The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFα synthesis. Intravenous injection of SB203580 successfully inhibited (P < 0.01) synthesis of IL-1β and reduced (P < 0.01) the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P < 0.01) gene expression of TNFα but its effect was not observed at the level of TNFα protein synthesis. SB203580 also reduced (P < 0.01) LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.
The cosmetic industry adapts to the needs of consumers seeking to limit the use of preservatives and develop of preservative-free or self-preserving cosmetics, where preservatives are replaced by raw materials of plant origin. The aim of study was a comparison of the antimicrobial activity of extracts (Matricaria chamomilla, Aloe vera, Calendula officinalis) and essential oils (Lavandulla officinallis,Melaleuca alternifolia, Cinnamomum zeylanicum) with methylparaben. Extracts (2.5 %), essential oils (2.5 %) and methylparaben (0.4 %) were tested against Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC25922,Staphylococcus aureus ATCC 29213, Candida albicans ATCC 14053. Essentials oils showed higher inhibitory activity against tested microorganism strain than extracts and methylparaben. Depending on tested microorganism strain, all tested extracts and essential oils show antimicrobial activity 0.8–1.7 and 1–3.5 times stronger than methylparaben, respectively. This shows that tested extracts and essential oils could replace use of methylparaben, at the same time giving a guarantee of microbiological purity of the cosmetic under its use and storage.
Antimicrobial activity; Essential oils; Herbal extracts; Methylparaben
This study was performed to evaluate dosimetric differences between current intensity modulated radiation therapy (IMRT) delivery modes: Step-and-shoot (SS), sliding window (SW), and volumetric modulated arc therapy (VMAT). Plans for 15 prostate cancer patients with 10 MV photon beams using each IMRT mode were generated. Patients had three planning target volumes (PTVs) including prostate, prostate plus seminal vesicles, and pelvic lymphatics. Dose volume histograms (DVHs) of PTVs and organs at risk (OARs), tumor control probability (TCP) and normal tissue complication probabilities (NTCPs), conformation number, and monitor units (MUs) used were compared. Statistical analysis was performed using the analysis of variance (ANOVA) technique. The TCPs were < 99% with insignificant differences among modalities (P > 0.99). Doses to all critical structures were higher on average with SW method compared to SS, but insignificant. NTCP values were lowest for VMAT in all structures excepting bladder. Normal tissue volumes receiving doses in the 20-30 Gy range were reduced for VMAT compared to SS. Percentage of MUs required for VMAT to deliver a comparable plan to SS and SW was at least 40% less. In conclusion, similar target coverage and normal tissue doses were found by the three compared modes and the dosimetric differences were small.
Intensity modulated radiation therapy; prostate cancer; step-and-shoot; sliding window; volumetric modulated arc therapy
Acting at the level of the brain, interleukin- (IL-)1β is considered to be one of the most potent downregulators of reproduction processes during immune/inflammatory challenge. IL-1β suppresses gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus resulting in the inhibition of the luteinizing hormone (LH) release from the anterior pituitary (AP). However, the presence of IL-1β receptors in the AP suggests the possible direct action of this cytokine on LH secretion. The study was designed to determine the effect of IL-1β on the LH secretion from the AP explants collected from saline and LPS-treated ewes in the follicular phase. It was found that IL-1β suppressed (P ≤ 0.01) GnRH-stimulated LH release and LHβ gene expression in AP explants in both groups. However, IL-1β action was more potent in the explants collected from LPS-treated animals. Pituitaries from LPS-treated animals were characterized by increased (P ≤ 0.01) IL-1 type I receptor and decreased (P ≤ 0.01) GnRH receptor gene expression level compared to the saline-treated group. IL-1β also affected the GnRH-R gene expression in explants collected from LPS-treated animals. Our results show that direct action of IL-1β on the pituitary gonadotropes could be one of the reasons of the reproductive processes disorders accompanying an inflammatory state.
