Medicine by Alexandros G.Sfakianakis: 07/28/18

Σάββατο 28 Ιουλίου 2018

Effect of transcription terminator usage on the establishment of transgene transcriptional gene silencing

Obtaining high and stable transgene expression is of vital importance for plant genetic engineering. A lot is known about the relationship between terminator efficiency and gene expression, but no studies have...

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Changes in vigilance, self rated sleep and state anxiety in military personnel in India following yoga

To study the effects of 9 days of yoga on self-rated sleep, state anxiety and performance in a vigilance test among border security force (BSF) personnel. Seven hundred and twenty-two BSF personnel took part i...

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Prevalence and predictors of recreational drug use among medical and nursing students in Cameroon: a cross sectional analysis

Medical and nursing students in Cameroon are likely to have mental health problems given the stressful nature of their studies. Paucity of mental health institutions in the country implies they hardly get acce...

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Utilization and cost of electronic resources in adult cancer center

This study aims to evaluate the knowledge of healthcare providers and the cost of the current institutional e-resources in an adult oncology setting. To assess the awareness, accessibility, and utilization of ...

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The Sierra Platinum Service for generating peak-calls for replicated ChIP-seq experiments

Sierra Platinum is a fast and robust peak-caller for replicated ChIP-seq experiments with visual quality-control and -steering. The required computing resources are optimized but still may exceed the resources...

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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 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.

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Simulation and modeling of dietary changes in the infant gut microbiome

ABSTRACT

The early gut microbiome is essential for health, and diet has a profound influence in its composition. Oligosaccharides in breast milk or formula act as prebiotics, influencing gut microbiome structure. Here we simulated the impact of a dietary switch from fructooligosaccharides (FOS) to 2-fucosyllactose (2FL) in a continuous culture containing a consortium of species of the infant gut microbiome. During growth on FOS the consortium was dominated by Lactobacillus acidophilus, characterized by high amounts of lactate. Switching to 2FL led to a decrease in total biomass, and a recovery in Bifidobacterium infantis and Escherichia coli levels. While FOS was rapidly metabolized by the consortium, 2FL was utilized only after a delay. 2FL consumption was followed by a gradual switch from lactate to acetate. The activity of these bacterial species correlated well with gene expression analysis. Mathematical modeling of a multi-species consortium in continuous culture was capable to explain in great part the behavior of the system. The model was finally used to represent the outcome of the system after 48 h after each regime. This work highlights the impact of dietary changes in the gut microbiome, and provides a modeling framework to predict this influence.

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Trichoderma atroviride promotes tomato development and alters the root exudation of carbohydrates, which stimulates fungal growth and the biocontrol of the phytopathogen Phytophthora cinnamomi in a tripartite interaction system

ABSTRACT

Several species of Trichoderma promote plant growth and help in defense against root pathogens. The role of root-exuded carbohydrates as chemo-attractive stimuli for Trichoderma colonization is attracting considerable interest. In this project, we studied the interaction between Trichoderma atroviride and tomato (Lycopersicon esculentum L. cv. Río Grande) plants in two different stages, before and during root colonization. In addition, the biocontrol capacity of T. atroviride against the phytopathogen Phytophthora cinnamomi in a tripartite interaction system was examined. We found that the beneficial effects of T. atroviride on plant growth were fine-tuned depending on the progress of interaction. Interestingly, the composition of the carbohydrate exudate from plants interacting with T. atroviride was different from that produced by other treatments and probably provided a nutritional source for the fungus. Particularly, sucrose was found only during root colonization by the fungus. Our data show that root-derived sugars enabled a higher Trichoderma growth rate, and that, in the tripartite interaction system with P. cinnamomi, the fungus competes for space and available soil nutrients more efficiently than P. cinnamomi, thereby antagonizing the growth of the phytopathogen.

https://ift.tt/2vcRh31

Agricultural contamination impacts antibiotic resistance gene abundances in river bed sediment temporally

ABSTRACT

Kewaunee County, Wisconsin is an agricultural area dominated by concentrated animal feeding operations and manure fertilized cropland. The objective of this study was to characterize chemical and antibiotic resistance gene (ARG) profiles of 20 surface water locations in Kewaunee County to better understand relationships between agricultural contamination and ARG abundance over one year. Surface water (n = 101) and bed sediment (n = 93) were collected from 20 sites during five timepoints between July 2016 and May 2017. Samples were analyzed for six genes (erm(B), tet(W), sul1, qnrA, intI1 and 16S rRNA) and water chemistry and pollution indicators. qnrA, intI1 and sul1 genes in surface water were significantly higher than erm(B) and tet(W); however, no difference was present in sediment samples. Redundancy analysis identified positive correlations of nitrate, Escherichia coli, and coliforms with tet(W) and intI1 genes in sediment and intI1, sul1 and tet(W) genes in water. Temporal patterns of ARG abundance were identified with significantly higher gene abundances found in sediment during Kewaunee County's manure fertilization period; however, surface water patterns were not distinct. Together, these results suggest Kewaunee County sediments serve as a site of accumulation for non-point source agricultural pollution and ARGs on a temporal scale associated with manure fertilization.

https://ift.tt/2OqPkcj

Circulating PGRN Levels Are Increased but Not Associated with Insulin Sensitivity or β-Cell Function in Chinese Obese Children

Progranulin (PGRN), a novel peptide that has recently emerged as an important regulatory adipokine, is relevant to energy homeostasis and obesity in animals and adult humans. Little is known about its roles in children. The aim of the current study was to determine the potential role of PGRN and explore its relationship to various obesity-related markers in obese children. This was a cross-sectional study composed of 77 children (43 obese and 34 healthy, age 8.68 ± 0.28 and 8.46 ± 0.45 years, resp.). The PGRN levels were significantly higher in obese children (102.44 ± 4.18 ng/mL) comparing to controls (69.32 ± 5.49 ng/mL) (). Moreover, the PGRN levels were positively correlated with triglyceride (TG), total cholesterol (TC), IL-6, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in obese children after adjusted for BMI and age. However, there was no correlation of serum PGRN levels with OGTT-derived dynamic parameters, HOMA-IR, or HOMA-β in obese children. The results suggest that serum PGRN levels are significantly higher in obese children in China and correlate significantly with obesity-related markers. Increased PGRN levels may be involved in the pathological mechanism of childhood obesity.

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A Comparison of Ki67, Syndecan-1 (CD138), and Molecular RANK, RANKL, and OPG Triad Expression in Odontogenic Keratocyts, Unicystic Ameloblastoma, and Dentigerous Cysts

Background and Objective. Reduced expression of syndecan-1 (CD138), increased proliferation index, and modifications in the expression of the molecular RANK/RANKL/OPG triad are related to an intensified potential of aggressiveness and invasion of diverse tumors and cysts. The aim was to compare the expression of Ki-67, CD138, and the molecular triad RANK, RANKL, and OPG in odontogenic keratocysts (OKC), unicystic ameloblastomas (UA), and dentigerous cysts (DC). Methods. Immunohistochemistry for Ki-67, CD138, RANK, RANKL, and OPG was performed in 58 odontogenic cystic lesions (22 OKC, 17 DC, and 19 UA). Results. A higher expression of Ki-67 was identified in OKC as compared to UA (). UA exhibited a greater loss of CD138 expression versus OKCs (). RANKL was expressed higher in the epithelium () and in the stroma () of UA. DC had a lower expression of these markers. Conclusion. Higher RANKL expression together with the reduction on CD138 expression in UA could be linked to a greater invasive and destructive potential, while the increased proliferation rate observed in OKC could be related to its continuous intrabony growth. The expansion of DC does not seem to be related to such factors, justifying the different therapeutic approaches proposed for each of these entities.

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Yinzhihuang oral liquid combined with phototherapy for neonatal jaundice: a systematic review and meta-analysis of randomized clinical trials

Neonatal jaundice affects at least 481,000 newborns every year. Phototherapy is recommended but it's effects are limited and adverse reactions can occur. In China, phototherapy combined with Yinzhihuang oral l...

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Disseminated Tuberculosis Presenting as Chronic Orchiepididymitis in a Military Trainee: A Case Report and Review of the Literature

Orchiepididymitis is a clinical diagnosis. The acute form secondary to sexually transmitted or enteric pathogens is well known to primary care providers. However, chronic orchiepididymitis may be secondary to genitourinary tuberculosis (TB), and physicians in countries with a low prevalence of TB might not consider it in their differential diagnosis. Indeed, cognitive errors, such as anchoring or availability bias, may contribute to a delayed diagnosis of genitourinary TB. We present a case of chronic orchiepididymitis as a result of disseminated TB in a Cameroonian male who was visiting the United States for military training. He experienced diagnostic delay and was ultimately diagnosed by orchiectomy. Early consideration of a diagnosis of TB for chronic or recurrent orchiepididymitis in a patient with epidemiologic risk factors is of utmost importance because delayed diagnosis could lead to organ loss.

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Ectopic expression of band 3 anion transport protein in colorectal cancer revealed in an autoimmune hemolytic anemia patient

Cancer patients occasionally have anemia with high mean corpuscular volume in addition to iron deficiency anemia. Secondary autoimmune hemolytic anemia (AIHA) following cancer is also observed with low frequency. To date, no causal mechanisms for these disease states have been reported. Here, we present the case of an 80-year-old woman with AIHA that was resistant to prednisolone. Further examinations revealed primary adenocarcinoma of the sigmoid colon and primary squamous cell carcinoma in the right lung.

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A Call To Arms: Radiation Therapy Quality Assurance In The Next Generation Of Clinical Trials

The fervor surrounding immunotherapy has resulted in an unprecedented progression from safety and efficacy studies to large-scale randomized trials across the oncology trials landscape. As we embark on the journey of investigating these new agents, we should pause to remember the successes and mistakes of the past. Championing the role of the quality assurance in radiotherapy (RT-QA) clinical trials is one of these successes.

