No abstract available
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Δευτέρα 12 Φεβρουαρίου 2018
Intensive Care Unit Enhanced Recovery Pathway for Patients Undergoing Orthotopic Liver Transplants Recipients: A Prospective, Observational Study
BACKGROUND: Liver transplant recipients continue to have high perioperative resource utilization and prolonged length of stay despite improvements in perioperative care. Enhanced recovery pathways have been shown in other surgical populations to produce reductions in hospital resource utilization. METHODS: A prospective, observational study was performed to examine the effect of an enhanced recovery pathway for postoperative care after liver transplantation. Outcomes from patients undergoing liver transplantation from November 1, 2013, to October 31, 2014, managed by the pathway were compared to transplant recipients from the year before pathway implementation. Multivariable regression analysis was used to assess the association of the clinical pathway on clinical outcomes. RESULTS: The intervention and control groups included 141 and 106 patients, respectively. There were no demographic differences between the control and intervention group including no differences between the length of surgery and cold ischemic time. Median intensive care unit length of stay was reduced from 4.4 to 2.6 days (P
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http://ift.tt/2o2CDb2
The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews
Abstract
Purpose of Review
Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects.
Recent Findings
We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms.
Summary
Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.
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Hypertonicity primes malignant melanoma cells for apoptosis
Abstract
The tumor environment critically influences responsiveness of cancer cells to chemotherapies, most of which activate the mitochondria-regulated (intrinsic) apoptotic cascade to kill malignant cells. Especially skin tumors encounter an environment with remarkable biophysical properties. Cutaneous accumulation of Na+ locally establishes osmotic pressure gradients in vivo (hypertonicity or hyperosmotic stress), but whether cutaneous hypertonicity is a factor that modulates the responsiveness of skin cancers to therapeutic apoptosis-induction has thus far not been investigated. Here, we show that hyperosmotic stress lowers the threshold for apoptosis induction in malignant melanoma, the deadliest form of skin cancer. Hypertonic conditions enforce addiction to BCL-2-like proteins to prevent initiation of the mitochondria-regulated (intrinsic) apoptotic pathway. Essentially, hyperosmotic stress primes mitochondria for death. Our work identifies osmotic pressure in the tumor microenvironment as a cell extrinsic factor that modulates responsiveness of malignant melanoma cells to therapy.
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Efficacy of pre-hospital rapid sequence intubation in paediatric traumatic brain injury: a 9-year observational study
Publication date: Available online 12 February 2018
Source:Injury
Author(s): Stefan Heschl, Ben Meadley, Emily Andrew, Warwick Butt, Stephen Bernard, Karen Smith
IntroductionPrehospital airway management of the paediatric patient with traumatic brain injury (TBI) is controversial. Endotracheal intubation of children in the field requires specific skills and has potential benefits but also carries potentially serious complications. We aimed to compare mortality and functional outcomes after six months between children with TBI who either underwent prehospital rapid sequence intubation (RSI) by trained Intensive Care paramedics (ICP) or received no intubation.MethodsWe conducted a retrospective study of patients aged ≤14 years with suspected TBI in Victoria, Australia. Patients were either transported via helicopter and received RSI by an ICP (2005-2013) or via road ambulance and received no intubation (2006-2013). Prehospital data was linked to hospital and 6-month follow-up data to assess mortality and functional outcome.ResultsA total of 106 patients were included in the study of which 87 received RSI by paramedics and 19 did not receive intubation. Overall, the intubation success rate was 99% (86/87), with a first-pass success rate of 93% (81/87). In total, 67% of patients (n = 41) receiving RSI had a favourable functional outcome, compared with 54% of non-intubated patients (n = 7) (p = 0.36). In the 75 children with major trauma, prehospital RSI was associated with a significant decrease in length of hospital stay (523 hours vs. 1939 hours, p = 0.03). In the 53 children in this subgroup with available six months data the difference in favourable functional outcome increased to 66% (n = 31)vs. 17% (n = 1) (p = 0.06).DiscussionPrehospital RSI in paediatric patients with TBI can safely be performed by highly trained paramedics. Overall, we observed more favourable long-term outcomes in patients who received prehospital intubation than those who did not, however our study is not powered to detect a significant difference. Intubation prior to transport might be beneficial for major trauma patients.
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Trauma Theatre Productivity – Does the Individual Surgeon, Anaesthetist or Consultant Presence Matter?
Publication date: Available online 12 February 2018
Source:Injury
Author(s): Gareth S. Turnbull, Mounir Hakimi, George J. McLauchlan
IntroductionWith rising NHS clinical and financial demands, improving theatre efficiency is essential to maintain quality of patient care. Consistent teams and consultant presence have been shown to improve outcomes and productivity in elective orthopaedic surgery. The aim of this study was to investigate the impact on trauma theatre productivity of different surgeons and anaesthetists working together in a Major Trauma Centre. The influence of consultant presence and weekend operating on productivity was also considered.MethodsData relating to a single orthopaedic trauma theatre was gathered retrospectively for a two- year period. Variables including orthopaedic and anaesthetic consultant presence, number and complexity of operations performed and procedure start times were collected for daily trauma lists. Individual anaesthetic and orthopaedic consultants were compared by productivity outcomes. The impact of surgeons operating more frequently with one anaesthetist was also examined.ResultsData relating to 2384 patients undergoing a total of 2787 procedures was collected. Orthopaedic consultant presence at the first surgical case (p < 0.05) and for 50% or greater of cases (p < 0.05) lead to higher mean number of cases performed per list and reduced turnaround time. Despite working with a significantly higher number of different consultant anaesthetists (p < 0.001) in year two, the productivity of surgeons as judged by list start time, total cases per list and total operating time was not significantly affected. Significantly earlier start times (p < 0.001) and shorter turnaround times (p < 0.001) at weekends led to maintained productivity despite shorter theatre time. No significant difference in productivity was found when comparing individual anaesthetic and orthopaedic consultants. Productivity was not significantly increased by surgeons operating more frequently with one individual anaesthetist.ConclusionIn the setting of an acute trauma theatre, orthopaedic consultant presence led to increased productivity. Furthermore, individual surgeon and anaesthetist pairings had no effect on overall productivity. Future efforts to improve productivity should focus on achieving earlier start times, consultant supervision of lists and reduced turnaround times between cases
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Submersion Injuries in the United States: Patients Characteristics and Predictors of Mortality and Morbidity
Publication date: Available online 13 February 2018
Source:Injury
Author(s): Rayan El Sibai, Rana Bachir, Mazen El Sayed
IntroductionDrowning leads to 372,000 deaths annually worldwide and to severe morbidity secondary to asphyxiation or aspiration. Previous studies described submersion injuries mainly in the pediatric population. This study describes characteristics of patients presenting with submersion injuries to United States emergency departments (EDs) and identifies predictors of poor outcomes (death or long term neurologic deficits) after drowning.MethodsThis retrospective cross-sectional study included ED visits for submersion injuries from the United States 2013 Nationwide Emergency Department Sample (NEDS) dataset using discharge data (CCS diagnosis codes). Descriptive analysis was done for the collected variables and was followed by a multivariate regression analysis to identify predictors of poor outcomes (mortality and morbidity).ResultsA total of 12,529 weighted patients presented to EDs for submersion injury in 2013 yielding a rate of 9.29 per 100,000 ED visits. Patients were more frequently males (65.8%, 95%CI: 64.0–67.6) and in the 19–65 years age group (41.8%, 95%CI: 40.0–43.6). Poor outcomes were present in 11.7% (95%CI: 10.5–13.0) of patients. Significant positive predictors of poor outcomes were: male gender (OR = 1.761, 95%CI: 1.247–2.487); presence of chronic conditions involving infectious and parasitic disease (OR = 2.824, 95%CI: 1.155–6.908), the circulatory system (OR = 12.818, 95%CI: 8.953–18.351), the respiratory system (OR = 1.498, 95%CI: 1.079–2.079) or the digestive system (OR = 2.006, 95%CI: 1.106–3.636); associated motor vehicle traffic injury (OR = 5.221, 95%CI: 1.563–17.441) and self-payers.ConclusionSubmersion remains a high impact emergency condition in the United States. Significant predictors of poor outcomes were identified. Prevention efforts targeting susceptible population are needed to reduce the impact of submersion injuries on different communities in the United States.
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Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab
Abstract
Background
There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab.
Methods
We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed.
Results
The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of ≥ 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.0 months (p = 0.00515).