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
LC3; autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
The aim of this study was to evaluate differences in dose distributions in stereotactic body radiation therapy treatment plans for lung tumors calculated with pencil beam convolution (PBC) algorithm with modified Batho power law (MBPL) versus heterogeneity corrected anisotropic analytical algorithm (AAA) of the Varian Eclipse treatment planning system. The four-dimensional computed tomography images from 20 patients with lung cancer were used to create treatment plans. Plans used five to seven nonopposing coplanar 6 MV beams. Plans generated with the PBC algorithm and MBPL for tissue heterogeneity corrections were optimized to deliver 60 Gy in three fractions to at least 95% of the planned target volume, and the normal tissue doses for spinal cord, esophagus, heart, and ipsilateral bronchus were restricted to less than 18, 27, 30, and 30 Gy, respectively. Plans were recalculated with AAA, retaining identical beam arrangements, photon beam fluences, and monitor units. The pencil beam plans, designed to deliver 60 Gy, delivered on average 51.6 Gy when re-calculated with the AAA, suggesting a reduction of at least 10% to prescription dose is appropriate when calculating with the AAA.
Anisotropic analytical algorithm; dose calculation algorithm; lung cancer; pencil beam convolution
This study aims at evaluating the impact of tissue heterogeneity corrections on dosimetry of stereotactic body radiation therapy treatment plans. Four-dimensional computed tomography data from 15 low stage non-small cell lung cancer patients was used. Treatment planning and dose calculations were done using pencil beam convolution algorithm of Varian Eclipse system with Modified Batho Power Law for tissue heterogeneity. Patient plans were generated with 6 MV co-planar non-opposing four to six field beams optimized with tissue heterogeneity corrections to deliver a prescribed dose of 60 Gy in three fractions to at least 95% of the planning target volume, keeping spinal cord dose <10 Gy. The same plans were then regenerated without heterogeneity correction by recalculating previously optimized treatment plans keeping identical beam arrangements, field fluences and monitor units. Compared with heterogeneity corrected plans, the non-corrected plans had lower average minimum, mean, and maximum tumor doses by 13%, 8%, and 6% respectively. The results indicate that tissue heterogeneity is an important determinant of dosimetric optimization of SBRT plans.
Heterogeneity corrections; NSCLC; SBRT
The effect of oral folic acid on jejunal glycolytic enzyme activity in five fasting obese patients and in three normal male volunteers on a constant 3000 cal diet was studied. The glycolytic enzymes, fructokinase, hexokinase, glucokinase, fructose-1-phosphate aldolase, and fructose diphosphate aldolase, and the disaccharidases, sucrase, maltase, and lactase were measured.
In both the fasting patients and the normal volunteers, oral folic acid significantly increased the jejunal glycolytic enzyme activities but had no effect on disaccharidase activity. When oral folic acid was discontinued in the normal volunteers, the glycolytic enzyme activities returned to control values. In the obese patients, refeeding and folic acid caused a further increase in glycolytic enzyme activities above that seen with fasting and folic acid.
In contrast to oral folic acid, intramuscular folic acid, oral vitamin B12, and oral tetracycline had no effect on glycolytic enzyme activities.
These studies demonstrate that oral folic acid which is neither a substrate nor a coenzyme of these enzymes, increases human jejunal glycolytic enzyme activity in a specific fashion. This would appear to be an action of oral folic acid which has not been recognized previously.
Allergic sensitization is an important risk factor for the development of atopic disease. The National Health and Nutrition Examination Survey (NHANES) 2005–2006 provides the most comprehensive information on IgE-mediated sensitization in the general US population.
We investigated clustering, sociodemographic and regional patterns of allergic sensitization and examined risk factors associated with IgE-mediated sensitization.
Data for this cross-sectional analysis were obtained from NHANES 2005–2006. Participants aged ≥1 year (N=9440) were tested for sIgEs to inhalant and food allergens; participants ≥6 years were tested for 19 sIgEs, and children aged 1–5 years for 9 sIgEs. Serum samples were analyzed using the ImmunoCAP System. Information on demographics and participant characteristics was collected by questionnaire.