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P30. A novel application of the Phase-lag-Index in functional connectivity research

The phase-lag-index (PLI) (Stam et al., 2007) is a commonly used method to quantify functional connectivity (FC) in EEG/MEG data. When calculated for short epochs in the order of several seconds, PLI varies considerably from epoch to epoch. Using resting-state EEG data from 105 healthy subjects, we demonstrate that the pattern of correlations between PLI time-series is characteristic for an individual's brain. In addition to acting as an identifying fingerprint, this pattern is also highly gender-specific and bears characteristics that are shared among people and also between hemispheres.

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Circumcision status at HIV infection is not associated with plasma viral load in men: analysis of specimens from a randomized controlled trial

Male circumcision provides men with approximately 60% protection from acquiring HIV infection via heterosexual sex, and has become a key component of HIV prevention efforts in sub-Saharan Africa. Possible mech...

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Maternal vaginal colonization with selected potential pathogens of neonatal sepsis in the era of antimicrobial resistance, a single center experience from Sri Lanka

Maternal vaginal colonization with antibiotic resistant organisms is a growing concern in countries with high antibiotic resistance rates.

https://ift.tt/2LGMMbf

AIDS-related opportunistic illnesses and early initiation of HIV care remain critical in the contemporary HAART era: a retrospective cohort study in Taiwan

No study has reported the epidemiology of AIDS-related opportunistic illnesses (AOIs) in patients with newly diagnosed HIV infection in Taiwan in the past decade. Understanding the current trends in AOI-relate...

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A case of Naegleria fowleri related primary amoebic meningoencephalitis in China diagnosed by next-generation sequencing

Primary amoebic meningoencephalitis (PAM), caused by Naegleria fowleri, is a rare protozoan infectious disease in China. A fatality rate of over 95% had been reported due to extremely rapid disease progression in...

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Using the Influenza Patient-reported Outcome (FLU-PRO) diary to evaluate symptoms of influenza viral infection in a healthy human challenge model

In clinical studies involving a healthy volunteer human challenge model, a valid and reliable measure to assess the evolution of patient-reported symptom type and severity following viral exposure is necessary...

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Perineal squamous cell carcinoma arising from an epidermal cyst: a case report

Abstract

Background

Epidermal cysts and squamous cell carcinomas (SCCs) are common skin lesions. However, a malignant change in an epidermal cyst is very rare. The incidence of a malignant change from an epidermal cyst to cutaneous SCC is 0.011–0.045%. In particular, malignant transformation of an epidermal cyst in the perineum is extremely rare. To date, three cases have been reported in the English literature.

Case presentation

We report a case of 51-year-old male with an approximately 15-cm perineal mass. This mass started to grow suddenly 4 months previously and caused great discomfort in the perineum due to the large size. The patient underwent excision of the mass with a negative margin. Histopathological analysis confirmed a microinvasive SCC arising from a proliferating epidermoid cyst.

Conclusions

Even if benign tumors are suspected, a change in size, pain, ulceration, or discharge should indicate the need for surgical resection due to the possibility of a malignant change.

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Molecular characterization of extended spectrum β -lactamases enterobacteriaceae causing lower urinary tract infection among pediatric population

The β-lactam antibiotics have traditionally been the main treatment of Enterobacteriaceae infections, nonetheless, the emergence of species producing β- Lactamases has rendered this class of antibiotics largel...

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Intra-hospital differences in antibiotic use correlate with antimicrobial resistance rate in Escherichia coli and Klebsiella pneumoniae: a retrospective observational study

Monitoring antimicrobial use and resistance in hospitals are important tools of antimicrobial stewardship programs. We aimed to determine the association between the use of frequently prescribed antibiotics an...

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Estimating metabolic equivalents for activities in daily life using acceleration and heart rate in wearable devices

Herein, an algorithm that can be used in wearable health monitoring devices to estimate metabolic equivalents (METs) based on physical activity intensity data, particularly for certain activities in daily life...

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Adipo-Clear: A Tissue Clearing Method for Three-Dimensional Imaging of Adipose Tissue

Due to the high lipid content, adipose tissue has been challenging to visualize using traditional histological methods. Adipo-Clear is a tissue clearing technique that allows robust labeling and high-resolution volumetric fluorescent imaging of adipose tissue. Here, we describe the methods for sample preparation, pretreatment, staining, clearing, and mounting for imaging.

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In Vitro Reconstitution of Self-Organizing Protein Patterns on Supported Lipid Bilayers

We provide a protocol for in vitro self-organization assays of MinD and MinE on a supported lipid bilayer in an open chamber. Additionally, we describe how to enclose the assay in lipid-clad PDMS microcompartments to mimic in vivo conditions by reaction confinement.

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Sampling, Sorting, and Characterizing Microplastics in Aquatic Environments with High Suspended Sediment Loads and Large Floating Debris

Most microplastic research to date has occurred in marine systems where suspended solid levels are relatively low. Focus is now shifting to freshwater systems, which may feature high sediment loads and floating debris. This protocol addresses collecting and analyzing microplastic samples from aquatic environments that contain high suspended solid loads.

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A Volumetric Method for Quantification of Cerebral Vasospasm in a Murine Model of Subarachnoid Hemorrhage

The goal of this article is to present a method that allows a 3-dimensional reconstruction of the cerebrovascular tree in mice after micro computed tomography and determination of volumes of entire vessel segments that can be used to quantify cerebral vasospasm in murine models of subarachnoid hemorrhage.

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Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells

Abstract

Cholangiocarcinoma (CCA) is a cancer of the bile ducts that is associated with poor prognosis and poor treatment outcome. Approximately one-third of CCA patients can undergo surgery, but the recurrence rate is high and chemotherapy often cannot satisfactorily prolong survival. Cellular immunotherapy based on adoptive T-cell transfer is a potential treatment for CCA; however, the development of this technology and the search for an appropriate tumor-associated antigen are still ongoing. To enhance the cytotoxic activity of effector T cells against CCA, we developed self-differentiated monocyte-derived dendritic cells (SD-DC) presenting cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A), which is an overexpressed protein that plays a role in the regulation of tumor growth to activate T cells for CCA cell killing. Dendritic cells (DCs) transduced with lentivirus harboring tri-cistronic cDNA sequences (SD-DC-PR) could produce granulocyte–macrophage colony-stimulating factor, interleukin-4, and PRKAR1A. SD-DC showed similar phenotypes to those of DCs derived by conventional method. Autologous effector T cells (CD3+, CD8+) activated by SD-DC-PR exhibited greater cytotoxic activity against CCA than those activated by conventionally-derived DCs. Effector T cells activated by SD-DC-PR killed 60% of CCA cells at an effector-to-target ratio of 15:1, which is approximately twofold greater than the cell killing performance of those stimulated with control DC. The cytotoxic activities of effector T cells activated by SD-DC-PR against CCA cells were significantly associated with the expression levels of PRKR1A in CCA cells. This finding that SD-DC-PR effectively stimulated autologous effector T cells to kill CCA cells may help to accelerate the development of novel therapies for treating CCA.

https://ift.tt/2Ok3pIt

Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells

Abstract

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Application of Elemental Lanthanides in the Selective C-F Activation of Trifluoromethylated Benzofulvenes Providing Access to Various Difluoroalkenes

This protocol describes the preparation of elemental lanthanides under inert atmosphere and their application in a selective C-F activation process involving trifluoromethylated benzofulvenes.

https://ift.tt/2uUsukS

Bedside Ultrasound for Guiding Fluid Removal in Patients with Pulmonary Edema: The Reverse-FALLS Protocol

We describe an imaging protocol that enables the clinician to visualize, in real-time, the patient's intravascular and extravascular space volumes and set diuresis and fluid removal parameters accordingly for the safe and efficient treatment of pulmonary edema.

https://ift.tt/2LTcE0r

Fish Sperm Assessment Using Software and Cooling Devices

The present protocol describes a procedure of fish sperm assessment using computer-assisted sperm analysis and cooling devices. The software gives a rapid, accurate and quantitative analysis of fish sperm quality based on spermatozoa motility, which can be a useful tool in aquaculture to improve reproduction success.

https://ift.tt/2LJsWMt

Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression

Abstract

Background

Adaptation to ER stress has been indicated to play an important role in resistance to therapy in human melanoma. However, the relationship between adaptation to ER stress and cell metastasis in human melanoma remains unclear.

Methods

The relationship of adaptation to ER stress and cell metastasis was investigated using transwell and mouse metastasis assays. The potential molecular mechanism of KLF4 in regulating the adaptation to ER stress and cell metastasis was investigated using RNA sequencing analysis, q-RT-PCR and western blot assays. The transcriptional regulation of nucleobindin 2 (NUCB2) by KLF4 was identified using bioinformatic analysis, luciferase assay, and chromatin immunoprecipitation (ChIP). The clinical significance of KLF4 and NUCB2 was based on human tissue microarray (TMA) analysis.

Results

Here, we demonstrated that KLF4 was induced by ER stress in melanoma cells, and increased KLF4 inhibited cell apoptosis and promoted cell metastasis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of NUCB2, facilitating its transcription. Additionally, an increase in KLF4 promoted melanoma ER stress resistance, tumour growth and cell metastasis by regulating NCUB2 expression in vitro and in vivo. Elevated KLF4 was found in human melanoma tissues, which was associated with NUCB2 expression.

Conclusion

Our data revealed that the promotion of ER stress resistance via the KLF4-NUCB2 axis is essential for melanoma cell metastasis, and KLF4 may be a promising specific target for melanoma therapy.

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EMCrit – When it comes to Preintubation Terminology we stink like POO

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What we have here is a failure to communicate

EMCrit Project by Scott Weingart.

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Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma

https://ift.tt/2mMZI18

First-in-human study of LY3039478, an Oral Notch signaling inhibitor in advanced or metastatic cancer

Abstract

Background

Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. Gamma-secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer.

Methods

This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5–100 mg, TIW on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478.