Conclusion
The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.
http://ift.tt/2nVCRSj
Advanced imaging technology applications in cytology
Novel techniques have been developed to image cells at cellular and subcellular levels. They allow images to be analyzed with ultra-high resolution, in 2D and/or 3D. Several of these tools have been tested on cytology specimens demonstrating emerging applications that are likely to change the field of cytopathology. This review covers several of these advanced imaging methods. The use of optical coherence tomography to perform optical biopsies during endoscopic ultrasound procedures or visualize cells within effusion samples is discussed. The potential for quantitative phase microscopy to accurately screen Pap test slides or resolve indeterminate diagnoses in urine cytology is reviewed. The article also examines the application of 3D cytology using LuCED for lung cancer detection in sputum samples and the feasibility of imaging flow and mass cytometry to measure multiple biomarkers at the single cell level. Although these novel technologies have great potential, further research is necessary to validate their routine use in cytopathology practice.
http://ift.tt/2HctuWn
Immune Checkpoint Blockade: The New Frontier in Cancer Treatment
Abstract
Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise. 
http://ift.tt/2sqNMbd
Scoping review on the use of socially assistive robot technology in elderly care
Objective
With an elderly population that is set to more than double by 2050 worldwide, there will be an increased demand for elderly care. This poses several impediments in the delivery of high-quality health and social care. Socially assistive robot (SAR) technology could assume new roles in health and social care to meet this higher demand. This review qualitatively examines the literature on the use of SAR in elderly care and aims to establish the roles this technology may play in the future.
DesignScoping review.
Data sourcesSearch of CINAHL, Cochrane Library, Embase, MEDLINE, PsychINFO and Scopus databases was conducted, complemented with a free search using Google Scholar and reference harvesting. All publications went through a selection process, which involved sequentially reviewing the title, abstract and full text of the publication. No limitations regarding date of publication were imposed, and only English publications were taken into account. The main search was conducted in March 2016, and the latest search was conducted in September 2017.
Eligibility criteriaThe inclusion criteria consist of elderly participants, any elderly healthcare facility, humanoid and pet robots and all social interaction types with the robot. Exclusions were acceptability studies, technical reports of robots and publications surrounding physically or surgically assistive robots.
ResultsIn total, 61 final publications were included in the review, describing 33 studies and including 1574 participants and 11 robots. 28 of the 33 papers report positive findings. Five roles of SAR were identified: affective therapy, cognitive training, social facilitator, companionship and physiological therapy.
ConclusionsAlthough many positive outcomes were reported, a large proportion of the studies have methodological issues, which limit the utility of the results. Nonetheless, the reported value of SAR in elderly care does warrant further investigation. Future studies should endeavour to validate the roles demonstrated in this review.
Systematic review registrationNIHR 58672.
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Correction: Predictors of HIV virological failure and drug resistance in Chinese patients after 48 months of antiretroviral treatment, 2008-2012: a prospective cohort study
Kan W, Teng T, Liang S, et al. Predictors of HIV virological failure and drug resistance in Chinese patients after 48 months of antiretroviral treatment, 2008–2012: a prospective cohort study. BMJ Open 2017;7:e016012. doi: 10.1136/bmjopen-2017-016012
The Funding statement in this article should read:
Funding This study was supported by the Guangxi Science and Technology Bureau (AB16380213), Guangxi Bagui Honor Scholars.
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Portuguese version of a stress and well-being evaluation tool (ASSET)at the workplace: validation of the psychometric properties
Objective
The main objective of this work was to translate the English version of ASSET (A Shortened Stress Evaluation Tool) into the Portuguese version and to validate its psychometric properties. Additionally, this work tested the convergent validity of the instrument.
MethodsThe translation and retroversion were conducted by experts and submitted to the authors for approval. Within an observational, cross-sectional study, regarding mental health at the workplace, ASSET together with other scales was applied to a sample of 405 participants. The psychometric validity of the subscales was studied using confirmatory factorial analysis.
ResultsThe factorial structure of ASSET is globally supported by the results, with the Perceptions of Your Job and Attitudes Towards your Organisation subscales requiring slight adjustments in the item structure and the Your Health subscales replicating the original structure. The convergent validity also supports the ASSET, showing that all subscales are significantly correlated with variables used to test convergence.
ConclusionsGlobally, the results constitute an important contribution to ASSET and open the possibility of its usage among Portuguese-speaking countries. The results provide an evidence on the validity of the instrument and, in particular, of the mental and physical health subscales.
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To what extent do hospitalised patients receive appropriate CT and MRI scans? Results of a cross-sectional study in Southern Italy
Objectives
The aim of this study was to assess the frequency of appropriateness of inpatient CT and MRI scans performed in Southern Italy.
MethodsThe study was carried out by retrospectively reviewing medical records of adult patients admitted between 1 January and 31 December 2012 in two hospitals. The evaluation of appropriateness was performed according to the American College of Radiology Appropriateness Criteria, which assigns a score between 1 and 9.
ResultsEight hundred and fifty-three medical records were reviewed. Six hundred and thirty-nine patients received CT examinations and 256 received MRI examinations. Four hundred and ninety-six (77.6%) of the patient population had appropriate CT and 202 (78.9%) received appropriate MRI examinations. The appropriateness was associated with: a confirmation of the diagnostic hypothesis, only one examination performed during hospital stay, the anatomical scan region, with musculoskeletal system being the least appropriate anatomical scan region. Moreover, for CT examinations, appropriateness was also associated with no use of contrast agent.
ConclusionsOur findings highlight the need to reduce inappropriate use of CT and MRI. The study showed that the tool used is reliable to measure the extent of appropriateness of diagnostic imaging for inpatient examinations.
http://ift.tt/2F0IC8x
Using big data to improve cardiovascular care and outcomes in China: a protocol for the CHinese Electronic health Records Research in Yinzhou (CHERRY) Study
Introduction
Data based on electronic health records (EHRs) are rich with individual-level longitudinal measurement information and are becoming an increasingly common data source for clinical risk prediction worldwide. However, few EHR-based cohort studies are available in China. Harnessing EHRs for research requires a full understanding of data linkages, management, and data quality in large data sets, which presents unique analytical opportunities and challenges. The purpose of this study is to provide a framework to establish a uniquely integrated EHR database in China for scientific research.
Methods and analysisThe CHinese Electronic health Records Research in Yinzhou (CHERRY) Study will extract individual participant data within the regional health information system of an eastern coastal area of China to establish a longitudinal population-based ambispective cohort study for cardiovascular care and outcomes research. A total of 1 053 565 Chinese adults aged over 18 years were registered in the health information system in 2009, and there were 23 394 deaths from 1 January 2009 to 31 December 2015. The study will include information from multiple epidemiological surveys; EHRs for chronic disease management; and health administrative, clinical, laboratory, drug and electronic medical record (EMR) databases. Follow-up of fatal and non-fatal clinical events is achieved through records linkage to the regional system of disease surveillance, chronic disease management and EMRs (based on diagnostic codes from the International Classification of Diseases, tenth revision). The CHERRY Study will provide a unique platform and serve as a valuable big data resource for cardiovascular risk prediction and population management, for primary and secondary prevention of cardiovascular events in China.
Ethics and disseminationThe CHERRY Study was approved by the Peking University Institutional Review Board (IRB00001052-16011) in April 2016. Results of the study will be disseminated through published journal articles, conferences and seminar presentations, and on the study website (http://www.cherry-study.org).
http://ift.tt/2EnNMu7
Characterization of mesenchymal stem/stromal cells with lymphoid tissue organizer cell potential in tonsils from children
Abstract
Lymphoid tissue organizer (LTo) cells, identified in mouse and human embryos, are thought to be precursors of stromal cells in secondary lymphoid organs. Whether LTo cells are present in human adults, however remains unknown. We obtained 15 stromal cell lines from tonsils from children who underwent tonsillectomy, and studied the antigen phenotype of these tonsil stromal cell (TSC) lines by flow cytometry and RT-PCR. Cell lines met the minimal criteria proposed by the International Society for Cellular Therapy to define human mesenchymal stem/stromal cells (MSCs): plastic-adherent capacity; expression of CD73, CD90 and CD105, lack of CD45, CD19 and HLA-DR; and capacity to differentiate into adipocytes, osteoblasts and chondrocytes. Furthermore, our TSC lines exhibited an antigen phenotype and functional characteristics very similar to those seen in murine embryo LTo cells: they expressed chemokines CCL19, CCL21 and CXCL13, cytokines TRANCE and IL-7, and adhesion molecules ICAM-1, mucosal addressin cell adhesion molecule (MadCAM)-1 and VCAM-1. The expression of LTo cell-associated markers and functions were upregulated by lymphotoxin (LT)α1β2 and TNF, two cytokines involved in the development and maturation of secondary lymphoid tissues. Our results show that TSCs are tonsil MSCs that differentiate into LTo-like cells in response to the effects of these cytokines.
This article is protected by copyright. All rights reserved
http://ift.tt/2Chsbl0
Route previewing results in altered gaze behaviour, increased self-confidence and improved stepping safety in both young and older adults during adaptive locomotion
Abstract
Older adults with falls risk tend to look away prematurely from targets for safe foot placement to view future hazards; behaviour associated with increased anxiety and stepping inaccuracies. We aimed to determine the effectiveness of route previewing in reducing anxiety and optimizing gaze behaviour and stepping performance of younger and older adults. Nine younger and nine older adults completed six walks with three task complexities over two sessions. Each trial used either an isolated stepping target, or a target followed by either one or two obstacles. Participants with eyes closed, on hearing a signal, opened their eyes and initiated walking (go trials) or stood previewing the route for 10 s before starting (preview trials). Kinematic data were collected using a Vicon motion analysis system. Gaze behaviour was recorded using a Dikablis eye tracker. On average, both older and younger adults fixated the target for significantly longer during walking when they had previewed the route than when they had not. Self-confidence scores were also significantly higher following 'preview trials' than 'go trials'. Stepping performance significantly improved following route previewing (reduced Medial lateral foot placement variability for both groups and reduced anterior/posterior foot placement error in older adults only). These findings implicate route previewing as a potential intervention to increase self-confidence and reduce the risk of tripping in older adults.
http://ift.tt/2sswN8o
Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN
Human Gene Therapy , Vol. 0, No. 0.