Of the study population aged 6 and older, 44.6% had detectable sIgEs, while 36.2% of children aged 1–5 years were sensitized to ≥1 allergen. Allergen-specific IgEs clustered into 7 groups that might have largely reflected biological cross-reactivity. Although sensitization to individual allergens and allergen types showed regional variation, the overall prevalence of sensitization did not differ across census regions, except in early childhood. In multivariate modeling, young age, male gender, non-Hispanic black race/ethnicity, geographic location (census region), and reported pet avoidance measures were most consistently associated with IgE-mediated sensitization.
The overall prevalence of allergic sensitization does not vary across US census regions, except in early life, although allergen-specific sensitization differs by sociodemographic and regional factors. Biological cross-reactivity may be an important, but not a sole, contributor to the clustering of allergen-specific IgEs.
IgE-mediated sensitization shows clustering patterns and differs by sociodemographic and regional factors, but the overall prevalence of sensitization may not vary across US census regions.
allergen; allergy; allergic sensitization; serum IgE
The in vivo rat model is a workhorse in neuroscience research, preclinical studies and drug development. A repertoire of MR tools has been developed for its investigation, however, high levels of B0 magnetic field homogeneity are required for meaningful results. The homogenization of magnetic fields in the rat brain, i.e. shimming, is a difficult task due to a multitude of complex, susceptibility-induced field distortions. Conventional shimming with spherical harmonic (SH) functions is capable of compensating shallow field distortions in limited areas, e.g. in the cortex, but performs poorly in difficult-to-shim subcortical structures or for the entire brain. Based on the recently introduced multi-coil approach for magnetic field modeling, the DYNAmic Multi-coIl TEchnique (DYNAMITE) is introduced for magnetic field shimming of the in vivo rat brain and its benefits for gradient-echo echo-planar imaging (EPI) are demonstrated.
An integrated multi-coil/radio-frequency (MC/RF) system comprising 48 individual localized DC coils for B0 shimming and a surface transceive RF coil has been developed that allows MR investigations of the anesthetized rat brain in vivo. DYNAMITE shimming with this MC/RF setup is shown to reduce the B0 standard deviation to a third of that achieved with current shim technology employing static first through third order SH shapes. The EPI signal over the rat brain increased by 31% and a 24% gain in usable EPI voxels could be realized.
DYNAMITE shimming is expected to critically benefit a wide range of preclinical and neuroscientific MR research. Improved magnetic field homogeneity, along with the achievable large brain coverage of this method will be crucial when signal pathways, cortical circuitry or the brain’s default network are studied. Along with the efficiency gains of MC-based shimming compared to SH approaches demonstrated recently, DYNAMITE shimming has the potential to replace conventional SH shim systems in small bore animal scanners.
shimming; dynamic shimming; magnetic field modeling; multi-coil; spherical harmonics
The translational value of zebrafish high-throughput screens can be improved when more knowledge is available on uptake characteristics of potential drugs. We investigated reference antibiotics and 15 preclinical compounds in a translational zebrafish-rodent screening system for tuberculosis. As a major advance, we have developed a new tool for testing drug uptake in the zebrafish model. This is important, because despite the many applications of assessing drug efficacy in zebrafish research, the current methods for measuring uptake using mass spectrometry do not take into account the possible adherence of drugs to the larval surface. Our approach combines nanoliter sampling from the yolk using a microneedle, followed by mass spectrometric analysis. To date, no single physicochemical property has been identified to accurately predict compound uptake; our method offers a great possibility to monitor how any novel compound behaves within the system. We have correlated the uptake data with high-throughput drug-screening data from Mycobacterium marinum-infected zebrafish larvae. As a result, we present an improved zebrafish larva drug-screening platform which offers new insights into drug efficacy and identifies potential false negatives and drugs that are effective in zebrafish and rodents. We demonstrate that this improved zebrafish drug-screening platform can complement conventional models of in vivo
Mycobacterium tuberculosis-infected rodent assays. The detailed comparison of two vertebrate systems, fish and rodent, may give more predictive value for efficacy of drugs in humans.
The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor “A” allele of rs6311 to offspring with ASD (permuted p=0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5′ untranslated region in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5′UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk.