Results

A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared to 75 mg. The pharmacokinetics of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an approximately 80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1 and Notch-regulated ankyrin repeat at 45-to 100-mg dose. Clinical activity (tumor necrosis, metabolic response or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma.

Conclusion

Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing.

Clinicaltrials.gov ID

NCT01695005

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Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study

Abstract

Background

Venetoclax is a selective, potent inhibitor of the anti-apoptotic BCL-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).

Patients and methods

BR was given for 6 cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50mg–1200mg daily doses. Co-primary objectives included safety, pharmacokinetics, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D); secondary objective was preliminary efficacy.

Results

Sixty patients were enrolled: 32 with follicular lymphoma (FL), 22 with diffuse large B-cell lymphoma (DLBCL), and 6 with marginal zone lymphoma (MZL). Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax pharmacokinetic exposure with and without BR was comparable. For all patients, overall response rate (ORR) was 65%. Median duration of overall response (DOR), overall survival (OS), and progression-free survival (PFS) was 38.3 months (95% confidence interval (CI): 10.4–NR), not yet reached, and 10.7 months (95% CI: 4.3–21.0), respectively.

Conclusions

This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.

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Toxicity of oxaliplatin rechallenge in metastatic colorectal cancer

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Phase 3, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment for patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

Abstract

Background

There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase 3 JAVELIN Gastric 300 trial compared avelumab vs physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.

Patients and methods

Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m² on days 1, 8, and 15 or irinotecan 150 mg/m² on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety.

Results

A total of 371 patients were randomised. The trial did not meet its primary endpoint of improving OS (median, 4.6 vs 5.0 months; hazard ratio [HR] = 1.1 [95% CI 0.9–1.4]; P = 0.81) or the secondary endpoints of PFS (median, 1.4 vs 2.7 months; HR = 1.73 [95% CI 1.4–2.2]; P > 0.99) or ORR (2.2% vs 4.3%) in the avelumab vs chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.

Conclusions

Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared to chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.

Trial registration

ClinicalTrials.gov: NCT02625623

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HER2 status in patients with residual rectal cancer after preoperative chemoradiotherapy: the relationship with molecular results and clinicopathologic features

Abstract

The specific role of human epidermal growth factor receptor-2 (HER2) status in rectal cancers remains unclear. This study therefore aimed to explore clinicopathologic and molecular characteristics, and prognostic value of HER2-positivity in residual mid- and/or low-rectal cancers after preoperative chemoradiotherapy (CRT). Surgical specimens from 145 patients with residual rectal cancer after preoperative CRT between January 2006 and January 2011 were used to evaluate HER2 status. HER2 protein expression and gene amplification were determined using immunohistochemistry (IHC) and silver in situ hybridization (SISH) on whole tissue sections, respectively. Polymerase chain reaction was used to analyze molecular characteristics, including microsatellite instability (MSI) and mutations in KRAS exon 2 (codon 12 and 13) and BRAF V600E mutation. Of 139 eligible patients, 8 (5.8%) had HER2 overexpression (IHC 2+ and 3+) that was not associated with clinicopathologic characteristics and patient survival, except positive circumferential resection margin (CRM) (P = 0.012). SISH was performed on 24 patient samples with IHC 1+ (n = 16), 2+ (n = 6), and 3+ (n = 2). HER2 amplification was identified in 3 patients (2.2%); however, this was also associated with positive CRM (P = 0.009) but not survival (all P > 0.05). Moreover, HER2 overexpression and amplification had no relationship with KRAS or BRAF mutations, and MSI status (all P > 0.05). HER2 positivity was found in a minority of rectal cancer patients and was not significantly associated with clinicopathologic and molecular characteristics. Our findings can be helpful in understanding the clinicopathologic bases of HER2 status in rectal cancers.

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Cancers, Vol. 10, Pages 250: The Tip of an Iceberg: Replication-Associated Functions of the Tumor Suppressor p53

Cancers, Vol. 10, Pages 250: The Tip of an Iceberg: Replication-Associated Functions of the Tumor Suppressor p53

Cancers doi: 10.3390/cancers10080250

Authors: Vanesa Gottifredi Lisa Wiesmüller

The tumor suppressor p53 is a transcriptional factor broadly mutated in cancer. Most inactivating and gain of function mutations disrupt the sequence-specific DNA binding domain, which activates target genes. This is perhaps the main reason why most research has focused on the relevance of such transcriptional activity for the prevention or elimination of cancer cells. Notwithstanding, transcriptional regulation may not be the only mechanism underlying its role in tumor suppression and therapeutic responses. In the past, a direct role of p53 in DNA repair transactions that include the regulation of homologous recombination has been suggested. More recently, the localization of p53 at replication forks has been demonstrated and the effect of p53 on nascent DNA elongation has been explored. While some data sets indicate that the regulation of ongoing replication forks by p53 may be mediated by p53 targets such as MDM2 (murine double minute 2) and polymerase (POL) eta other evidences demonstrate that p53 is capable of controlling DNA replication by directly interacting with the replisome and altering its composition. In addition to discussing such findings, this review will also analyze the impact that p53-mediated control of ongoing DNA replication has on treatment responses and tumor suppressor abilities of this important anti-oncogene.

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Inter-institutional variations regarding Barrett’s esophagus diagnosis

Abstract

Background

Barrett's esophagus (BE) is a known precursor for development of esophageal adenocarcinoma and surveillance of affected patients is necessary when cancer progression risk is considered to be high. However, the accuracy of BE diagnosis may not be homogenous among institutions with endoscopy units. We investigated inter-institutional variability by examining the accuracy of endoscopic diagnosis of BE at 4 different hospitals.

Methods

The accuracy of BE diagnosis at the 4 hospitals was retrospectively reviewed by 6 expert endoscopists, who independently reviewed endoscopic images of approximately 500 consecutive patients examined at each hospital without information regarding the diagnosis by the on-site endoscopists. When the expert reviewers made different diagnosis, a final diagnosis was made by consensus. That was then compared with the diagnosis of the attending endoscopists at each hospital and their concordance was calculated separately for each endoscopy unit. In addition, the relationship between diagnostic accuracy and endoscopic experience was assessed.

Results

The prevalence of BE diagnosis by the on-site endoscopists was not homogenous and varied widely (17.2–96.8%). In 1 hospital, over-diagnosis was the cause of dissimilarity, while under-diagnosis was the cause in two hospitals. Diagnostic accuracy by the attending endoscopists in all 4 hospitals ranged from 44.6 to 83.1% (P < 0.05). There was no significant association between diagnostic accuracy and endoscopic experience or board licensing status of the on-site endoscopists.

Conclusion

Diagnostic accuracy for BE was not homogenous among 4 hospitals, and problems related to over- and under-diagnosis should be considered.

https://ift.tt/2NQNiAR

Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study

Abstract

Introduction

The utility of immunotherapy in elderly melanoma patients is debated. We aimed in this study to evaluate the efficacy and tolerability of immunotherapy among elderly patients.

Method

This is a retrospective single-institution cohort study. Patients aged 75 years and above who had been treated with nivolumab, pembrolizumab or ipilimumab for advanced or metastatic melanoma, were included. Patients and disease characteristics were collected using electronic medical records. Objective response was determined according to the immune-related response criteria. Drug-related toxicities (DRT) were graded according to the CTCAE v4.03.

Results

99 patients were included with a mean age of 80 years (SD = 4). One patient received nivolumab and ipilimumab combination, but died because of drug-related diverticulitis. Median PFS on pembrolizumab, nivolumab or ipilimumab were equal to 11.9 (95% CI 5.4–18.4), 1.4 (95% CI 0.01–2.8), and 2.8 months (95% CI 2.6-3), respectively, while objective response rates were equal to 51.6, 12.5, and 17.3%, respectively. Median OS was not reached in patients who received only pembrolizumab, 8.7 months in the ipilimumab only group, and 23 months in patients receiving several immune therapies sequentially. Pembrolizumab, nivolumab, and ipilimumab grade 3–4 DRT rates were equal to 24.2, 62.5, and 32.7% respectively, while discontinuation rates were equal to 43.5, 62.5, and 28.8%, respectively.

Conclusions

Our study suggests that immunotherapy is effective and well tolerated in the elderly. The PFS on pembrolizumab was greater than expected, a finding that needs to be investigated further.

https://ift.tt/2NRyF0l

Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study

Abstract

Introduction

The utility of immunotherapy in elderly melanoma patients is debated. We aimed in this study to evaluate the efficacy and tolerability of immunotherapy among elderly patients.

Method

Results

Conclusions

Our study suggests that immunotherapy is effective and well tolerated in the elderly. The PFS on pembrolizumab was greater than expected, a finding that needs to be investigated further.

https://ift.tt/2NRyF0l

A risk stratification model for nodal peripheral T-cell lymphomas based on the NCCN-IPI and posttreatment Deauville score

Abstract

Purpose

The aim of this study was to establish a risk-stratification model integrating posttreatment metabolic response using the Deauville score and the pretreatment National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) in nodal PTCLs'.

Methods

We retrospectively analysed 326 patients with newly diagnosed nodal PTCLs between January 2005 and June 2016 and both baseline and posttreatment PET/CT data. The final model was validated using an independent prospective cohort of 79 patients.