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The clinical impact of molecular breast imaging in women with proven invasive breast cancer scheduled for breast-conserving surgery
Abstract
Purpose
To investigate the clinical utility of molecular breast imaging (MBI) in patients with proven invasive breast cancer scheduled for breast-conserving surgery (BCS).
Methods
Following approval by the institutional review board and written informed consent, records of patients with newly diagnosed breast cancer scheduled for BCS who had undergone MBI for local staging in the period from March 2012 till December 2014 were retrospectively reviewed.
Results
A total of 287 women (aged 30–88 years) were evaluated. MBI showed T stage migration in 26 patients (9%), with frequent detection of in situ carcinoma around the tumor. Surgical management was adjusted in 14 of these patients (54%). In 17 of 287 patients (6%), MBI revealed 21 proven additional lesions in the ipsilateral, contralateral breast or both. In 18 of these additional foci (86%), detected in 15 patients, malignancy was found. Thirteen of these 15 patients had ipsilateral cancer and 2 patients bilateral malignancy. In total, MBI revealed a larger tumor extent, additional tumor foci or both in 40 patients (14%), leading to treatment adjustment in 25 patients (9%).
Conclusion
MBI seems to be a useful imaging modality with a high predictive value in revealing ipsilateral and bilateral disease not visualized by mammography and ultrasound. It may play an important role in delineating the extent of the index lesion during preoperative planning. Incorporation of MBI in the clinical work-up as an adjunct modality to mammography and ultrasound may lead to better selection of patients who could benefit from BCS.
http://ift.tt/2BrFeDZ
Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma
Summary
Diagnosis of endometrial cancer is primarily based on symptoms and imaging, with early-stage disease being difficult to diagnose. Therefore, development of potential diagnostic biomarkers is required. Metabolomics, a quantitative measurement of the dynamic metabolism in living systems, can be applied to determine metabolite profiles in different disease states. Here, serum metabolomics was performed in forty-six early stage endometrial cancer patients and forty-six healthy volunteers. In addition, the effect of identified metabolites on tumour cell behavior (invasion, migration, proliferation, apoptosis, autophagy), was examined in endometrial cancer cell lines. Compared with controls, phenylalanine, indoleacrylic acid (IAA), phosphocholine and lyso-platelet activating factor-16 (lyso-PAF), were differentially detected in patients. Functional analyses demonstrated that IAA, PAF and phenylalanine all dose-dependently inhibited tumour cell invasion and migration, and suppressed cell proliferation. PAF also induced tumour cell apoptosis and autophagy, while phenylalanine had no effect on apoptosis or autophagy. IAA triggered apoptosis and had a biphasic effect on autophagy: inhibiting autophagy with doses less than 1mM but inducing at 1mM. Interestingly, the alterations in proliferation, apoptosis and autophagy caused by 1mM IAA, were all reversed by the concomitant treatment of tryptophan (100μM). Phosphocholine inhibited tumour cell invasion and migration, and promoted cell proliferation and autophagy all in a dose-dependent manner. Phosphocholine also protected cells from TNF-α-induced apoptosis. In conclusion, four serum metabolites were identified by serum metabolomics in endometrial cancer patients and functional analyses suggested that they may play roles in modulation of tumour cell behavior, although their exact mode of action still needs to be determined.
This article is protected by copyright. All rights reserved.
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Effects of changes in eating speed on obesity in patients with diabetes: a secondary analysis of longitudinal health check-up data
Objective
Few studies have examined the causal relationships between lifestyle habits and obesity. With a focus on eating speed in patients with type 2 diabetes, this study aimed to analyse the effects of changes in lifestyle habits on changes in obesity using panel data.
MethodsPatient-level panel data from 2008 to 2013 were generated using commercially available insurance claims data and health check-up data. The study subjects comprised Japanese men and women (n=59 717) enrolled in health insurance societies who had been diagnosed with type 2 diabetes during the study period. Body mass index (BMI) was measured, and obesity was defined as a BMI of 25 or more. Information on lifestyle habits were obtained from the subjects' responses to questions asked during health check-ups. The main exposure of interest was eating speed ('fast', 'normal' and 'slow'). Other lifestyle habits included eating dinner within 2 hours of sleeping, after-dinner snacking, skipping breakfast, alcohol consumption frequency, sleep adequacy and tobacco consumption. A generalised estimating equation model was used to examine the effects of these habits on obesity. In addition, fixed-effects models were used to assess these effects on BMI and waist circumference.
ResultsThe generalised estimating equation model showed that eating slower inhibited the development of obesity. The ORs for slow (0.58) and normal-speed eaters (0.71) indicated that these groups were less likely to be obese than fast eaters (P<0.001). Similarly, the fixed-effects models showed that eating slower reduced BMI and waist circumference. Relative to fast eaters, the coefficients of the BMI model for slow and normal-speed eaters were –0.11 and –0.07, respectively (P<0.001).
DiscussionChanges in eating speed can affect changes in obesity, BMI and waist circumference. Interventions aimed at reducing eating speed may be effective in preventing obesity and lowering the associated health risks.
http://ift.tt/2EA7xSu
How can positive and negative trainer feedback in the operating theatre impact a surgical trainees confidence and well-being: a qualitative study in the north of England
Objective
To identify the perception of positive feedback (PF) and negative feedback (NF) provided by trainers in the operating theatre on surgical trainees' confidence and well-being.
DesignNarrative interview study.
SettingTwelve hospitals that form part of one deanery within the UK.
ParticipantsMaximum variation sampling of 15 higher general surgical trainees provided insight into how PF and NF from trainers in the operating theatre affect confidence and well-being.
MethodsNarrative telephone interviews were conducted with general surgical trainees between April and June 2016. All interviews were recorded, transcribed and anonymised. Transcriptions were analysed using the five-step framework analysis by two independent researchers.
ResultsFifteen trainees (age 28–38 years) were interviewed (median interview time: 29 min). Thematic framework analysis identified nine themes within the data. PF, which included corrective feedback, helped the trainees to relax and seemed to enhance their operative performance. All trainees reported significant and unjustified NF, some of which would be defined as undermining and bullying. Many believed this to have a negative impact on their training with minimal educational benefit. Many trainees felt NF adversely affected their performance in the operating theatre with some expressing a wish to leave the profession as a consequence.
ConclusionBoth PF and NF exist in the operating theatre. Both have an important influence on the trainee, their performance and career. PF, if specific, helped aid progression of learning, increased motivation and performance of surgical trainees. In contrast, NF was perceived to have detrimental effects on trainees' performance and their well-being and, in some, introduced a desire to pursue an alternative career.
http://ift.tt/2EC8cTv
pSTM6-275, a conjugative IncHI2 plasmid of Salmonella that confers antibiotic and heavy metal resistance under changing physiological conditions [PublishAheadOfPrint]
Detailed annotation of an IncHI2 plasmid, pSTM6-275, from Salmonella enterica serotype 1,4,5,12:i:- TW-Stm6 revealed a composite structure including antimicrobial resistance genes on mobile genetic elements. The plasmid was thermosensitive for transfer to E.coli and conferred reduced susceptibility to antibiotics, copper sulphate and silver nitrate. Metal ion susceptibility was dependent on physiological conditions, giving an insight into the environments where this trait might confer a fitness advantage.
http://ift.tt/2nWv1rD
Prediction model for anti-malarial activities of hemozoin inhibitors using physicochemical properties [PublishAheadOfPrint]
The rapid spread of strains of malaria parasites resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the anti-malarial activity of chemical compounds possessing anti-hemozoin formation activity as a new means of anti-malarial drug discovery. After the initial in vitro anti-hemozoin formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 compounds were tested for in vitro erythrocytic anti-malarial activity at 10 μM using the chloroquine-mefloquine sensitive Plasmodium falciparum strain, 3D7A. Two independent experiments were conducted. The physicochemical properties of the active compounds were extracted from ChemSpider and SciFinder databases. We analyzed the extracted data using Bayesian model averaging (BMA). Our findings revealed that lower numbers of S atoms, lower values of log D pH 3, 4 and 5, and higher values of ACD log D pH 7.4 had a significant association with anti-malarial activity among compounds possessing anti-hemozoin formation activity. The BMA model revealed an accuracy of 91.23%. We report new prediction models containing the physicochemical properties that shed light on effective chemical groups for synthetic anti-malarial compounds and help in silico screening for novel anti-malarial drugs.
http://ift.tt/2o2iged
Novel zinc attenuating compounds as potent broad spectrum antifungal agents with in vitro and in vivo efficacy. [PublishAheadOfPrint]
An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here, we report the identification and characterization of two novel zinc-attenuating compounds ZAC307 and ZAC989, which exhibit broad-spectrum in vitro antifungal activity and in vivo efficacy in a fungal kidney burden candidiasis model.