Autism; serotonin; gene expression; HTR2A; rs6311; monoamine
The response of a Silicon Photomultiplier (SiPM) to optical signals is affected by many factors including photon-detection efficiency, recovery time, gain, optical crosstalk, afterpulsing, dark count, and detector dead time. Many of these parameters vary with overvoltage and temperature. When used to detect scintillation light, there is a complicated non-linear relationship between the incident light and the response of the SiPM. In this paper, we propose a combined discrete-time discrete-event Monte Carlo (MC) model to simulate SiPM response to scintillation light pulses. Our MC model accounts for all relevant aspects of the SiPM response, some of which were not accounted for in the previous models. We also derive and validate analytic expressions for the single-photoelectron response of the SiPM and the voltage drop across the quenching resistance in the SiPM microcell. These analytic expressions consider the effect of all the circuit elements in the SiPM and accurately simulate the time-variation in overvoltage across the microcells of the SiPM. Consequently, our MC model is able to incorporate the variation of the different SiPM parameters with varying overvoltage. The MC model is compared with measurements on SiPM-based scintillation detectors and with some cases for which the response is known a priori. The model is also used to study the variation in SiPM behavior with SiPM-circuit parameter variations and to predict the response of a SiPM-based detector to various scintillators.
Circuit transient analysis; electrical characteristics; Monte Carlo model; silicon photomultiplier; single-photoelectron response
Fixation failure is a relatively common sequela of surgical management of proximal humerus fractures (PHF). The purpose of this study is to understand the current state of the literature with regard to the biomechanical testing of proximal humerus fracture implants.
A scoping review of the proximal humerus fracture literature was performed, and studies testing the mechanical properties of a PHF treatment were included in this review. Descriptive statistics were used to summarize the characteristics and methods of the included studies.
1,051 proximal humerus fracture studies were reviewed; 67 studies met our inclusion criteria. The most common specimen used was cadaver bone (87 %), followed by sawbones (7 %) and animal bones (4 %). A two-part fracture pattern was tested most frequently (68 %), followed by three-part (23 %), and four-part (8 %). Implants tested included locking plates (52 %), intramedullary devices (25 %), and non-locking plates (25 %). Hemi-arthroplasty was tested in 5 studies (7 %), with no studies using reverse total shoulder arthroplasty (RTSA) implants. Torque was the most common mode of force applied (51 %), followed by axial loading (45 %), and cantilever bending (34 %). Substantial testing diversity was observed across all studies.
The biomechanical literature was found to be both diverse and heterogeneous. More complex fracture patterns and RTSA implants have not been adequately tested. These gaps in the current literature will need to be addressed to ensure that future biomechanical research is clinically relevant and capable of improving the outcomes of challenging proximal humerus fracture patterns.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-015-0627-x) contains supplementary material, which is available to authorized users.
Proximal humerus fracture; Biomechanics; Proximal humerus fracture implant
Nationally representative observational and translational research is needed to address the public health challenges in Indonesia due to the geographic disparity, recently decentralized health system, and diverse infectious disease priorities. To accomplish this, the Indonesian Ministry of Health in collaboration with the US National Institute of Health has established INA-RESPOND (Indonesia Research Partnership on Infectious Disease) – a clinical research network comprising 9 referral hospitals, 7 medical faculties, and 2 research centres across Indonesia. The network provides a forum to conduct research at a national scale and to address scientific questions that would be difficult to address in smaller research settings. Further, it is currently conducting multi-centre research on the etiologies of fever, sepsis, and tuberculosis. There are opportunities to leverage existing network resources for other public health research needs. INA-RESPOND is an Indonesian-led network in a country with diverse population groups and public health needs which is poised to collaborate with researchers, universities, donors, and industry worldwide. This paper describes the network and its goals and values, as well as the management structure, process for collaboration, and future vision.
Clinical; Disease; Indonesia; Infectious; Network; Research; Trial
To examine the efficacy and safety profile of antiepileptic repetitive transcranial magnetic stimulation (rTMS) for refractory status epilepticus (RSE) in the intensive care unit (ICU) setting. In addition, hypothetical concerns about electrical interference of rTMS with ICU equipment have been previously raised.