Results

Posttreatment Deauville score (1/2, 3, and 4/5) and the NCCN-IPI (low, low-intermediate, high-intermediate, and high) were independently associated with progression-free survival: for the Deauville score, the hazard ratios (HRs) were 1.00 vs. 2.16 (95% CI 1.47–3.18) vs. 7.86 (5.66–10.92), P < 0.001; and for the NCCN-IPI, the HRs were 1.00 vs. 2.31 (95% CI 1.20–4.41) vs. 4.42 (2.36–8.26) vs. 7.09 (3.57–14.06), P < 0.001. Based on these results, we developed a simplified three-group risk model comprising a low-risk group (low or low-intermediate NCCN-IPI with a posttreatment Deauville score of 1 or 2, or low NCCN-IPI with a Deauville score of 3), a high-risk group (high or high-intermediate NCCN-IPI with a Deauville score of 1/2 or 3, or low-intermediate NCCN-IPI with a Deauville score of 3), and a treatment failure group (Deauville score 4 or 5). This model was significantly associated with progression-free survival (5-year, 70.3%, 31.4%, and 4.7%; P < 0.001) and overall survival (5-year, 82.1%, 45.5%, and 14.7%; P < 0.001).", 31.4% in high-risk group and 4.7% in treatment failure group; P < 0.001) and overall survival (5-year survival, 82.1%, 45.5% and 14.7%, respectively; P < 0.001). Similar associations were also observed in the independent validation cohort.

Conclusion

The risk-stratification model integrating posttreatment Deauville score and pretreatment NCCN-IPI is a powerful tool for predicting treatment failure in patients with nodal PTCLs.

https://ift.tt/2LWPR43

Local and whole-body staging in patients with primary breast cancer: a comparison of one-step to two-step staging utilizing 18 F-FDG-PET/MRI

Abstract

Objectives

The purpose of this study was to compare the diagnostic value of a one-step to a two-step staging algorithm utilizing ¹⁸F-FDG PET/MRI in breast cancer patients.

Methods

A total of 38 patients (37 females and one male, mean age 57 ± 10 years; range 31–78 years) with newly diagnosed, histopathologically proven breast cancer were prospectively enrolled in this trial. All PET/MRI examinations were assessed for local tumor burden and metastatic spread in two separate reading sessions: (1) One-step algorithm comprising supine whole-body ¹⁸F-FDG PET/MRI, and (2) Two-step algorithm comprising a dedicated prone ¹⁸F-FDG breast PET/MRI and supine whole-body ¹⁸F-FDG PET/MRI.

Results

On a patient based analysis the two-step algorithm correctly identified 37 out of 38 patients with breast carcinoma (97%), while five patients were missed by the one-step ¹⁸F-FDG PET/MRI algorithm (33/38; 87% correct identification). On a lesion-based analysis 56 breast cancer lesions were detected in the two-step algorithm and 44 breast cancer lesions could be correctly identified in the one-step ¹⁸F-FDG PET/MRI (79%), resulting in statistically significant differences between the two algorithms (p = 0.0015). For axillary lymph node evaluation sensitivity, specificity and accuracy was 93%, 95 and 94%, respectively. Furthermore, distant metastases could be detected in seven patients in both algorithms.

Conclusion

The results demonstrate the necessity and superiority of a two-step ¹⁸F-FDG PET/MRI algorithm, comprising dedicated prone breast imaging and supine whole-body imaging, when compared to the one-step algorithm for local and whole-body staging in breast cancer patients.

https://ift.tt/2LFotKS

Cancers, Vol. 10, Pages 249: Multimodal Radiomic Features for the Predicting Gleason Score of Prostate Cancer

Cancers, Vol. 10, Pages 249: Multimodal Radiomic Features for the Predicting Gleason Score of Prostate Cancer

Cancers doi: 10.3390/cancers10080249

Authors: Ahmad Chaddad Michael J Kucharczyk Tamim Niazi

Background: Novel radiomic features are enabling the extraction of biological data from routine sequences of MRI images. This study’s purpose was to establish a new model, based on the joint intensity matrix (JIM), to predict the Gleason score (GS) of prostate cancer (PCa) patients. Methods: A retrospective dataset comprised of the diagnostic imaging data of 99 PCa patients was used, extracted from The Cancer Imaging Archive’s (TCIA) T2-Weighted (T2-WI) and apparent diffusion coefficient (ADC) images. Radiomic features derived from JIM and the grey level co-occurrence matrix (GLCM) were extracted from the reported tumor locations. The Kruskal-Wallis test and Spearman’s rank correlation identified features related to the GS. The Random Forest classifier model was implemented to identify the best performing signature of JIM and GLCM radiomic features to predict for GS. Results: Five JIM-derived features: contrast, homogeneity, difference variance, dissimilarity, and inverse difference were independent predictors of GS (p < 0.05). Combined JIM and GLCM analysis provided the best performing area-under-the-curve, with values of 78.40% for GS ≤ 6, 82.35% for GS = 3 + 4, and 64.76% for GS ≥ 4 + 3. Conclusion: This retrospective study produced a novel predictive model for GS by the incorporation of JIM data from standard diagnostic MRI images.

https://ift.tt/2Aj5j96

Freshwater copepod carcasses as pelagic microsites of dissimilatory nitrate reduction to ammonium

Abstract

A considerable fraction of freshwater zooplankton was recently found to consist of dead specimens that sink to the lake bottom. Such carcasses host intense microbial activities that may promote oxygen depletion at the microscale. Therefore, we tested the hypothesis that sinking zooplankton carcasses are microsites of anaerobic nitrogen cycling that contribute to pelagic fixed-nitrogen loss even in the presence of ambient oxygen. Incubation experiments were performed with the ubiquitous copepods Eudiaptomus sp. and Megacyclops gigas at different ambient oxygen levels that sinking carcasses encounter during their descent in stratified lakes. ¹⁵N-stable-isotope incubations revealed intense carcass-associated anaerobic nitrogen cycling only at low ambient oxygen levels (<25% air saturation). Dissimilatory nitrate reduction to ammonium (DNRA) dominated over denitrification and thus the potential for fixed-nitrogen loss was low. Consistent with this partitioning of anaerobic nitrogen cycling, the relative abundance of the carcass-associated marker gene for DNRA (nrfA) was ∼20–400 times higher than that for denitrification (nirS). Additionally, the relative nrfA and nirS abundances were ∼90–180 times higher on copepod carcasses than in lake water. This functional distinctiveness of carcass-associated bacterial communities was further substantiated by 16S rDNA-based fingerprinting. We conclude that the unique bacterial communities and microenvironments provided by zooplankton carcasses influence pelagic nitrogen cycling in lakes, but mainly at seasonally low ambient O₂ levels in the bottom water.

https://ift.tt/2Ls96pT

Assessment of Sep1virus interaction with stationary cultures by transcriptional and flow cytometry studies

Abstract

The majority of phage infection studies are performed in bacteria that are growing exponentially, although in nature, phages usually interact also with non-replicating cells. These stationary-phase cells differ from exponential cells morphologically, physiologically and metabolically. The interaction of a Sep1virus with Staphylococcus epidermidis stationary and exponential phase cells was explored. Phage SEP1 efficiently infected both cell culture states, without the addition of any fresh nutrients to stationary cultures. Phage-host interactions, analysed by flow cytometry, showed stationary-phase cells response to phage immediately after SEP1 addition. Quantitative PCR experiments corroborate that phage genes are expressed within 5 min of contact with stationary phase cells. The increase of host RNA polymerase transcripts in stationary cells, suggests that SEP1 infection leads to upregulation of host machinery fundamental for completion of its lytic life cycle. SEP1 infection and replication process highlights its potential clinical interest targeting stationary phase cells.

https://ift.tt/2vdlorg

Pancreatic adenocarcinoma: insights into patterns of recurrence and disease behavior

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with high metastatic potential. Clinical observations suggest that there is disease heterogeneity among patients with different sites of distant metastases, yielding distinct clinical outcomes. Herein, we investigate the impact of clinical and pathological parameters on recurrence patterns and compare survival outcomes for patients with a first site of recurrence in the liver versus lung from PDAC following original curative surgical resection.

Methods

Using the Memorial Sloan Kettering Cancer Center ICD billing codes and tumor registry database over a 10 years period (January 2004–December 2014), we identified PDAC patients who underwent resection and subsequently presented with either liver or lung recurrence. Time from relapse to death (TRD) was calculated from date of recurrence to date of death. Using the Kaplan-Meier method, TRD was estimated and compared by recurrence site using log-rank test.

Results

The median overall follow-up was 37.3 months among survivors in the entire cohort. Median TRD in this cohort was 10.7 months (95%CI: 8.9–14.6 months). Patients with first site of lung recurrence had a more favorable outcome compared to patients who recurred with liver metastasis as the first site of recurrence (median TRD of 15 versus 9 months respectively, P = 0.02). Moderate to poorly or poor differentiation was associated more often with liver than lung recurrence (40% vs 21% respectively, P = 0.047). A trend to increased lymph node metastasis in the lung recurrence cohort was observed.

Conclusion

PDAC patients who recur with a first site of lung metastasis have an improved clinical outcome compared to patients with first site of liver recurrence. Our data suggests there may be epidemiologic and pathologic determinants related to patterns of recurrence in PDAC.

https://ift.tt/2mNLOMl

CD36 – a plausible modifier of disease phenotype in familial adenomatous polyposis

Abstract

Background

Familial adenomatous polyposis (FAP) is a well characterised genetic predisposition to early onset colorectal cancer (CRC) that is characterised by polyposis of the colon and rectum. Animal models have consistently suggested the role of modifier genes in determining disease phenotype, yet none have been substantiated in the human population. The mouse homologue of cluster of differentiation 36 (CD36) has been proposed as a modifier of disease in the MIN mouse model of FAP.

Methods

Three single nucleotide polymorphisms (SNPs); rs1049673, rs1761667 and rs1984112 in CD36, have been investigated in 275 FAP patients to determine if they were associated with age of polyposis or risk of developing disease.

Results

The results revealed a substantially lower age of polyposis diagnosis for patients belonging to the severe FAP group (harbouring adenomatous polyposis coli (APC) variants in the mutation cluster region (MCR)) and high age for patients in the attenuated familial adenomatous polyposis (AFAP) group for SNPs rs1761667 and rs1984112.

Conclusions

This study provides evidence for patients belonging to the MCR and AFAP groups harbouring specific genotypes for SNPs in CD36 to initiate screening/treatment for FAP at much earlier (MCR) and much later (AFAP) ages than the norm in today's clinical practice. The findings need to be verified in an independent FAP patient cohort.

https://ift.tt/2AhMB1z

Radium and other alpha emitters in prostate cancer.