The compounds were identified serendipitously as part of a drug discovery process aimed at finding novel inhibitors of the fungal plasma membrane proton ATPase, Pma1. Based on their structure, we hypothesized that they might act as zinc chelators. Indeed, both fluorescence-based affinity determination and potentiometric assays revealed these compounds, subsequently termed zinc attenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on Candida albicans and Aspergillus fumigatus could be inactivated by the addition of exogenous zinc to fungal growth media. We determined the ZACs to be fungistatic, with a low propensity for resistance development. Gene expression analysis suggested that the ZACs interfere negatively with the expression of genes encoding the major components of the A. fumigatus zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. Taken together, with demonstrated in vitro and in vivo antifungal activity, low propensity for resistance development, and a novel mode of action, the ZACs represent a promising new class of antifungal compounds, and their advancement in a drug development program is therefore warranted.
http://ift.tt/2nX7g2x
Efficacy of systemically administered polymyxins in mouse burn wound infection caused by multidrug-resistant Gram-negative pathogens: A proof-of-concept study [PublishAheadOfPrint]
The efficacy of subcutaneously administered polymyxins against burn wound infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae was examined in a murine infection model. Subcutaneously administered colistin and polymyxin B achieved a >2-log10 reduction in the bacterial load for P. aeruginosa and A. baumannii infections, while wound infections by K. pneumoniae were less responsive (<1-log10 reduction). This study highlights the potential therapeutic benefits of parenteral polymyxins for treating burn wound infections.
http://ift.tt/2o2m8fn
Inactivation of Plasmepsin 2 and 3 sensitizes Plasmodium falciparum to the antimalarial drug piperaquine [PublishAheadOfPrint]
Dihydroartemisinin-piperaquine (DHA-PPQ), the current frontline artemisinin combination therapy used to treat Plasmodium falciparum malaria in multiple Southeast Asian countries is now increasingly failing in Cambodia where artemisinin resistance is nearly fixed which suggests that PPQ resistance has emerged and is spreading rapidly in the Greater Mekong Subregion. Recent reports have shown that amplification of Plasmepsins 2 and 3 is a molecular marker of PPQ resistance however whether these enzymes play a role in the mechanism of resistance is currently unknown. We here show that inactivating Plasmepsin-2 or Plasmepsin-3 individually in the 3D7 P. falciparum reference strain results in hyper-susceptibility to PPQ. Interestingly, no significant differences in the susceptibility to other antimalarials were observed which suggests specific roles of Plasmepsin 2 and 3 in PPQ susceptibility. The piperaquine hyper-sensitivity of the Plasmepsin 2 and 3 inactivated lines provides direct evidence that these enzymes modulate parasite susceptibility to PPQ in the context of a single copy of PfMDR1 and independent of Kelch13 mutations conferring ART resistance.
http://ift.tt/2nWBz9s
The Pharmacokinetics of 2000 mg Ertapenem in Tuberculosis Patients [PublishAheadOfPrint]
Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis. Dose simulations in a hollow fiber infection model showed that 2000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study is to confirm the pharmacokinetics of 2000 mg once daily in TB patients. Twelve TB patients received a single intravenous dose of 2000 mg ertapenem as 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post administration. Drug concentrations were measured using a validated LC-MS/MS assay. A large inter-individual variation in the pharmacokinetics of ertapenem was observed. The median (IQR) area under the plasma concentration-time curve to infinity (AUC (t=) (h*mg/l)) was 2032 (1751 – 2346) mg*h/L, the inter-compartmental clearance (CL12) 1.941 (0.979 – 2.817) L/h and the volume of distribution in the central compartment (V1) 1.514 (1.064 – 2.210) L. A more than dose-proportional increase in AUC was observed comparing the results to reported 1000 mg ertapenem in MDR-TB patients. Based on a minimal inhibitory concentration (MIC) of 1.0 mg/L, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of time (f40% T>MIC). In conclusion, this study shows that 2000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients and exploration in a phase 2 study can be advocated.
http://ift.tt/2o1Hw4k
The coexistence of two blaNDM-5 genes on an IncF plasmid as revealed by nanopore sequencing [PublishAheadOfPrint]
In a carbapenem-resistant Escherichia coli clinical isolate of sequence type 167, two copies of blaNDM-5 were found on a 144,225-bp IncF self-transmissible plasmid of the F36:A4:B- type. Both blaNDM-5 genes were located in 11,065-bp regions flanked by two copies of IS26. The two regions were identical in sequence but were present at different locations on the plasmid, suggesting a duplication of the same region. This study highlights the complex genetic contexts of blaNDM-5.
http://ift.tt/2nVkahA
Susceptibility of clinical isolates of Trichomonas vaginalis to metronidazole and secnidazole--an in vitro study [PublishAheadOfPrint]
Nitroimidazoles (metronidazole [MTZ] and tinidazole [TNZ]) are the only drugs recommended for treating Trichomonas vaginalis (TV) infection. MTZ resistance occurs in 4%–10% of cases of vaginal trichomoniasis (1, 2), and TNZ resistance in 1% of patients (2). Emerging nitroimidazole-resistant trichomoniasis is concerning because few alternatives to standard therapy exist. We assessed the prevalence of in vitro aerobic MTZ and secnidazole resistance among TV isolates from 100 women in Birmingham, AL with positive cultures during the period 2015-2016.. Archived specimens were treated with secnidazole or MTZ (0.2–400 μg/mL) for 48 hours, as per the United States Centers for Disease Control and Prevention protocols. Ninety-six of the 100 clinical trichomonas isolates tested (96%) demonstrated a lower minimal lethal concentration for secnidazole than for MTZ, suggesting that secnidazole has better in vitro activity than MTZ.
http://ift.tt/2o1FFfW
A next-generation sequencing and bioinformatics protocol for Malaria drug Resistance marker Surveillance (MaRS) [PublishAheadOfPrint]
The recent advances in next-generation sequencing technologies provide a new and effective way of tracking malaria drug resistant parasites. To take advantage of this technology an end-to-end Illumina targeted amplicon deep sequencing (TADS) and bioinformatics pipeline for molecular surveillance of drug resistance in P. falciparum, called Malaria Resistance Surveillance (MaRS), was developed. TADS relies on PCR enriching genomic regions, specifically target genes of interest, prior to deep sequencing. MaRS enables researchers to simultaneously collect data on allele frequencies of multiple full-length P. falciparum drug resistance genes (crt, mdr1, k13, dhfr, dhps, and cytochrome b) as well as the mitochondrial genome. Information is captured at the individual patient level for both known and potential new single nucleotide polymorphisms associated with drug resistance. MaRS pipeline was validated using 245 imported malaria cases that were reported to the Centers for Disease Control and Prevention (CDC). The chloroquine resistant crt CVIET genotype was observed in 42% of samples, the highly pyrimethamine resistant triple mutant dhps IRN in 92% of samples, and the sulfadoxine resistant dhps SGEAA in 26% of samples. The mdr1 NFSND genotype was found in 40% of samples. With the exception of two cases imported from Cambodia, no artemisinin resistant K13 alleles were identified and 99% of patients carried parasites susceptible to atovaquone-proguanil. Our goal is to implement MaRS at the CDC for routine surveillance of imported malaria cases in the U.S. and aid in the adoption of this system in participating state public health laboratories as well as global partners.
http://ift.tt/2nVk3Tc
Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus [PublishAheadOfPrint]
Sofosbuvir and ribavirin exert their anti-hepatitis C virus (HCV) activity following metabolic activation in the liver. However, intrahepatic concentrations of the pharmacologically active nucleotide metabolites in humans are poorly characterized due to the inaccessibility of tissue and technical challenges with measuring nucleotide levels. A clinical study assessing the efficacy of sofosbuvir and ribavirin administered prior to liver transplant to prevent HCV reoccurrence provided a unique opportunity to quantify nucleotide concentrations in human liver. We analyzed nucleotides using high performance liquid chromatography coupled to tandem mass spectrometry in liver tissue from 30 HCV-infected patients with hepatocellular carcinoma who were administered sofosbuvir (400 mg/day) and ribavirin (1,000-1,200 mg/day) for between 3 and 52 weeks prior to liver transplantation. Median total hepatic metabolite concentrations (sum of nucleoside and mono-, di-, and tri-phosphates) were 77.1 μM for sofosbuvir and 361 μM for ribavirin in patients on therapy at the time of transplant. Ribavirin and sofosbuvir efficiently loaded the liver, with total hepatic concentrations exceeding maximal plasma levels by approximately 30-fold. Ribavirin metabolite levels suggest its monophosphate is in great excess of its inhibition constant for inosine monophosphate dehydrogenase and triphosphate is approaching the binding constant for incorporation by the HCV NS5B RNA-dependent RNA polymerase. Consistent with the potent antiviral activity of sofosbuvir, these results illustrate that liver triphosphate levels achieved following sofosbuvir administration greatly exceed the inhibition constant for HCV NS5B. In conclusion, this study expands the quantitative understanding of the pharmacology of sofosbuvir and ribavirin by establishing efficient hepatic delivery in the clinic.