We describe two cases of RSE treated with rTMS in the ICU.
In one case, rTMS contributed to decreased seizure frequency; in the second case, rTMS transiently decreased seizure frequency. In both cases, rTMS was safe and did not interfere with the functioning of the ICU equipment.
rTMS is a potential therapy for RSE when conventional therapies have failed. Future studies should investigate the efficacy of various rTMS stimulation parameters, safety issues, and bioengineering considerations in the ICU setting.
Transcranial Magnetic Stimulation; Refractory Status Epilepticus; Intensive Care Unit; Epilepsia Partialis Continua
The American College of Cardiology Foundation (ACCF), in partnership with
key specialty and subspecialty societies, conducted a review of common clinical
scenarios where noninvasive vascular testing (ultrasound and physiological
testing) is frequently considered. The indications (clinical scenarios) were
derived from common applications or anticipated uses, as well as from current
clinical practice guidelines and results of studies examining the implementation
of the original appropriate use criteria (AUC). The 159 indications in this
document were developed by a diverse writing group and scored by a separate
independent technical panel on a scale of 1 to 9, to designate appropriate use
(median 7 to 9), uncertain use (median 4 to 6), and inappropriate use (median 1
A total of 255 indications (with the inclusion of surveillance
timeframes) were rated. One hundred and seventeen indications were rated as
appropriate, 84 were rated as uncertain, and 54 were rated as inappropriate. The
AUC for peripheral vascular disease have the potential to impact physician
decision making, healthcare delivery, and reimbursement policy. Furthermore,
recognition of uncertain clinical scenarios facilitates identification of areas
that would benefit from future research.
Although the responses to many pathogen associated molecular patterns (PAMPs) in cell cultures and extracted organs are well characterized, there is little known of transcriptome responses to PAMPs in whole organisms. To characterize this in detail, we have performed RNAseq analysis of responses of zebrafish embryos to injection of PAMPs in the caudal vein at one hour after exposure. We have compared two ligands that in mammals have been shown to specifically activate the TLR2 and TLR5 receptors: Pam3CSK4 and flagellin, respectively.
We identified a group of 80 common genes that respond with high stringency selection to stimulations with both PAMPs, which included several well-known immune marker genes such as il1b and tnfa. Surprisingly, we also identified sets of 48 and 42 genes that specifically respond to either Pam3CSK4 or flagellin, respectively, after a comparative filtering approach. Remarkably, in the Pam3CSK4 specific set, there was a set of transcription factors with more than 2 fold-change, as confirmed by qPCR analyses, including cebpb, fosb, nr4a1 and egr3. We also showed that the regulation of the Pam3CSK4 and flagellin specifically responding sets is inhibited by knockdown of tlr2 or tlr5, respectively.
Our studies show that Pam3CSK4 and flagellin can stimulate the Tlr2 and Tlr5 signaling pathways leading to common and specific responses in the zebrafish embryo system.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1740-9) contains supplementary material, which is available to authorized users.
TLR signaling; Zebrafish; TLR2; TLR5; Flagellin; Pam3CSK4; Innate immunity
The function of dendritic cells (DCs) in the immune system is based on their ability to sense and present foreign antigens. Powerful tools to research DC function and to apply in cell-based immunotherapy are either silencing or overexpression of genes achieved by lentiviral transduction. To date, efficient lentiviral transduction of DCs or their monocyte derived counterparts (MDDCs) required high multiplicity of infection (MOI) or the exposure to the HIV-2/SIV protein Vpx to degrade viral restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1). Here we present a Vpx-independent method for efficient (>95%) transduction of MDDCs at lower MOI. The protocol can be used both for ectopic gene expression and knock-down. Introducing shRNA targeting viral entry receptor CD4 and restriction factor SAMHD1 into MDDCs resulted in down-regulation of targeted proteins and, consequently, expected impact on HIV infection. This protocol for MDDCs transduction is robust and free of the potential risk arising from the use of Vpx which creates a virus infection-prone environment, potentially dangerous in clinical setting.