Radium and other alpha emitters in prostate cancer.

Transl Androl Urol. 2018 Jun;7(3):436-444

Authors: Sartor O, Sharma D

Abstract
223Radium (223Ra) is the first alpha-emitting therapy proven effective in human cancer. Prospective randomized trials indicate that 223Ra, which concentrates after intravenous injection in areas of osteoblastic metastatic disease, can prolong survival in bone-dominant castrate resistant prostate cancer patients. Though radium isotopic therapy is conceptually critical to demonstrate that alpha emitters can be safe and effective, 223Ra has inherent limitations given its restriction to bone metastatic disease. To overcome this limitation, targeted alpha therapy (TAT) is now being actively evaluated in prostate cancer, and other neoplasms. Key to TAT in prostate tumors in current studies is the overexpression of prostate specific membrane antigen (PSMA), a folate hydrolase expressed on the cell surface of malignant adenocarcinomas of the prostate. Using PSMA targeting (small molecules or antibodies), alpha emitting agents such as 225Actinium (225Ac) or 213Bismuth (213Bi) can be delivered to PSMA expressing tumors regardless of their metastatic location. Initial results from TAT in prostate cancer are highly promising and rapid development of these agents is anticipated in the years ahead assuming adequacy of isotope availability and appropriate clinical trial design. TAT may be develop as an independent approach, or synergize with a variety of other approaches including external beam radiation, hormonal therapies, chemotherapies, various radiation sensitizers, DNA repair inhibitors, and/or immune modulators. Clinical investigation opportunities in this field will rapidly increase in the years ahead.

PMID: 30050802 [PubMed]

https://ift.tt/2uXazKt

Randomised, open-label, multicentre trial comparing haemodialysis plus haemoperfusion versus haemodialysis alone in adult patients with end-stage renal disease (HD/HP vs HD): study protocol

Introduction

Haemodialysis (HD) is the cornerstone treatment for patients with end-stage renal disease (ESRD). However, highly protein bound or large molecular weight uremic toxins such as phenolic and indolic compounds and homocysteine, which are associated with adverse outcomes such as cardiovascular disease of patients with ESRD, are difficult to remove via HD but can be effectively eliminates by haemoperfusion (HP). The proposed trial (referred to as HD/HP vs HD below) is a randomised, open-label, multicentre trial comparing HD plus HP versus HD alone in adult patients with ESRD. The primary endpoint measure is all-cause mortality.

Methods and analysis

We plan to enrol 1364 maintenance HD patients from 11 medical centres in Shanghai. Participants will be randomised to receive HD plus HP or HD alone at a 1:1 ratio after 1-month run-in period. In both arms, patients will receive low-flux HD at a frequency of two times a week and haemodiafiltration at a frequency of once a week. In the intervention group, subjects also received HP once every 2 weeks. Follow-up is scheduled at 3, 6, 12, 18 and 24 months after randomisation, and will consist the following: routine physical examinations, standard lab panels (blood routine, liver/residual kidney functions, tests of the coagulation system, etc), dialysis adequacy (standard Kt/V), chest X-ray, ECG, echocardiography, heart function rating. Adverse events will be assessed according to the international conference on harmonisation guidelines. The primary outcome is 24-month all-cause mortality. Secondary outcomes will include cardiovascular-related mortality, the occurrence of major cardiovascular events and the quality of life.

Ethics and dissemination

The study protocol has been approved by the Ethical Committees of all 11 participating centres. Clinical Research Unit of Xin Hua Hospital will oversee the study. The results will be presented at national and international academic meetings, and submitted to peer-reviewed journals for publications.

Trial registration number

NCT03227770; Pre-results.

https://ift.tt/2NSI4F0

Volume-outcome relationship in transcatheter aortic valve implantations in Germany 2008-2014: a secondary data analysis of electronic health records

Objectives

We examine the volume–outcome relationship in isolated transcatheter aortic valve implantations (TAVI). Our interest was whether the volume–outcome relationship for TAVI exists on the centre level, whether it occurs equally for different outcomes and how it develops over time.

Design

Secondary data analysis of electronic health records. The comprehensive German Federal Bureau of Statistics Diagnosis Related Groups database was queried for data on all isolated TAVI procedures performed in Germany between 2008 and 2014. Logistic and linear regression analyses were carried out. Risk adjustment was applied using a predefined set of patient characteristics to account for differences in the risk factor composition of the patient populations between centres and over time. Centres performing TAVI were stratified into groups performing <50, 50–99 and ≥100 procedures per year.

Setting

Germany 2008–2014.

Participants

All patients undergoing isolated TAVI in the observation period.

Interventions

None.

Primary and secondary outcome measures

In-hospital mortality, bleeding, stroke, probability of ventilation >48 hours, length of hospital stay and reimbursement.

Results

Between 2008 and 2014, a total of 43 996 TAVI procedures were performed in 113 different centres in Germany with a total of 2532 cases of in-hospital mortality. Risk-adjusted in-hospital mortality decreases over the years and is lower the higher the annual procedure volume at the centre is. The magnitude of the latter effect declines over the observation period. Our results indicate a ceiling effect in the volume–outcome relationship: the volume–outcome relationship is eminent in circumstances of relatively unfavourable outcomes. Alongside improving outcomes, however, the volume–outcome relationship decreases. Also, a volume–outcome relationship seems to be absent in circumstances of constantly low event rates.

Conclusions

The hypothesised volume–outcome relationship for TAVI exists but diminishes and may disappear over time. This should be taken into account when considering mandatory minimum thresholds.

https://ift.tt/2LErriV

Life after breast cancer: moving on, sitting down or standing still? A prospective study of Canadian breast cancer survivors

Introduction

Breast cancer (BC) is associated with serious physical and psychological health sequelae that affect quality and quantity of life. Physical activity (PA) and sedentary behaviour can prevent or diminish these sequelae; yet, little is known about how these lifestyle behaviours change after cancer treatment and if these changes affect post-treatment health. The first aim of this study is to describe natural trends in lifestyle behaviours (ie, PA, sedentary behaviour) in women treated for BC. The second aim is to examine the longitudinal associations between lifestyle behaviour changes and (1) physical health (eg, acute symptoms, chronic conditions, body composition, patient-reported fatigue, pain and functioning), (2) psychological health and illness (eg, depression, stress, affect, post-traumatic growth, cancer worry, mood, body image) and (3) biological functioning (eg, cortisol and C-reactive protein). The third aim is to examine modifiable self-regulation (ie, goal adjustment strategies) and motivation constructs (ie, self-determined regulations) that predict trends in lifestyle behaviours.

Method and analysis

This is a prospective longitudinal study of 201 women treated for BC. Data (eg, surveys, accelerometers, saliva, blood) are collected every 3 months during the first year after women complete systemic treatment for a first diagnosis of BC, and once every year for 4 years thereafter. Data analyses assess trends and changes in PA and sedentary lifestyle behaviours, examine associations between these trends and changes in health outcomes and identify modifiable predictors of PA and sedentary lifestyle behaviours using multilevel modelling.

Ethics and dissemination

Ethical approval was obtained from the University of Toronto (REB# 28180) and has been funded by the Canadian Institutes of Health Research (#186128). Study findings will be disseminated through peer-reviewed publications, academic conferences, local community-based presentations such as the Canadian Cancer Society and similar organisations.

https://ift.tt/2NQMNXG

Developing a new clinical governance framework for chronic diseases in primary care: an umbrella review

Objectives

Our goal is to conceptualise a clinical governance framework for the effective management of chronic diseases in the primary care setting, which will facilitate a reorganisation of healthcare services that systematically improves their performance.

Setting

Primary care.

Participants

Chronic Care Model by Wagner et aland Clinical Governance statement by Scally et alwere taken for reference. Each was reviewed, including their various components. We then conceptualised a new framework, merging the relevant aspects of both.

Interventions

We conducted an umbrella review of all systematic reviews published by the Cochrane Effective Practice and Organisation of Care Group to identify organisational interventions in primary care with demonstrated evidence of efficacy.

Results

All primary healthcare systems should be patient-centred. Interventions for patients and their families should focus on their values; on clinical, professional and institutional integration and finally on accountability to patients, peers and society at large. These interventions should be shaped by an approach to their clinical management that achieves the best clinical governance, which includes quality assurance, risk management, technology assessment, management of patient satisfaction and patient empowerment and engagement. This approach demands the implementation of a system of organisational, functional and professional management based on a population health needs assessment, resource management, evidence-based and patient-oriented research, professional education, team building and information and communication technologies that support the delivery system. All primary care should be embedded in and founded on an active partnership with the society it serves.

Conclusions

A framework for clinical governance will promote an integrated effort to bring together all related activities, melding environmental, administrative, support and clinical elements to ensure a coordinated and integrated approach that sustains the provision of better care for chronic conditions in primary care setting.

https://ift.tt/2LL1sX4

Using primary care-based paper and telephone interventions to increase uptake of bowel scope screening in Yorkshire: a protocol of a randomised controlled trial

Introduction

Evidence suggests bowel scope screening (BSS) can significantly reduce an individual's risk of developing colorectal cancer (CRC). BSS for 55 year olds was therefore introduced to the English Bowel Cancer Screening Programme (BCSP) in 2013. However, the benefits are only gained from test completion and uptake is low (43%). Primary care involvement has consistently shown benefits to cancer screening uptake and so this study aims to build on this knowledge and evaluate general practitioner (GP) practice led interventions designed to increase BSS attendance.

