Search

High-quality research underpins the best healthcare practice. This article focuses on analyzing the current literature to promote research integrity across clinical trials.Recent admissions of questionable practices by researchers have undermined practitioner and public confidence. There is limited evidence specifically for ethical and professional standards in clinical trials to guide researchers and institutions to embed integrity into research practice.Unintentional errors and spin in research are not uncommon as training in design and conduct of clinical trials is not part of health education for medical and allied health professions. There is unfamiliarity with procedures, such as prospective registration, a priori documentation of statistical analysis plans, openness in data sharing, and so forth. This, combined with the academic culture of secrecy, has led to an environment where scientific suspicion, instead of trust, is the norm. Existing science integrity documents are devoid of specific recommendations about how to translate any guidance into clinical trial practice. There is a need for constructive, supportive and multidisciplinary approaches based on open dialogue and continuous training, targeting the research environment. Research integrity now needs to take centre stage to re-instill confidence in randomized trial evidence to inform clinical practice.

The study aims to investigate the effect of the different lignocellulosic pulp on the composite properties for active packaging application. Microfibrillated cellulose from bleached and unbleached Kraft and thermomechanical pulp (TMP) having different cellulose, hemicellulose, lignin, and extractive content were used as the matrix phase with antimicrobial bis-phosphinato bismuth complex as the dispersed phase. The Kraft pulp has thinner fibres as observed in the SEM images and have higher aspect ratio (EMT 109–157) compared to TMP (EMT 43–51). So, it is more easily fibrillated resulting in a strong close network and therefore resulting in low water vapor transmission rate (WVTR) and high tensile index (20–91 g/m2.day and 59–78 Nm/g respectively) compared to the TMP ones (153–261 g/m2.day and 35–43 Nm/g respectively). While the physical dimension of the fibres controls the mechanical and barrier properties, the leaching and antibacterial performance is related to the bonding of the complex with the matrix. The high hydrophilicity of the bleached kraft pulp results in a weak bond with the hydrophobic bismuth complex, easing its release to kill the surrounding microbial population and thus resulting in larger zones of inhibition against both Gram-positive and Gram-negative bacteria. Therefore, bleached kraft pulp was found to be the most suitable with promising barrier, mechanical and antibacterial properties.

Major pathways involving high-comboscore candidates

Supplementary Figure 1. Representative flow cytometry plots and gates.

Purpose: Targeted MEK inhibition is an emerging therapy in a number of solid tumors. It holds particular promise in BRAF V600E mutation–positive malignant melanoma, where constitutive activation and cell growth through the MAP kinase (MAPK) pathway is well established. In vitro and preclinical research indicates that MAPK pathway activation is important in chronic myeloid leukemia (CML) leukemogenesis; however, the potential of MEK inhibition has not yet been investigated clinically in the setting of such hematologic malignancies.Experimental Design: We report a case of complete hematologic response of CML to MEK inhibition in a patient with synchronous metastatic melanoma, who received treatment with combination BRAF and MEK1/2 inhibitors. We studied the effects of these agents on proliferation and outgrowth of myeloid precursors, and longitudinal shifts in peripheral blood phenotyping during the course of treatment. A model cell line system was used to examine the effects of dabrafenib and trametinib on MAPK and BCR–ABL1 signaling.Results: After 35 weeks on treatment with BRAF and MEK inhibitors, complete hematologic response was observed without recourse to BCR–ABL1–targeted therapy. MEK inhibition was principally responsible for impaired proliferation of both mature and primitive myeloid precursors, as well as growth and hemoglobinization of erythroid precursors. Paradoxical activation of the MAPK pathway was seen in response to BRAF inhibitor therapy but this was easily overcome by clinically relevant doses of concurrent MEK inhibitor.Conclusions: These studies suggest that further evaluation of the optimal MAPK targeting approach is warranted to extend therapeutic options in CML. Clin Cancer Res; 21(23); 5222–34. ©2015 AACR.

Supplementary Figure 3. Effects of kinase inhibitor treatment on expression of the pro-apoptotic molecule BIM.

Supplementary Figure 2. Additional K562 BCR-ABL Western Blot densitometry.