http://ift.tt/2o2L2vh
Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis [PublishAheadOfPrint]
Scedosporium apiospermum is a medically important fungal pathogen that causes a wide range of infections in humans. There are relatively few antifungal agents that are active against Scedosporium spp. Little is known about the pharmacodynamics of voriconazole against Scedosporium. Both static and dynamic in vitro models of invasive scedosporiosis were developed. Monoclonal antibodies that target a soluble cell wall antigen secreted by Scedosporium apiospermum were used to describe the pharmacodynamics of voriconazole. Mathematical pharmacokinetic-pharmacodynamic models were fitted to the data to estimate the drug exposure required to suppress the release of fungal antigen. The experimental results were bridged to humans using Monte Carlo simulation. All 3 strains of S. apiospermum tested invaded through the cellular bilayer of the in vitro models and liberated antigen. There was a concentration-dependent decline in antigen with near maximal antifungal activity in all 3 strains with 10 mg/L. Similarly, there was a drug exposure dependent decline in circulating antigen in the dynamic model and complete suppression of antigen with an AUC of approximately 80 mg.h/L. A regression of the AUC:MIC versus area under the antigen time curve showed that near maximal effect was obtained with AUC:MIC of approximately 100. Monte Carlo simulation suggested that only isolates with an MIC of 0.5 mg/L enable pharmacodynamic targets to be acheived with a standard regimen of voriconazole. Isolates with higher MICs may need higher drug exposure targets than are currently recommended for other fungi.
http://ift.tt/2nVjY1Q
Anidulafungin pharmacokinetics in ascites and pleural effusion of critically ill patients [PublishAheadOfPrint]
Anidulafungin concentrations were quantified with high pressure liquid chromatography (HPLC) and UV detection in ascites and in pleural effusion of ten adult critically ill patients. Samples were collected from ascites and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites (0.12-0.99 μg/ml) and in pleural effusion (0.32-2.02 μg/ml) were below the simultaneous plasma levels (1.04-7.70 and 2.48-13.36 μg/ml, respectively) and below the MIC values of several pathogenic Candida strains.
http://ift.tt/2o2m4w9
A Phase 1 Study in Healthy Subjects to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Oral Doses of DS-2969b, a Novel GyrB Inhibitor [PublishAheadOfPrint]
DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection (CDI). The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota of multiple daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled three sequential ascending dose cohorts (60 mg, 200 mg, and 400 mg). In each cohort, subjects received an oral dose of DS-2969b or placebo (six DS-2969b and two placebo) each morning for 14 days. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild, and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses, however, both Cmax and AUC increased less than dose-proportionally. In all cohorts, sufficient fecal levels of DS-2969a were achieved within 24 hours following the administration of the first dose and maintained for at least 17 days. Following treatment with DS-2696b, a clear reduction in Clostridium coccoides and Bifidobacterium groups was observed. However, populations of three other bacterial groups examined (Bacteroides fragilis, Clostridium leptum, and Prevotella) were not affected. Data from this study support and encourage further development of DS-2969b as a novel treatment for CDI.
http://ift.tt/2nVHCuS
Omadacycline: comparative in vitro activity against dog and cat bite wound isolates [PublishAheadOfPrint]
Omadacycline was tested against 125 isolates recovered from infected cat and dog bites in humans. Its activity was similar to other compounds in the tetracycline class and was active against strains exhibiting tetracycline resistance. Against anaerobic isolates, resistance to tetracyclines was more prominent, and omadacycline was the most active of the group. All isolates had omadacycline MICs <1 μg/ml with the exception of Eikenella corrodens which showed reduced susceptibility to the entire tetracycline group.
http://ift.tt/2o08Q2K
Probing the Mechanism of Inactivation of the FOX-4 Cephamycinase by Avibactam [PublishAheadOfPrint]
Ceftazidime-avibactam is a "second generation" β-lactam-β-lactamase inhibitor combination that is effective against Enterobacteriaceae expressing class A extended-spectrum β-lactamases, class A carbapenemases and/or class C cephalosporinases. Knowledge of the interactions of avibactam, a diazabicyclooctane with different β-lactamases is required to anticipate future resistance threats. FOX family β-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs. Interestingly, a single amino acid substitution at N346 in the Citrobacter AmpC is implicated in resistance to the aztreonam-avibactam combination. In order to understand how diverse active site topologies affect avibactam inhibition, we tested a panel of clinical Enterobacteriaceae isolates producing blaFOX using ceftazidime-avibactam, determined the biochemical parameters for inhibition using the FOX-4 variant, and probed the atomic structure of avibactam with FOX-4. Avibactam restored susceptibility to ceftazidime for most isolates producing blaFOX; two isolates expressing blaFOX-4 or blaFOX-5 displayed an MIC of 16 μg/mL for the combination. FOX-4 possessed a k2/K value of 1,800 ± 100 M-1s-1 and a koff of 0.0013 ± 0.0003 s-1. Mass spectrometry showed that the FOX-4-avibactam complex was stable for 24 hr. Analysis of the crystal structure of FOX-4 with avibactam at a 1.5 Å resolution revealed a unique characteristic of this AmpC β-lactamase. Unlike in the PDC-1 avibactam crystal structure, interactions (e.g., hydrogen bonding) between avibactam and position I346 in FOX-4 are not evident. Furthermore, another residue is not observed to be close enough to compensate for the loss of these critical hydrogen bonding interactions. This observation supports findings from the inhibition analysis of FOX-4; FOX-4 possessed the highest Kd value (1,600 nM) for avibactam compared to other AmpCs (7-660 nM). Medicinal chemists must consider the properties of extended-spectrum AmpCs, such as the FOX β-lactamases for the design of future diazabicyclooctanes.
http://ift.tt/2nSW7zN
In vitro and in vivo activities of DS-2969b, a novel GyrB inhibitor, against Clostridium difficile [PublishAheadOfPrint]
DS-2969b is a novel GyrB inhibitor, which is currently under clinical development for treatment of Clostridium difficile infection (CDI). In this study, the in vitro and in vivo activities of DS-2969b were evaluated. DS-2969b inhibited the supercoiling activity of C. difficile DNA gyrase. DS-2969b showed potent in vitro activity against C. difficile clinical isolates with an MIC90 of 0.06 μg/mL, which was 2-, 32-, and 16-fold lower than the MIC90 of fidaxomicin, vancomycin, and metronidazole, respectively. DS-2969b did not select spontaneous resistant mutant of various C. difficile strains at 4 x MICs and the frequency of resistance development was less than 4.8 x 10-9. In a hamster CDI model, 5-day oral administration of DS-2969b conferred complete protection from recurrence and mortality at 0.3 mg/kg once a day compared with 50% survival rate with fidaxomicin at 3 mg/kg once a day and 0% with vancomycin at 50 mg/kg/dose twice a day. Even a single oral administration of 1 mg/kg of DS-2969b in the CDI model exhibited 100% animal survival without recurrence. DS-2969b was also efficacious by 5-day subcutaneous administration in the CDI model. DS-2969b showed similar fecal excretion after intravenous and oral administrations in rats. These data support further development of DS-2969b as a drug for oral and intravenous treatment of CDI.
http://ift.tt/2o2lI8N
In Vitro and In Vivo Efficacy of a Novel and Long Acting Fungicidal Azole, PC1244 on Aspergillus fumigatus Infection [PublishAheadOfPrint]
The antifungal effects of the novel triazole, PC1244, designed for topical or inhaled administration, against A. fumigatus have been tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (N=96) with a MIC range of 0.016--0.25 μg/ml, whereas the MIC range for voriconazole was 0.25--0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with an IC50 of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC ranged from <0.0078~2 μg/ml), especially on Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans and Rhizopus oryzae. PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (MFC, 2 μg/ml), which was 8-fold more potent than voriconazole. In vivo, once daily intranasal administration of PC1244 (3.2 ~ 80μg/mL) to temporarily neutropenic, immunocompromised mice 24h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced fungal load in the lung, galactomannan in serum and circulating inflammatory cytokines. Furthermore, 7 days extended prophylaxis with PC1244 showed superior in vivo effects when compared against 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.
http://ift.tt/2nSVTIX
In vitro activity of lascufloxacin against Streptococcus pneumoniae with mutations in the quinolone resistance-determining regions (QRDRs) [PublishAheadOfPrint]
Lascufloxacin showed potent activity against Streptococcus pneumoniae with GyrA or ParC mutation (first-step mutants). The frequency of selecting resistant strains tended to be lower for lascufloxacin than levofloxacin and garenoxacin after drug exposure in first-step mutants, but was similar in the comparison between lascufloxacin and moxifloxacin. The increase in MIC was smaller for lascufloxacin than for levofloxacin, garenoxacin, and moxifloxacin when clinical strains with only ParC mutation were exposed to the corresponding drug.
http://ift.tt/2o2lu1r
Treatment of glioblastoma with herbal medicines
Abstract
Background
In the latest years, a lot of research studies regarding the usage of active agents from plants in the treatment of tumors have been published, but there is no data about successful usage of herbal remedies in the treatment of glioblastoma in humans.