Methods and analysis

A three-arm randomised controlled trial will be conducted to evaluate three interventions: one intervention for prospective BSS invitees (primer letter with locally tailored leaflet sent by an individual's GP practice) and two interventions for those who do not attend their BSS appointment (a self-referral letter sent by an individual's GP practice and a patient navigation call made on behalf of an individual's GP practice). The trial will be set in Yorkshire. Individuals soon to receive their invitation to attend BSS at one of the Hull and East Yorkshire Bowel Cancer Screening centre sites, will be randomly assigned to one of three groups: control (usual care; no input from GP practice), Intervention group A (primer letter/leaflet and a self-referral letter), Intervention group B (primer letter/leaflet and a patient navigation call). Attendance data will be obtained from the BCSP database (via National Health Service (NHS) Digital) 3 months after the last intervention. Regression analysis will compare uptake, and additional clinical outcomes, across the three groups. The analysis will be multivariate and adjust for several covariates including gender and area-level deprivation.

Ethics and dissemination

NHS ethical approval has been obtained from London-Harrow Research Ethics Committee. The results will be submitted for publication in a peer-reviewed journal and presented at conferences.

Trial registration number

ISRCTN16252122; Pre-results.

https://ift.tt/2NTzp5g

Probiotics, prebiotics and synbiotics for chronic kidney disease: protocol for a systematic review and meta-analysis

Introduction

There is a growing interest in probiotic, prebiotic and synbiotic supplements for patients with chronic kidney disease (CKD). However, a systematic review and evaluation is lacking. The purpose of the present study is to assess the efficacy and safety of probiotics, prebiotics and synbiotics for non-dialysis or non-renal transplant patients with CKD.

Methods and analysis

An extensive literature search will be undertaken to identify potentially eligible studies from electronic databases including PubMed (1946 to present), EMBASE (1974 to present), Web of Science (1900 to present) and the Cochrane Central Register of Controlled Trials (CENTRAL, all years). No language restriction will be applied to the search. Both parallel and crossover randomised controlled trials will be included. The risk of bias of each included study will be assessed using the Cochrane Risk of Bias Tool. The primary outcome measures are uraemic toxins. Secondary outcomes include kidney function, adverse cardiovascular events, all-cause mortality, cause-specific death, progression to end-stage kidney disease, quality of life, gastrointestinal function and adverse events. Data will be synthesised using appropriate statistical methods. The quality of evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.

Ethics and dissemination

No ethical approval is required as no primary data will be collected. We will publish findings from this systematic review in a peer-reviewed scientific journal, and the data set will be made freely available.

PROSPERO registration number

CRD42017079177.

https://ift.tt/2uXJ0kf

Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test indicated aspirin for pre-eclampsia prevention (TEST study): a multicentre randomised controlled trial

Objective

Evaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction.

Design

Multicentre open-label feasibility randomised controlled trial.

Setting

Two tertiary maternity hospitals in Dublin, Ireland.

Participants

546 low-risk nulliparous women completed the study.

Interventions

Women underwent computerised randomisation to: Group 1—routine aspirin 75 mg from 11 until 36 weeks; Group 2—no aspirin and; Group 3—aspirin based on the Fetal Medicine Foundation screening test.

Primary and secondary outcome measures

(1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses.

Results

546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0–26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8).

Conclusion

Low-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach.

Trial registration number

ISRCTN (15191778); Post-results.

https://ift.tt/2NS39zd

Effectiveness of drug interventions to prevent sudden cardiac death in patients with heart failure and reduced ejection fraction: an overview of systematic reviews

Objectives

To summarise and synthesise the current evidence regarding the effectiveness of drug interventions to prevent sudden cardiac death (SCD) and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF).

Design

Overview of systematic reviews.

Data sources

MEDLINE, Embase, ISI Web of Science and Cochrane Library from inception to May 2017; manual search of references of included studies for potentially relevant reviews.

Eligibility criteria for study selection

We reviewed the effectiveness of drug interventions for SCD and all-cause mortality prevention in patients with HFrEF. We included overviews, systematic reviews and meta-analyses of randomised controlled trials of beta-blockers, angiotensin-converting enzyme inhibitors (ACE-i), angiotensin receptor blockers (ARBs), antialdosterones or mineralocorticoid-receptor antagonists, amiodarone, other antiarrhythmic drugs, combined ARB/neprilysin inhibitors, statins and fish oil supplementation.

Review methods

Two independent reviewers extracted data and assessed the methodological quality of the reviews and the quality of evidence for the primary studies for each drug intervention, using Assessing the Methodological Quality of Systematic Reviews (AMSTAR) and Grading of Recommendations, Assessment, Development and Evaluation(GRADE), respectively.

Results

We identified 41 reviews. Beta-blockers, antialdosterones and combined ARB/neprilysin inhibitors appeared effective to prevent SCD and all-cause mortality. ACE-i significantly reduced all-cause mortality but not SCD events. ARBs and statins were ineffective where antiarrhythmic drugs and omega-3 fatty acids had unclear evidence of effectiveness for prevention of SCD and all-cause mortality.

Conclusions

This comprehensive overview of systematic reviews confirms that beta-blockers, antialdosterone agents and combined ARB/neprilysin inhibitors are effective on SCD prevention but not ACE-i or ARBs. In patients with high risk of SCD, an alternative therapeutic strategy should be explored in future research.

Systematic review registration

PROSPERO 2017: CRD42017067442.

https://ift.tt/2uVB0jC

Changing use of antidiabetic drugs in the UK: trends in prescribing 2000-2017

Objectives

Guidelines for the use of drugs for type 2 diabetes mellitus (T2DM) have changed since 2000, and new classes of drug have been introduced. Our aim was to describe how drug choice at initiation and first stage of intensification have changed over this period, and to what extent prescribing was in accord with clinical guidelines, including adherence to recommendations regarding kidney function.

Design

Repeated cross-sectional study.

Setting

UK electronic primary care health records from the Clinical Practice Research Datalink.

Participants

Adults initiating treatment with a drug for T2DM between January 2000 and July 2017.

Primary and secondary outcome measures

The primary outcomes were the proportion of each class of T2DM drug prescribed for initiation and first-stage intensification in each year. We also examined drug prescribing by kidney function and country within the UK.

Results

Of 280 241 people initiating treatment with T2DM drugs from 2000 to 2017, 73% (204 238/280 241) initiated metformin, 15% (42 288/280 241) a sulfonylurea, 5% (12 956/280 241) with metformin and sulfonylurea dual therapy and 7% (20 759/280 241) started other options. Clinicians have increasingly prescribed metformin at initiation: by 2017 this was 89% (2475/2778) of drug initiations. Among people with an estimated glomerular filtration rate of ≤30 mL/min/1.73 m², the most common drug at initiation was a sulfonylurea, 58% (659/1135). In 2000, sulfonylureas were the predominant drug at the first stage of drug intensification (87%, 534/615) but by 2017 this fell to 30% (355/1183) as the use of newer drug classes increased. In 2017, new prescriptions for dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium/glucose cotransporter-2 inhibitors (SGLT2i) accounted for 42% (502/1183) and 22% (256/1183) of intensification drugs, respectively. Uptake of new classes differs by country with DPP4is and SGLT2is prescribed more in Northern Ireland and Wales than England or Scotland.

Conclusions

Our findings show markedly changing prescribing patterns for T2DM between 2000 and 2017, largely consistent with clinical guidelines.

https://ift.tt/2NQML20

Stability of home-based care arrangements for people living with dementia: protocol of a meta-study on mixed research

Introduction

Worldwide, most people with dementia live at home and are cared for by informal carers. During the dementia care trajectory, creating and maintaining a stable care situation is a guiding principle of informal carers and a desirable outcome of contemporary healthcare policies. However, though there is an extensive body of research focusing on the course of dementia care trajectories, it remains unclear how stability of home-based care arrangements is constituted and what are the essential factors that influence this stability. This paper outlines a protocol of a systematic review that aims to address these gaps in knowledge.

Methods and analysis

To theorise the complex phenomenon of stability of home-based care arrangements for people with dementia, we will conduct a meta-study. Meta-studies include three analytical components (meta-data analysis, meta-method and meta-theory) that are combined and finally culminate in an integrative knowledge synthesis. Originally, meta-study was designed to include qualitative studies only. To capture relevant contributions to our target phenomenon from all types of evidence, we will extend the original methodology and apply it to studies with qualitative, quantitative and mixed-methods designs and to (systematic) reviews. Eligible studies will be identified by systematic database searches (PubMed, CINAHL and PsycINFO), backward/forward citation tracking, snowballing and theoretical sampling. All identified studies will be screened against predefined inclusion criteria. The main analytical approach for all analyses is thematic synthesis. The meta-study will generate a more comprehensive understanding of dementia care trajectories and will be used to identify research gaps, develop future research questions and define relevant outcomes.

Dissemination

The findings of the meta-study will be published in a series of articles in peer-reviewed scientific journals and will be presented at national and international scientific conferences.

PROSPERO registration number

CRD42016041727.

https://ift.tt/2LFSMRz

Metagenomic analysis of gut microbial communities from a Central Asian population

Objective

Changes in the gut microbiota are increasingly recognised to be involved in many diseases. This ecosystem is known to be shaped by many factors, including climate, geography, host nutrition, lifestyle and medication. Thus, knowledge of varying populations with different habits is important for a better understanding of the microbiome.

Design

We therefore conducted a metagenomic analysis of intestinal microbiota from Kazakh donors, recruiting 84 subjects, including male and female healthy subjects and metabolic syndrome (MetS) patients aged 25–75 years, from the Kazakh administrative centre, Astana. We characterise and describe these microbiomes, the first deep-sequencing cohort from Central Asia, in comparison with a global dataset (832 individuals from five countries on three continents), and explore correlations between microbiota, clinical and laboratory parameters as well as with nutritional data from Food Frequency Questionnaires.