Current American Cancer Society recommendations for colon cancer screening include optical colonoscopy every 10 years or computed tomography colonography (CTC) every 5 years. Bowel preparation (BP) is currently required for both screening modalities.
To compare ACRIN 6664: the National CT Colonography Trial (NCTCT) participant experiences with CTC and optical colonoscopy (OC), procedure preference, and willingness to return for each procedure.
Materials and methods
Participants from fifteen NCTCT sites, who underwent CTC followed by OC under sedation, were invited to complete questionnaires 2 weeks postexam, asking about procedure preference, physical discomfort, and embarrassment experienced and whether that discomfort and embarrassment was better or worse than expected during BP, CTC, and OC, as well as willingness to return for repeat CTC and OC at different time intervals.
A total of 2,310 of 2,600 patients (89%) returned their questionnaires. Of patients reporting a preference, 1,058 (46.6%) preferred CTC, 569 (25.0%) preferred OC, and 626 (27.6%) reported no preference. Participant-reported discomfort worse than expected differed significantly between CTC (32.9%) and OC (5.0%) (P<0.001). About 79.3% were willing to be screened again with CTC in 5 years, and 96.6% with OC in 10 years. Discomfort and embarrassment worse than expected with OC were associated with increased intention to adhere with CTC in the future. Conversely, embarrassment experienced during CTC and discomfort worse than expected on CTC were associated with increased intention to adhere with OC in the future.
While a larger proportion of participants indicated that they preferred CTC to OC, willingness to undergo repeat CTC compared to OC was limited by unanticipated exam discomfort and embarrassment and CTC’s shorter screening interval.
CT colonography; colonoscopy; bowel preparation; adherence; patient preference
Progress in reducing the malaria disease burden through the substantial scale up of insecticide-based vector control in recent years could be reversed by the widespread emergence of insecticide resistance. The impact of insecticide resistance on the protective effectiveness of insecticide-treated nets (ITN) and indoor residual spraying (IRS) is not known. A multi-country study was undertaken in Sudan, Kenya, India, Cameroon and Benin to quantify the potential loss of epidemiological effectiveness of ITNs and IRS due to decreased susceptibility of malaria vectors to insecticides. The design of the study is described in this paper.
Malaria disease incidence rates by active case detection in cohorts of children, and indicators of insecticide resistance in local vectors were monitored in each of approximately 300 separate locations (clusters) with high coverage of malaria vector control over multiple malaria seasons. Phenotypic and genotypic resistance was assessed annually. In two countries, Sudan and India, clusters were randomly assigned to receive universal coverage of ITNs only, or universal coverage of ITNs combined with high coverage of IRS. Association between malaria incidence and insecticide resistance, and protective effectiveness of vector control methods and insecticide resistance were estimated, respectively.
Cohorts have been set up in all five countries, and phenotypic resistance data have been collected in all clusters. In Sudan, Kenya, Cameroon and Benin data collection is due to be completed in 2015. In India data collection will be completed in 2016.
The paper discusses challenges faced in the design and execution of the study, the analysis plan, the strengths and weaknesses, and the possible alternatives to the chosen study design.
The purpose of this study was to compare the diagnostic accuracy and interpretation times of breast MRI with and without use of a computer-aided detection (CAD) system by novice and experienced readers.
SUBJECTS AND METHODS
A reader study was undertaken with 20 radiologists, nine experienced and 11 novice. Each radiologist participated in two reading sessions spaced 6 months apart that consisted of 70 cases (27 benign, 43 malignant), read with and without CAD assistance. Sensitivity, specificity, negative predictive value, positive predictive value, and overall accuracy as measured by the area under the receiver operating characteristic curve (AUC) were reported for each radiologist. Accuracy comparisons across use of CAD and experience level were examined. Time to interpret and report on each case was recorded.