Methods
The phytotherapy involved five types of herbal medicine which the subjects took in the form of tea, each type once a day at regular intervals. Three patients took herbal medicine along with standard oncological treatment, while two patients applied for phytotherapy after completing medical treatment. The composition of herbal medicine was modified when necessary, which depended on the results of the control scans using the nuclear magnetic resonance technique and/or computed tomography.
Results
Forty-eight months after the introduction of phytotherapy, there were no clinical or radiological signs of the disease, in three patients; in one patient, the tumor was reduced and his condition was stable, and one patient lived for 48 months in spite of a large primary tumor and a massive recurrence, which developed after the treatment had been completed.
Conclusions
The results achieved in patients in whom tumor regression occurred exclusively through the use of phytotherapy deserve special attention.
In order to treat glioblastoma more effectively, it is necessary to develop innovative therapeutic strategies and medicines that should not be limited only to the field of conventional medicine. The results presented in this research paper are encouraging and serve as a good basis for further research on the possibilities of phytotherapy in the treatment of glioblastoma.
http://ift.tt/2ChrNmx
A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity
The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiological stemness of the resulting cell populations. Here we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn-cells intracytoplasmically. Release of Gn-cells occurred by ejection through crevices in P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1-cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1-cells were competent to horizontally transmit offspring Gn-cells into other specific proximal cells, injecting them to receptor R1-cells via cell-cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1-cells with low expression of stem cell markers despite their physiological stemness, the first offspring generations of daughter G1-cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1- and Gn-cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1-cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell-biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.
http://ift.tt/2o2J2Dh
Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts non-oncogenic PKM2 to a tumor promoter and induces cancer stem-like cells
The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed non-tumorigenic tetramers in non-transformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phospho-mimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing YAP protein nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.
http://ift.tt/2nSsrCY
Crosstalk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer
Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase (RTK) profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the monoclonal antibody CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that crosstalk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that co-targeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors
http://ift.tt/2o2gSZ7
RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma
Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis. Inhibition of RSK reduced PFKFB2 activity and glycolytic flux in melanoma cells, suggesting an important role for RSK in BRAF-mediated metabolic rewiring. Consistent with this, expression of a phosphorylation-deficient mutant of PFKFB2 decreased aerobic glycolysis and reduced the growth of melanoma in mice. Together these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF-mutated melanomas.
http://ift.tt/2nV2PW0
FOXO transcription factors both suppress and support breast cancer progression.
FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K-signaling, all of which must be carefully balanced for tumor cells to thrive.
http://ift.tt/2o5LQj8
Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?
Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints.
http://ift.tt/2EoExcU
A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma
Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age-dependence and predilection of RMC towards the right kidney.
http://ift.tt/2F1KeyU
Mechanical stretch-induced osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMMSCs) via inhibition of the NF-κB pathway
Mechanical stretch-induced osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMMSCs) via inhibition of the NF-κB pathway
Mechanical stretch-induced osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMMSCs) via inhibition of the NF-κB pathway, Published online: 12 February 2018; doi:10.1038/s41419-018-0279-5
Mechanical stretch-induced osteogenic differentiation of human jaw bone marrow mesenchymal stem cells (hJBMMSCs) via inhibition of the NF-κB pathwayhttp://ift.tt/2GaEVMX
Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation
Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation
Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na<sup>+</sup>/Ca<sup>2+</sup> exchanger 3 downregulation, Published online: 12 February 2018; doi:10.1038/s41419-017-0227-9
Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulationhttp://ift.tt/2H7qrP4
Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival
Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival
Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival, Published online: 12 February 2018; doi:10.1038/s41419-017-0242-x
Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survivalhttp://ift.tt/2G7JCH8
Association of cytosolic sialidase Neu2 with plasma membrane enhances Fas-mediated apoptosis by impairing PI3K-Akt/mTOR-mediated pathway in pancreatic cancer cells
Association of cytosolic sialidase Neu2 with plasma membrane enhances Fas-mediated apoptosis by impairing PI3K-Akt/mTOR-mediated pathway in pancreatic cancer cells
Association of cytosolic sialidase Neu2 with plasma membrane enhances Fas-mediated apoptosis by impairing PI3K-Akt/mTOR-mediated pathway in pancreatic cancer cells, Published online: 12 February 2018; doi:10.1038/s41419-017-0191-4
Association of cytosolic sialidase Neu2 with plasma membrane enhances Fas-mediated apoptosis by impairing PI3K-Akt/mTOR-mediated pathway in pancreatic cancer cellshttp://ift.tt/2H7q8no
Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson’s disease
Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson's disease
Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson's disease, Published online: 12 February 2018; doi:10.1038/s41419-017-0221-2
Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson's diseasehttp://ift.tt/2G99pir
Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat
Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat
Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat, Published online: 12 February 2018; doi:10.1038/s41419-017-0217-y
Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rathttp://ift.tt/2H7pZQS
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells, Published online: 12 February 2018; doi:10.1038/s41419-018-0263-0
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cellshttp://ift.tt/2G7jhJo
MiR-22 suppresses epithelial–mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop
MiR-22 suppresses epithelial–mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop
MiR-22 suppresses epithelial–mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop, Published online: 12 February 2018; doi:10.1038/s41419-017-0206-1
MiR-22 suppresses epithelial–mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loophttp://ift.tt/2H9UxkZ
Nutraceuticals: opening the debate for a regulatory framework
Summary
Currently, nutraceuticals do not have a specific definition distinct from those of other food-derived categories, e.g., food supplements, herbal products, pre- and probiotics, functional foods, and fortified foods. Many studies have led to an understanding of the potential mechanisms of action of pharmaceutically active components contained in food that may improve health and reduce the risk of pathological conditions while enhancing overall well-being. Nevertheless, there is a lack of clear information, and often, the claimed health benefits may not be properly substantiated by safety and efficacy information and in vitro and in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. An officially shared and accepted definition of nutraceuticals is still missing, as nutraceuticals are mostly referred to as pharma-foods, a powerful toolbox to be used "beyond the diet but before the drugs" to prevent and treat pathological conditions, e.g., in subjects who may not yet be eligible for conventional pharmaceutical therapy. Hence, it is of utmost importance to have a proper and unequivocal definition of nutraceuticals and shared regulations. It also seems wise to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nonetheless, given specific legislation from different countries, nutraceuticals are experiencing challenges with safety and health claim substantiation.
http://ift.tt/2EmaJBT
Risk of unplanned caesarean birth in Vietnamese-born women in Victoria, Australia: A cross-sectional study
Publication date: Available online 12 February 2018
Source:Women and Birth
Author(s): Paul A. Agius, Mary-Ann Davey, Rhonda Small
BackgroundUnderstanding the prevalence of, and factors associated with, caesarean birth among immigrant populations is essential for appropriate antenatal and postnatal resource allocation.AimsTo compare rates of caesarean birth between one of the largest immigrant populations of women giving birth in Australia (Vietnamese-born women) with those of Australian-born women and investigate the odds of unplanned caesarean in these women, controlling for maternal characteristics, pregnancy complications and labour management factors.MethodsCross-sectional analysis of data on singleton births in Victoria, Australia; using data from the routinely collected Victorian Perinatal Data Collection. Descriptive analyses comparing maternal and obstetric factors for Vietnamese-born women with Australian-born women were undertaken. Using the more recent nine years of routinely collected data, multivariable logistic regression explored the association between unplanned caesarean birth and maternal country of birth, adjusted for maternal and obstetric factors, admission status and time (n=468,131). This association was also explored for 'standard primiparae' (n=69,039).FindingsPlanned and unplanned caesarean births increased dramatically in both Australian-born and Vietnamese-born women between 1984 and 2007. After adjustment for obstetric and maternal factors, Vietnamese-born women were at greater odds of an unplanned caesarean birth compared to Australian-born women (adjusted odds ratio=1.32, 95% confidence interval=1.25–1.40). These greater odds were also found among the 'standard primiparae' (adjusted odds ratio=1.22, 95% confidence interval=1.07–1.40).ConclusionFactors other than clinical risk appear to predispose Vietnamese-born women to unplanned caesarean birth. These may include intrapartum communication, length of residence and familiarity with care systems, and variations in care practices for Vietnamese women.
http://ift.tt/2CeJinL
Cranial Electrical Stimulation: What Is It, and Should We Use It in Practice?