Results

We observe that Kazakh microbiomes are relatively different from both European and East Asian counterparts, though similar to other Central Asian microbiomes, with the most striking difference being significantly more samples falling within the Prevotella-rich enterotype, potentially reflecting regional diet and lifestyle. We show that this enterotype designation remains stable within an individual over time in 82% of cases. We further observe gut microbiome features that distinguish MetS patients from controls (eg, significantly reduced Firmicutes to Bacteroidetes ratio, Bifidobacteria and Subdoligranulum, alongside increased Prevotella), though these overlap little with previously published reports and thus may reflect idiosyncrasies of the present cohort.

Conclusion

Taken together, this exploratory study describes gut microbiome data from an understudied population, providing a starting point for further comparative work on biogeography and research on widespread diseases.

Trial registration number

ISRCTN37346212; Post-results.

https://ift.tt/2NNBZtp

Prevalence, associated factors and reasons for sickness presenteeism: a cross-sectional nationally representative study of salaried workers in Spain, 2016

Objectives

The aim of this study was to estimate the prevalence of sickness presenteeism (SP), its associated factors and the reasons given for SP episodes, among the overall salaried population and excluding the 'healthy' workers.

Design

Population-based cross-sectional study.

Setting

Salaried population in Spain.

Participants

Data were obtained from the third Spanish Psychosocial Risks Survey (2016), carried out between October and December 2016, n=1615.

Main outcome measures

Self-reported episodes of SP and their reasons.

Results

23.0% (95% CI 19.2 to 26.8) of the workers exhibit SP, whereas among those manifesting having had some health problem in the preceding year, the figure was 53.0% (95% CI 46.9 to 59.1). The factors associated with SP when we study all workers are age, seniority, salary structure, working more than 48 hours, the contribution of worker's wage to the total household income and downsizing; factors among the 'unhealthy' workers are working more than 48 hours and not having a contract. The most common reason for SP is 'did not want to burden my colleagues', 45.7% (95% CI 37.3 to 54.4), whereas 'I could not afford it for economic reasons' ranked third, 35.9% (29.4% to 42.9%), and 27.5% (21.3% to 34.6%) of the workers report 'worried about being laid off' as a reason for going to work despite being ill.

Conclusions

The estimated frequency of SP in Spain is lower than certain other countries, such as the Scandinavian countries. The factors associated vary depending on the population analysed (all workers or excluding 'healthy' workers). The reason 'I was worried about being laid off' was much more common than the estimates for Sweden or Norway.

https://ift.tt/2LIRpBz

Using home sensing technology to assess outcome and recovery after hip and knee replacement in the UK: the HEmiSPHERE study protocol

Introduction

Over 160 000 people with severe hip or knee pain caused by osteoarthritis undergo total hip (THR) or knee replacement (TKR) surgery each year in the UK within the National Health Service (NHS), and this number is expected to increase. Innovative approaches to evaluating surgical outcomes will be needed to respond to the increasing burden of joint replacement surgery. The Sensor Platform for Healthcare in a Residential Environment, Interdisciplinary Research Collaboration (SPHERE-IRC) have developed a system of sensors that can monitor the health-related behaviours of people living at home. The system includes sensors for the home environment (measuring temperature, humidity, room occupancy, water and electricity usage), a wristband body-worn activity monitor and silhouette (body outline) sensors. The aim of HEmiSPHERE (Hip and knEe study of a Sensor Platform of HEalthcare in a Residential Environment) is to (1) determine the accuracy and feasibility of the sensory data as it compares with conventional assessment of health outcomes after surgery using patient self-reported questionnaires, and (2) to explore how the SPHERE system is useful for everyday clinical decision-making.

Methods and analysis

A feasibility study recruiting and installing the SPHERE system in the homes of up to 30 NHS adult patients as they undergo a THR or TKR. Through a mixed-methods design, the SPHERE system will monitor and record continuous measurements of daily behaviour. Main outcomes will assess the relationships between environmental, behavioural and movement data and the parameters of interest from the standard clinical assessments measuring patient outcomes over time. Patient interviews and focus groups with consultant orthopaedic surgeons will provide in-depth understanding of the acceptability, feasibility and accuracy of the data.

Ethics and dissemination

We aim to disseminate the findings through regional talks and seminars, international conferences and peer-reviewed journals and social media.

https://ift.tt/2LTiz5L

Balancing the risk of the evacuation and sheltering-in-place options: a survival study following Japans 2011 Fukushima nuclear incident

Objective

The decision to evacuate or shelter-in-place is fundamental to emergency response, especially for a vulnerable population. While an elevated risk of mortality due to a hasty, unplanned evacuation has been well documented, there is little research on and knowledge about the health consequences of sheltering-in-place in disaster contexts. We compared hospital mortality in patients who sheltered-in-place (non-evacuees) after the incident with the baseline preincident mortality and articulated postincident circumstances of the hospital while sheltering-in-place.

Participants

We considered all 484 patients admitted to Takano Hospital (located 22 km South of the Fukushima Daiichi nuclear power plant) from 1 January 2008 to 31 December 2016.

Methods

Significant differences in mortality rates between preincident baseline and three postincident groups (evacuees, non-evacuees (our major interest) and new admittees) were tested using the Bayesian survival analysis with Weibull multivariate regression and survival probability using the Kaplan-Meier product limit method. All the analyses were separately performed by the internal and psychiatry department.

Results

After adjusting for covariates, non-evacuees in the internal department had a significantly higher mortality risk with an HR of 1.57 (95% credible intervals 1.11 to 2.18) than the baseline preincident. Of them, most deaths occurred within the first 100 days of the incident. No significant increase in mortality risk was identified in evacuees and new admittees postincident in the department, which were adjusted for covariates. In contrast, for the psychiatry department, statistical difference in mortality risk was not identified in any groups.

Conclusions

The mortality risk of sheltering-in-place in a harsh environment might be comparable to those in an unplanned evacuation. If sheltering-in-place with sufficient resources is not guaranteed, evacuation could be a reasonable option, which might save more lives of vulnerable people if performed in a well-planned manner with satisfactory arrangements for appropriate transportation and places to safely evacuate.

https://ift.tt/2LKvmug

JACK trial protocol: a phase III multicentre cluster randomised controlled trial of a school-based relationship and sexuality education intervention focusing on young male perspectives

Introduction

Teenage pregnancy remains a worldwide health concern which is an outcome of, and contributor to, health inequalities. The need for gender-aware interventions with a focus on males in addressing teenage pregnancy has been highlighted as a global health need by WHO and identified in systematic reviews of (relationship and sexuality education (RSE)). This study aims to test the effectiveness of an interactive film-based RSE intervention, which draws explicit attention to the role of males in preventing an unintended pregnancy by reducing unprotected heterosexual teenage sex among males and females under age 16 years.

Methods and analysis

A phase III cluster randomised trial with embedded process and economic evaluations. If I Were Jack encompasses a culturally sensitive interactive film, classroom materials, a teacher-trainer session and parent animations and will be delivered to replace some of the usual RSE for the target age group in schools in the intervention group. Schools in the control group will not receive the intervention and will continue with usual RSE. Participants will not be blinded to allocation. Schools are the unit of randomisation stratified per country and socioeconomic status. We aim to recruit 66 UK schools (24 in Northern Ireland; 14 in each of England, Scotland and Wales), including approximately 7900 pupils. A questionnaire will be administered at baseline and at 12–14 months postintervention. The primary outcome is reported unprotected sex, a surrogate measure associated with unintended teenage pregnancy. Secondary outcomes include knowledge, attitudes, skills and intentions relating to avoiding teenage pregnancy in addition to frequency of engagement in sexual intercourse, contraception use and diagnosis of sexually transmitted infections.

Ethics and dissemination

Ethical approval was obtained from Queen's University Belfast. Results will be published in peer-reviewed journals and disseminated to stakeholders. Funding is from the National Institute for Health Research.

Trial registration number

ISRCTN99459996

https://ift.tt/2LWBHzN

Feasibility of data linkage in the PARAMEDIC trial: a cluster randomised trial of mechanical chest compression in out-of-hospital cardiac arrest

Objectives

There is considerable interest in reducing the cost of clinical trials. Linkage of trial data to administrative datasets and disease-specific registries may improve trial efficiency, but it has not been reported in resuscitation trials conducted in the UK. To assess the feasibility of using national administrative and clinical datasets to follow up patients transported to hospital following attempted resuscitation in a cluster randomised trial of a mechanical chest compression device in out-of-hospital cardiac arrest.

Methods

Hospital data on trial participants were requested from Hospital Episode Statistics (HES), the Intensive Care National Audit and Research Centre, and Myocardial Ischaemia National Audit Project and National Audit of Percutaneous Coronary Interventions, using unique patient identifiers. Linked data were received between June 2014 and June 2015.

Results

Of 4471 patients randomised in the pre-hospital randomised assessment of a mechanical compression device in cardiac arrest (PARAMEDIC) trial, 2398 (53.6%) were not known to be deceased at emergency department arrival and were eligible for linkage. We achieved an overall match rate of 86.7% in the combined HES accident and emergency, inpatient and critical care dataset, with variable match rates (4.2%–80.4%) in individual datasets. Patient demographics, cardiac arrest-related characteristics and major outcomes were predominantly similar between HES matched and unmatched groups, in the linkage apart from location, response time and return of spontaneous circulation (ROSC) at handover.

Conclusions

This study shows that it is feasible to track patients from the prehospital setting through to hospital admission using routinely available administrative datasets with a moderate to high degree of success. This approach has the potential to complement the trial data with the demographic and clinical management information about the studied cohort, as well as to improve the efficiency and reduce the costs of follow-up in cardiac arrest trials.

Clinical trial registration

ISRCTN08233942; Post-results.

https://ift.tt/2uTXgKQ

Recent intimate partner violence against women and health: a systematic review and meta-analysis of cohort studies

Objective

We reviewed cohort studies to determine the magnitude and temporal direction of the association between recent intimate partner violence (IPV) and a range of adverse health outcomes or health risk behaviours.

Design

Systematic review and meta-analysis.