CAD improved sensitivity for both experienced (AUC, 0.91 vs 0.84; 95% CI on the difference, 0.04, 0.11) and novice readers (AUC, 0.83 vs 0.77; 95% CI on the difference, 0.01, 0.10). The increase in sensitivity was statistically higher for experienced readers (p = 0.01). Diagnostic accuracy, measured by AUC, for novices without CAD was 0.77, for novices with CAD was 0.79, for experienced readers without CAD was 0.80, and for experienced readers with CAD was 0.83. An upward trend was noticed, but the differences were not statistically significant. There were no significant differences in interpretation times.
MRI sensitivity improved with CAD for both experienced readers and novices with no overall increase in time to evaluate cases. However, overall accuracy was not significantly improved. As the use of breast MRI with CAD increases, more attention to the potential contributions of CAD to the diagnostic accuracy of MRI is needed.
accuracy; breast MRI; computer-aided diagnosis; reader study
Most gorgonian octocoral species are described using diagnostic characteristics of their sclerites (microscopic skeletal components). Species in the genus Pterogorgia, however, are separated primarily by differences in their calyx and branch morphology. Specimens of a morphologically unusual Pterogorgia collected from Saba Bank in the NE Caribbean Sea were found with calyx morphology similar to P. citrina and branch morphology similar to P. guadalupensis. In order to test morphological species boundaries, and the validity of calyx and branch morphology as systematic characters, a phylogenetic analysis was undertaken utilizing partial gene fragments of three mitochondrial (mtMutS, cytochrome b, and igr4; 726bp total) and two nuclear (ITS2, 166bp; and SRP54 intron, 143bp) loci. The datasets for nuclear and mitochondrial loci contained few phylogenetically informative sites, and tree topologies did not resolve any of the morphological species as monophyletic groups. Instead, the mitochondrial loci and SRP54 each recovered two clades but were slightly incongruent, with a few individuals of P. guadalupensis represented in both clades with SRP54. A concatenated dataset of these loci grouped all P. anceps and P. guadalupensis in a clade, and P. citrina and the Pterogorgia sp. from Saba Bank in a sister clade, but with minimal variation/resolution within each clade. However, in common with other octocoral taxa, the limited genetic variation may not have been able to resolve whether branch variation represents intraspecific variation or separate species. Therefore, these results suggest that there are at least two phylogenetic lineages of Pterogorgia at the species level, and the atypical Pterogorgia sp. may represent an unusual morphotype of P. citrina, possibly endemic to Saba Bank. Branch morphology does not appear to be a reliable morphological character to differentiate Pterogorgia species (e.g., branches “flat” or “3–4 edges” in P. guadalupensis and P. anceps, respectively), and a re-evaluation of species-level characters (e.g., sclerites) is needed.
Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.
Pelvic lymph node dissection in patients undergoing radical prostatectomy for clinically localised prostate cancer is not without morbidity and its therapeutical benefit is still a matter of debate. The objective of this study was to develop a model that allows preoperative determination of the minimum number of lymph nodes needed to be removed at radical prostatectomy to ensure true nodal status.
We analysed data from 4770 patients treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2011 from eight academic centres. For external validation of our model, we used data from a cohort of 3595 patients who underwent an anatomically defined extended pelvic lymph node dissection. We estimated the sensitivity of pathological nodal staging using a beta-binomial model and developed a novel clinical (preoperative) nodal staging score (cNSS), which represents the probability that a patient has lymph node metastasis as a function of the number of examined nodes.
In the development and validation cohorts, the probability of missing a positive lymph node decreases with increase in the number of nodes examined. A 90% cNSS can be achieved in the development and validation cohorts by examining 1–6 nodes in cT1 and 6–8 nodes in cT2 tumours. With 11 nodes examined, patients in the development and validation cohorts achieved a cNSS of 90% and 80% with cT3 tumours, respectively.
Pelvic lymph node dissection is the only reliable technique to ensure accurate nodal staging in patients treated with radical prostatectomy for clinically localised prostate cancer. The minimum number of examined lymph nodes needed for accurate nodal staging may be predictable, being strongly dependent on prostate cancer characteristics at diagnosis.
prostate cancer; pelvic lymph node dissection; lymph node metastasis; extended lymph node dissection; nodal yield