Cranial electrical stimulation (CES) is a form of brain stimulation that uses low levels of alternating current. The review by Shekelle and colleagues found limited and inconclusive evidence from randomized trials on the effectiveness and safety of CES for chronic pain, depression, anxiety, and insomnia. The editorialist discusses the findings and wonders whether the failure to demonstrate efficacy is due to inadequate studies or true lack of effectiveness. Regardless, he believes that this review should caution clinicians and patients to be more circumspect in CES use.
http://ift.tt/2o1YoHY
http://ift.tt/2o1YoHY
Prescription Opioids and Infection Risk: Research and Caution Needed
In their current Annals report, Wiese and colleagues provide evidence that prescription opioids are associated with an increased risk for serious infections. The editorialists discuss the study and what clinicians and researchers should do in light of its findings.
http://ift.tt/2nYqAvs
http://ift.tt/2nYqAvs
A Cautionary Tale of Warning Messages on Food Products: The Case of Sugar-Sweetened Beverages
To protect public health, the government may mandate the placement of warnings on products that it believes pose health risks. However, as a recent legal case demonstrates, such mandates require fulfillment of specific standards for compelled speech.
http://ift.tt/2o1ajWt
http://ift.tt/2o1ajWt
Balancing the Benefits and Harms of Electronic Cigarettes: A National Academies of Science, Engineering, and Medicine Report
Electronic cigarettes present a conundrum. They have the potential for benefit if they help smokers quit, but this must be balanced against potential harm if e-cigarettes entice youths who would otherwise not have become cigarette smokers to try e-cigarettes, then become addicted to nicotine and switch to combustible cigarettes. This commentary discusses the National Academies of Sciences, Engineering, and Medicine report Public Health Consequences of E-Cigarettes and provides advice on how to counsel patients who ask about e-cigarettes.
http://ift.tt/2nSDQ5F
http://ift.tt/2nSDQ5F
Scalar-on-image regression via the soft-thresholded Gaussian process
Summary
This work concerns spatial variable selection for scalar-on-image regression. We propose a new class of Bayesian nonparametric models and develop an efficient posterior computational algorithm. The proposed soft-thresholded Gaussian process provides large prior support over the class of piecewise-smooth, sparse, and continuous spatially varying regression coefficient functions. In addition, under some mild regularity conditions the soft-thresholded Gaussian process prior leads to the posterior consistency for parameter estimation and variable selection for scalar-on-image regression, even when the number of predictors is larger than the sample size. The proposed method is compared to alternatives via simulation and applied to an electroencephalography study of alcoholism.http://ift.tt/2EhIWhR
Dual regression
Summary
We propose dual regression as an alternative to quantile regression for the global estimation of conditional distribution functions. Dual regression provides the interpretational power of quantile regression while avoiding the need to repair intersecting conditional quantile surfaces. We introduce a mathematical programming characterization of conditional distribution functions which, in its simplest form, is the dual program of a simultaneous estimator for linear location-scale models, and use it to specify and estimate a flexible class of conditional distribution functions. We present asymptotic theory for the corresponding empirical dual regression process.http://ift.tt/2EXHemY
On overfitting and post-selection uncertainty assessments
Summary
In a regression context, when the relevant subset of explanatory variables is uncertain, it is common to use a data-driven model selection procedure. Classical linear model theory, applied naively to the selected submodel, may not be valid because it ignores the selected submodel's dependence on the data. We provide an explanation of this phenomenon, in terms of overfitting, for a class of model selection criteria.http://ift.tt/2EhIFvl
On bias reduction and incidental parameters
Summary
Firth (1993) introduced a method for reducing the bias of the maximum likelihood estimator. Here it is shown that the approach is also effective in reducing the sensitivity of inferential procedures to incidental parameters.http://ift.tt/2EhIAYz
Shape-constrained partial identification of a population mean under unknown probabilities of sample selection
Summary
Estimating a population mean from a sample obtained with unknown selection probabilities is important in the biomedical and social sciences. Using a ratio estimator, Aronow & Lee (2013) proposed a method for partial identification of the mean by allowing the unknown selection probabilities to vary arbitrarily between two fixed values. In this paper, we show how to use auxiliary shape constraints on the population outcome distribution, such as symmetry or log-concavity, to obtain tighter bounds on the population mean. We use this method to estimate the performance of Aymara students, an ethnic minority in the north of Chile, in a national educational standardized test. We implement this method in the R package scbounds.http://ift.tt/2EYwxAF
Robust and consistent variable selection in high-dimensional generalized linear models
Summary
Generalized linear models are popular for modelling a large variety of data. We consider variable selection through penalized methods by focusing on resistance issues in the presence of outlying data and other deviations from assumptions. We highlight the weaknesses of widely-used penalized M-estimators, propose a robust penalized quasilikelihood estimator, and show that it enjoys oracle properties in high dimensions and is stable in a neighbourhood of the model. We illustrate its finite-sample performance on simulated and real data.http://ift.tt/2EmHlHG
Approximate Bayesian inference under informative sampling
Summary
Statistical inference with complex survey data is challenging because the sampling design can be informative, and ignoring it can produce misleading results. Current methods of Bayesian inference under complex sampling assume that the sampling design is noninformative for the specified model. In this paper, we propose a Bayesian approach which uses the sampling distribution of a summary statistic to derive the posterior distribution of the parameters of interest. Asymptotic properties of the method are investigated. It is directly applicable to combining information from two independent surveys and to calibration estimation in survey sampling. A simulation study confirms that it can provide valid estimation under informative sampling. We apply it to a measurement error problem using data from the Korean Longitudinal Study of Aging.http://ift.tt/2F0QmXS
On causal estimation using $U$-statistics
Summary
We introduce a general class of causal estimands which extends the familiar notion of average treatment effect. The class is defined by a contrast function, prespecified to quantify the relative favourability of one outcome over another, averaged over the marginal distributions of two potential outcomes. Natural estimators arise in the form of $U$-statistics. We derive both a naive inverse propensity score weighted estimator and a class of locally efficient and doubly robust estimators. The usefulness of our theory is illustrated by two examples, one for causal estimation with ordinal outcomes, and the other for causal tests that are robust with respect to outliers.http://ift.tt/2EonqYI
A structural Markov property for decomposable graph laws that allows control of clique intersections
Summary
We present a new kind of structural Markov property for probabilistic laws on decomposable graphs, which allows the explicit control of interactions between cliques and so is capable of encoding some interesting structure. We prove the equivalence of this property to an exponential family assumption, and discuss identifiability, modelling, inferential and computational implications.http://ift.tt/2EWycXn
Kernel-based covariate functional balancing for observational studies
Summary
Covariate balance is often advocated for objective causal inference since it mimics randomization in observational data. Unlike methods that balance specific moments of covariates, our proposal attains uniform approximate balance for covariate functions in a reproducing-kernel Hilbert space. The corresponding infinite-dimensional optimization problem is shown to have a finite-dimensional representation in terms of an eigenvalue optimization problem. Large-sample results are studied, and numerical examples show that the proposed method achieves better balance with smaller sampling variability than existing methods.http://ift.tt/2BVAk2Y
Partial likelihood estimation of isotonic proportional hazards models
Summary
We consider the estimation of the semiparametric proportional hazards model with an unspecified baseline hazard function where the effect of a continuous covariate is assumed to be monotone. Previous work on nonparametric maximum likelihood estimation for isotonic proportional hazard regression with right-censored data is computationally intensive, lacks theoretical justification, and may be prohibitive in large samples. In this paper, partial likelihood estimation is studied. An iterative quadratic programming method is considered, which has performed well with likelihoods for isotonic parametric regression models. However, the iterative quadratic programming method for the partial likelihood cannot be implemented using standard pool-adjacent-violators techniques, increasing the computational burden and numerical instability. The iterative convex minorant algorithm which uses pool-adjacent-violators techniques has also been shown to perform well in related parametric likelihood set-ups, but evidences computational difficulties under the proportional hazards model. An alternative pseudo-iterative convex minorant algorithm is proposed which exploits the pool-adjacent-violators techniques, is theoretically justified, and exhibits computational stability. A separate estimator of the baseline hazard function is provided. The algorithms are extended to models with time-dependent covariates. Simulation studies demonstrate that the pseudo-iterative convex minorant algorithm may yield orders-of-magnitude reduction in computing time relative to the iterative quadratic programming method and the iterative convex minorant algorithm, with moderate reductions in the bias and variance of the estimators. Analysis of data from a recent HIV prevention study illustrates the practical utility of the isotonic methodology in estimating nonlinear, monotonic covariate effects.http://ift.tt/2BneKU5
A conditional composite likelihood ratio test with boundary constraints
Summary
Composite likelihood has been widely used in applications. The asymptotic distribution of the composite likelihood ratio statistic at the boundary of the parameter space is a complicated mixture of weighted $\chi^2$ distributions. In this paper we propose a conditional test with data-dependent degrees of freedom. We consider a modification of the composite likelihood which satisfies the second-order Bartlett identity. We show that the modified composite likelihood ratio statistic given the number of estimated parameters lying on the boundary converges to a simple $\chi^2$ distribution. This conditional testing procedure is validated through simulation studies.http://ift.tt/2BrGTcn
A robust goodness-of-fit test for generalized autoregressive conditional heteroscedastic models
Summary
The estimation of time series models with heavy-tailed innovations has been widely discussed, but corresponding goodness-of-fit tests have attracted less attention, primarily because the autocorrelation function commonly used in constructing goodness-of-fit tests necessarily imposes certain moment conditions on the innovations. As a bounded random variable has finite moments of all orders, we address the problem by first transforming the residuals with a bounded function. More specifically, we consider the sample autocorrelation function of the transformed absolute residuals of a fitted generalized autoregressive conditional heteroscedastic model. With the corresponding residual empirical distribution function naturally employed as the transformation, a robust goodness-of-fit test is then constructed. The asymptotic distributions of the test statistic under the null hypothesis and local alternatives are derived, and Monte Carlo experiments are conducted to examine finite-sample properties. The proposed test is shown to be more powerful than existing tests when the innovations are heavy-tailed.http://ift.tt/2BT9UyM
Two-sample tests of high-dimensional means for compositional data
Summary
Compositional data are ubiquitous in many scientific endeavours. Motivated by microbiome and metagenomic research, we consider a two-sample testing problem for high-dimensional compositional data and formulate a testable hypothesis of compositional equivalence for the means of two latent log basis vectors. We propose a test through the centred log-ratio transformation of the compositions. The asymptotic null distribution of the test statistic is derived and its power against sparse alternatives is investigated. A modified test for paired samples is also considered. Simulations show that the proposed tests can be significantly more powerful than tests that are applied to the raw and log-transformed compositions. The usefulness of our tests is illustrated by applications to gut microbiome composition in obesity and Crohn's disease.http://ift.tt/2BpS5X8
A randomization-based perspective on analysis of variance: a test statistic robust to treatment effect heterogeneity
Summary
Fisher randomization tests for Neyman's null hypothesis of no average treatment effect are considered in a finite-population setting associated with completely randomized experiments involving more than two treatments. The consequences of using the $F$ statistic to conduct such a test are examined, and we argue that under treatment effect heterogeneity, use of the $F$ statistic in the Fisher randomization test can severely inflate the Type I error under Neyman's null hypothesis. We propose to use an alternative test statistic, derive its asymptotic distributions under Fisher's and Neyman's null hypotheses, and demonstrate its advantages through simulations.http://ift.tt/2BTOLVp
Optimal discrimination designs for semiparametric models
Summary
Much work on optimal discrimination designs assumes that the models of interest are fully specified, apart from unknown parameters. Recent work allows errors in the models to be nonnormally distributed but still requires the specification of the mean structures. Otsu (2008) proposed optimal discriminating designs for semiparametric models by generalizing the Kullback–Leibler optimality criterion proposed by López-Fidalgo et al. (2007). This paper develops a relatively simple strategy for finding an optimal discrimination design. We also formulate equivalence theorems to confirm optimality of a design and derive relations between optimal designs found here for discriminating semiparametric models and those commonly used in optimal discrimination design problems.http://ift.tt/2BpS4Cy
Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists
The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.