Methods

Medline, EMBASE and PsycINFO were searched from the first record to November 2016. Recent IPV was defined as occurring up to and including the last 12 months; all health outcomes were eligible for inclusion. Results were combined using random-effects meta-analysis.

Results

35 separate cohort studies were retrieved. Eight studies showed evidence of a positive association between recent IPV and subsequent depressive symptoms, with a pooled OR from five estimates of 1.76 (95% CI 1.26 to 2.44, I²=37.5%, p=0.172). Five studies demonstrated a positive, statistically significant relationship between depressive symptoms and subsequent IPV; the pooled OR from two studies was 1.72 (95% CI 1.28 to 2.31, I²=0.0%, p=0.752). Recent IPV was also associated with increased symptoms of subsequent postpartum depression in five studies (OR=2.19, 95% CI 1.39 to 3.45, p=0.000), although there was substantial heterogeneity. There was some evidence of a bidirectional relationship between recent IPV and hard drug use and marijuana use, although studies were limited. There was no evidence of an association between recent IPV and alcohol use or sexually transmitted infections (STIs), although there were few studies and inconsistent measurement of alcohol and STIs.

Conclusions

Exposure to violence has significant impacts. Longitudinal studies are needed to understand the temporal relationship between recent IPV and different health issues, while considering the differential effects of recent versus past exposure to IPV. Improved measurement will enable an understanding of the immediate and longer term health needs of women exposed to IPV. Healthcare providers and IPV organisations should be aware of the bidirectional relationship between recent IPV and depressive symptoms.

PROSPERO registration number

CRD42016033372.

https://ift.tt/2LVrtQl

Does early intervention improve outcomes in the physiotherapy management of lumbar radicular syndrome? Results of the POLAR pilot randomised controlled trial

Objective

To investigate the feasibility of undertaking a definitive randomised controlled trial (RCT).

Setting

This was a pilot, pragmatic superiority RCT with a qualitative element, recruiting from 14 general practitioner (GP) practices in England.

Participants

Patients over 18 years of age presenting to their GP with unilateral lumbar radicular syndrome (LRS), defined as radicular pain and/or neurological symptoms originating from lumbar nerve roots, were eligible to participate in the study, those who did not have a clear understanding of the English language or had comorbidities preventing rehabilitation were ineligible.

Interventions

Participants were randomised into early intervention physiotherapy or usual care with the former receiving their treatment within 2 weeks after randomisation and the latter 6 weeks postrandomisation. Both groups received a patient-centred, goal-orientated physiotherapy programme specific to their needs. Participants received up to six treatment sessions over an 8-week period.

Outcome measures

Process outcomes to determine the feasibility of the study and an exploratory analysis of patient-reported outcomes, including self-rated disability, pain and general health, these were collected at baseline, 6, 12 and 26 weeks postrandomisation.

Results

80 participants were recruited in 10 GP practices over 34 weeks and randomised to (early intervention physiotherapy n=42, usual care n=38). Follow-up rates at 26 weeks were 32 (84%) in the usual care and 36 (86%) in the early intervention physiotherapy group. The mean area under the curve (larger values indicating more disability) for the Oswestry Disability Index over the 26 weeks was 16.6 (SD 11.4) in the usual care group and 16.0 (SD 14.0) in the intervention group. A difference of –0.6 (95% CI –0.68 to 5.6) in favour of the intervention group.

Conclusions

The results of the study suggest a full RCT is feasible and will provide evidence as to the optimal timing of physiotherapy for patients with LRS.

Trial registration number

NCT02618278, ISRCTN25018352.

https://ift.tt/2LJPD3f

A cross-sectional survey of awareness of human papillomavirus-associated oropharyngeal cancers among general practitioners in the UK

Objectives

To examine the level of awareness of the link between human papillomavirus (HPV) and oropharyngeal cancer (OPC) and epidemiological trends in HPV-related OPC among general practitioners (GPs) in the UK.

Design

Cross-sectional survey.

Participants

384 GPs from England, Scotland, Wales and Northern Ireland.

Setting

The survey was administered at GP training courses and via email to lists of training course attendees.

Primary and secondary outcome measures

Proportion of respondents aware of the link between HPV and OPC; respondents' self-rated knowledge of OPC; proportion of participants aware of the epidemiological trends in HPV-associated OPC.

Results

384 questionnaires were completed with an overall response rate of 72.9%. 74.0% of participants recognised HPV as a risk factor for OPC, which was lower than knowledge about the role of smoking, chewing tobacco and alcohol consumption (all >90% recognition). Overall, 19.4% rated their knowledge of OPC as very good or good, 62.7% as average and 17.7% as poor or very poor. The majority (71.9%) were aware that rates of HPV-associated OPC have increased over the last two decades. Fewer than half (41.5%) of the participants correctly identified being male as a risk factor of HPV-associated OPC, while 58.8% were aware that patients with HPV-associated OPC tend to be younger than those with non-HPV-associated disease.

Conclusions

The association of HPV infection with OPC is a relatively recent discovery. Although the level of awareness of HPV and OPC among GPs was high, the characteristics of HPV-associated OPC were less well recognised, indicating the need for further education.

https://ift.tt/2NS0TIo

Microneedle arrays for vaccine delivery: The possibilities, challenges and use of nanoparticles as a combinatorial approach for enhanced vaccine immunogenicity.

Microneedle arrays for vaccine delivery: The possibilities, challenges and use of nanoparticles as a combinatorial approach for enhanced vaccine immunogenicity.

Expert Opin Drug Deliv. 2018 Jul 27;:

Authors: Rodgers AM, Cordeiro AS, Kissenpfennig A, Donnelly RF

Abstract
INTRODUCTION: Vaccination is undoubtedly one of the greatest breakthroughs of modern preventative medicine. Despite this, there remain problems surrounding delivery, efficacy and compliance. Thus, there is a pressing need to develop cost-effective vaccine delivery systems that could expand the use of vaccines, particularly within developing countries. Microneedle (MN) arrays, due to their ease of use, painlessness and ability to target skin antigen presenting cells, provide an attractive technological platform for improved vaccine delivery and efficacy. Studies have demonstrated enhanced immunogenicity with the use of MN in comparison to that of the conventional needle. More recently, dissolving MN have been used for efficient delivery of nanoparticles (NP), as a means to enhance antigen immunogenicity.
AREAS COVERED: This review introduces the fields of MN technology and nanotechnology and highlights the recent advances which have been made combining these two technologies for enhanced vaccine delivery and efficacy. Some of the key questions that remain to be addressed for adoption of MN in a clinical setting are also evaluated.
EXPERT OPINION: MN-mediated vaccine delivery holds potential for expanding access to vaccines, with individuals in developing countries likely to be the principal beneficiaries. The combinatorial approach of utilising MN coupled with NP, provides the opportunity to enhance the immunogenicity of vaccine antigens.

PMID: 30051726 [PubMed - as supplied by publisher]

https://ift.tt/2K41sfQ

The Well-Developed Mucosal Immune Systems of Birds and Mammals Allow for Similar Approaches of Mucosal Vaccination in Both Types of Animals.

The Well-Developed Mucosal Immune Systems of Birds and Mammals Allow for Similar Approaches of Mucosal Vaccination in Both Types of Animals.

Front Nutr. 2018;5:60

Authors: Nochi T, Jansen CA, Toyomizu M, van Eden W

Abstract
The mucosal immune system is a compartmentalized part of the immune system that provides local immunity in the mucosa of the respiratory, gastrointestinal, and digestive tracts. It possesses secondary lymphoid tissues, which contain immune cells, such as T, B, and dendritic cells. Once the cells of the mucosal immune system are stimulated by luminal antigens, including microorganisms, they infiltrate into diffuse areas of mucosal tissues (e.g., respiratory mucosa and lamina propria of intestinal villi) and exhibit immune effector functions. Inducing the antigen-specific immune responses in mucosal tissues by mucosal vaccination would be an ideal strategy for not only humans, but also mammals and birds, to protect against infectious diseases occurring in mucosal tissues (e.g., pneumonia and diarrhea). Infectious diseases cause huge economic losses in agriculture, such as livestock and poultry industries. Since most infectious diseases occur in mucosal tissues, vaccines that are capable of inducing immune responses in mucosal tissues are in high need. In this review, we discuss the current understanding of mucosal immunity in mammals and birds, and recent progress in the development of mucosal vaccines.

PMID: 30050906 [PubMed]

https://ift.tt/2LuIKDM

Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium.

https:--linkinghub.elsevier.com-ihub-ima

Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium.

J Control Release. 2017 Nov 28;266:27-35

Authors: de Groot AM, Du G, Mönkäre J, Platteel ACM, Broere F, Bouwstra JA, Sijts AJAM

Abstract
The skin is an attractive organ for immunization due to the presence of a large number of epidermal and dermal antigen-presenting cells. Hollow microneedles allow for precise and non-invasive intradermal delivery of vaccines. In this study, ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles with and without TLR3 agonist poly(I:C) were prepared and administered intradermally by hollow microneedles. The capacity of the PLGA nanoparticles to induce a cytotoxic T cell response, contributing to protection against intracellular pathogens, was examined. We show that a single injection of OVA-loaded PLGA nanoparticles, compared to soluble OVA, primed both adoptively transferred antigen-specific naïve transgenic CD8+ and CD4+ T cells with markedly high efficiency. Applying a triple immunization protocol, PLGA nanoparticles primed also endogenous OVA-specific CD8+ T cells. Immune response, following immunization with in particular anionic PLGA nanoparticles co-encapsulated with OVA and poly(I:C), provided protection against a recombinant strain of the intracellular bacterium Listeria monocytogenes, secreting OVA. Taken together, we show that PLGA nanoparticle formulation is an excellent delivery system for protein antigen into the skin and that protective cellular immune responses can be induced using hollow microneedles for intradermal immunizations.

PMID: 28917531 [PubMed - indexed for MEDLINE]

https://ift.tt/2v7vtG6

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Σάββατο 28 Ιουλίου 2018

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