCMV). Among 1349 cases of cCMV identified, investigators identified non-Hispanic black race, government-sponsored insurance, and birth in the American South and West as having significantly increased odds ratios (95% CIs ranging from 1.37 to 2.83) for cCMV.

https://ift.tt/2uVn2xG

Fractures and diuretics

As pediatricians have become more focused on bone health, a host of chronic disorders and their therapy have been identified as risk factors for decreased bone density and fractures. There have been previous studies suggesting that children with congenital heart disease were at risk for fractures, but the specific mechanisms have not been well-defined.

https://ift.tt/2LAH36K

Prevalence of nephrocalcinosis in pseudohypoparathyroidism: Is screening necessary?

Clinical practice for evaluating uncommon conditions frequently follows care pathways established by a combination of tradition, local convention, best reasoning from pathophysiologic knowledge, expert opinion, and trade-offs of testing cost and invasiveness with the potential knowledge to be gained and the risk of missing actionable information—among other considerations. Therefore, data to better inform clinical decision making in uncommon conditions is most welcome.

https://ift.tt/2uX6zZz