http://ift.tt/2nV0gmM
Respiratory symptoms of an abdominal origin
Description
A 75-year-old, fully dependent woman was sent to the emergency department due to a sudden onset of fever (38°C), polypnoea and dyspnoea. The patient had a history of Parkinson's disease and vascular dementia, making it impossible to cooperate in the medical interview. She was feverish, breathing rapidly, although haemodynamically stable and with peripheral oxygen saturation of over 95%. Blood tests showed increase in C-reactive protein (8.51 mg/dL), leucocytosis (13x109/L, 67% neutrophils and 23.1% lymphocytes) and slight hypokalaemia (3 mmol/L), without respiratory insufficiency in the arterial blood. Chest X-ray showed no clear infectious consolidation.
Acute tracheobronchitis was assumed, so she was given an antibiotic and potassium chloride and was discharged. The patient returned the next day without fever but with all of the other symptoms, adding to them prostration. She was still breathing rapidly but her abdomen was larger and tympanic, with noticeable pain while it was being palpated, adding therefore...
http://ift.tt/2o0TLhB
Basilar artery fenestration: an unusual possible cause of ischaemic stroke?
Basilar artery fenestration is an uncommon congenital dysplasia and may be associated with ischaemic stroke. We present a case of a previously healthy 36-year-old man who presented with vertigo and vomiting. MRI showed posterior circulation territory infarction. High-resolution magnetic resonance angiography revealed a slit-like fenestration in the basilar artery. This patient had no traditional vascular risk factors or aetiology of cryptogenic stroke. The patient recovered from his neurological deficit after antiplatelet therapy and was given prophylactic aspirin therapy. There was no recurrence of symptoms after 12 months of follow-up.
http://ift.tt/2nVJwMm
Propionibacterium acnes and Staphylococcus epidermidis olecranon bursitis/osteomyelitis: a case involving surgical and antibiotic treatment
This report describes a 63-year-old generally healthy male with septic olecranon bursitis caused by Propionibacterium acnes. The patient sustained a small laceration after striking the posterior aspect of his left elbow on a metal railing when he was at a public swimming pool. We concluded that P. acnes was not initially detected because cultures were only kept for 5 days. Consequently, initial antibiotic treatment failed. P. acnes and Staphylococcus epidermidis grew in a subsequent tissue culture. The infection did not respond to intravenous vancomycin although soft-tissue debridements were done. This likely reflected the presence of olecranon osteomyelitis (seen on MRI scans) in addition to inadequate treatment with this antibiotic in the setting of a polymicrobial infection. Eventually, the infection was eradicated with multiple soft-tissue debridements in addition to the continuation of vancomycin with daily intravenous piperacillin/tazobactam that was added for the final 4 weeks of antibiotic treatment.
http://ift.tt/2o0TGKP
DJ-1 is a useful biomarker for invasive extrahepatic cholangiocarcinoma
We have previously reported that DJ-1 protein is up-regulated in cholangiocarcinoma compared with non-neoplastic epithelium of the bile duct in a study using liquid chromatography mass spectrometry-based proteomics. The aim of this study was to clarify whether DJ-1 expression offers a biomarker for patients with invasive extrahepatic cholangiocarcinoma (EHCC) who undergo surgical resection with curative intent. Positive immunohistochemical (IHC) staining of DJ-1 was significantly more frequent in the cytoplasm of 96 invasive EHCCs (n=28, 29.2%) than in that of 66 non-neoplastic epithelial lesions adjacent to invasive EHCC (n=7, 10.6%; P=.006).
http://ift.tt/2ElJhQP
Over-expression of BCAT1 is a prognostic marker in gastric cancer
As one form of branched chain amino-acid transaminase(BCAT) enzymes, It has been found that up-regulation of BCAT1 is associated with poor prognosis in numerous types of tumors, but studies on the role of BCAT1 expression in gastric cancer(GC) are rare. The aim of this study was to detect BCAT1 expression in (GC) and to analyze its association with prognosis of GC patients.Microarray experiments were performed on the Affymetrix U133 plus 2.0 GeneChip Array. The protein and mRNA levels of BCAT1 were validated by immunohistochemistry (IHC) and Real-Time quantitative PCR (RT-qPCR) in GC tissues and adjacent noncancerous tissues (ANCT).
http://ift.tt/2EYsswl
New prostate cancer grade grouping system predicts survival after radical prostatectomy
Histological Gleason grading of prostate cancer has been through modifications and conjoined into a Grade Grouping system recently. The aim of this study was to determine whether the new Grade Grouping system predicts disease-specific and all-cause mortality after radical prostatectomy. We constructed a clinical database consisting of all consecutively radical prostatectomy treated men between 1983 and 1998 and between 2000 and 2005 at the Helsinki University Hospital and at the Turku University Hospital, respectively.
http://ift.tt/2ElJfsb
Expression of Programmed cell death protein 1 (PD-1) and Indoleamine 2,3-dioxygenase (IDO) in the tumor microenvironment and in tumor-draining lymph nodes of breast cancer
Programmed cell death protein 1 (PD-1) and Indoleamine 2,3-dioxygenase (IDO) are both immunosuppressive proteins. Here, we investigated the relationship between PD-1 and IDO in the tumor microenvironment (TME) and in tumor-draining lymph nodes (TDLNs) in breast cancer patients. First, the protein and mRNA expression levels of PD-1 and IDO in 20 frozen tissues were examined using Western blotting and RT-PCR. Second, 151 paraffin-embedded breast samples and 52 lymph node samples were analyzed by immunohistochemistry.
http://ift.tt/2EWtLfb
DNA demethylation of claudin-4 suppresses migration and invasion in laryngeal squamous carcinoma cells
Claudin-4 (CLDN4) is a member of the claudin transmembrane protein family, which consists of integral membrane proteins that are components of the epithelial cell tight junctions; these tight junctions regulate movement of solutes and ions through the paracellular space. CLDN4 is also a differentiation marker and is believed to indicate an epithelial phenotype. However, the role of CLDN4 in laryngeal squamous carcinoma is still unclear. Here, we showed that CLDN4 expression was down-regulated in laryngeal squamous carcinoma tissues and negatively correlated with Methyl-CpG-binding protein 2 (MeCP2).
http://ift.tt/2EmrJnJ
Regional lymph node sampling in lung carcinoma: a single institutional and national database comparison
Assessing regional lymph node metastasis is a key component of lung carcinoma staging and prognostication. Recent guidelines have suggested a quality metric of 10 total regional lymph nodes sampled with each stage I-II primary lung carcinoma resection. However, the extent of mediastinal lymph node sampling remains controversial. We assessed factors contributing to regional lymph node counts and effect on overall patient survival in an institutional cohort of 888 cases and the Surveillance, Epidemiology, and End Results (SEER) national cancer registry (10 856 cases).
http://ift.tt/2EBljnN
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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