Purpose: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy.Experimental Design: To identify genes mediating resistance to T-cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous tumor-infiltrating lymphocytes (TIL).Results: The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti–PD-1–treated melanoma patient tumor samples suggested that higher MEX3B expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3′ untranslated region (UTR) of HLA-A to destabilize the mRNA.Conclusions: MEX3B mediates resistance to cancer immunotherapy by binding to the 3′ UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells. Clin Cancer Res; 24(14); 3366–76. ©2018 AACR.See related commentary by Kalbasi and Ribas, p. 3239

Supplementary figure and table legends

Supplementary Tables 1-3. Supplementary Table 1: Changes in manual differential white cell counts over time under treatment with BRAF/MEK inhibitor combination therapy for melanoma. Supplementary Table 2. BCR-ABL monitoring during treatment. Supplementary Table 3. Leukocyte sub-populations as defined by flow cytometry.

Staphylococcus aureus is a common colonizer of the human gut and in doing so it must be able to resist the actions of the host’s innate defences. Bile salts are a class of molecules that possess potent antibacterial activity that control growth. Bacteria that colonize and survive in that niche must be able to resist the action of bile salts, but the mechanisms by which S. aureus does so are poorly understood. Here we show that FadB is a bile-induced oxidoreductase which mediates bile salt resistance and when heterologously expressed in Escherichia coli renders them resistant. Deletion of fadB attenuated survival of S. aureus in a model of the human distal colon.

Digital adherence technologies (DATs) are increasingly used for tuberculosis (TB) adherence support, but information about their costs remains limited. We used microcosting to estimate health system costs (in 2022 US dollars) of 99DOTS pill sleeves and video-observed treatment (VOT), implemented in demonstration projects during 2018-21. Local cost estimates for standard directly observed treatment (DOT) were also obtained. The estimated per-person costs of 99DOTS for drug-sensitive (DS-) TB were $98, $106, and $174 in Bangladesh (n=719), the Philippines (n=396), and Tanzania (n=976) respectively. The estimated per-person costs of VOT were $1 154, $304, $457, and $661 in Haiti (n=87 DS-TB), Moldova (n=173 DS-TB), Moldova (n=135 drug-resistant [DR]-TB) and the Philippines (n=110 DR-TB) respectively. Health system costs of 99DOTS may be similar to or cheaper than standard DOT. VOT is considerably more expensive; labor cost offsets and/or economies of scale may yield savings relative to standard DOT in some settings.SummaryIn diverse settings, health system costs of 99DOTS pill sleeves may be similar to or cheaper than standard directly observed treatment for TB; video-observed treatment is considerably more expensive, but labor cost offsets and/or economies of scale may yield savings.

This study investigated whether and how STEM instructors noticed exclusionary racialized events experienced by Black students in classroom narratives. Color-evasive racial ideology was pervasive. This paper qualitatively characterizes incarnations of color-evasion enacted by STEM instructors and the racialized events they noticed.

Could co-teaching be a mechanism to support the adoption of evidence-based teaching strategies? Co-teaching has been proposed as a lever for fostering pedagogical change and has key attributes of a successful change strategy, but does research indicate co-teaching effectively shifts instructional practices? Based on our review of the emerging evidence, we wrote this essay for multiple audiences, including science, technology, engineering, and mathematics (STEM) instructors, education development professionals, leaders who oversee teaching, and researchers. We define co-teaching in the context of STEM higher education and summarize what is known about the pedagogical changes that co-teaching could support and the potential mechanisms behind these changes. We share recommendations based on the available evidence for those who need productive ideas right now. We also lay out a variety of future directions for research about co-teaching as a lever for pedagogical change. Achieving widespread and impactful pedagogical change is a monumental undertaking facing STEM higher education, and multiple approaches will be needed to meet this challenge. Co-teaching has potential to shift ways of thinking and pedagogical practices among undergraduate STEM faculty, but how co-teaching is enacted is likely crucial to its impact, as is the context in which it occurs.

One often observes small but measurable differences in the diffraction data measured from different crystals of a single protein. These differences might reflect structural differences in the protein and may reveal the natural dynamism of the molecule in solution. Partitioning these mixed-state data into single-state clusters is a critical step that could extract information about the dynamic behavior of proteins from hundreds or thousands of single-crystal data sets. Mixed-state data can be obtained deliberately (through intentional perturbation) or inadvertently (while attempting to measure highly redundant single-crystal data). To the extent that different states adopt different molecular structures, one expects to observe differences in the crystals; each of the polystates will create a polymorph of the crystals. After mixed-state diffraction data have been measured, deliberately or inadvertently, the challenge is to sort the data into clusters that may represent relevant biological polystates. Here, this problem is addressed using a simple multi-factor clustering approach that classifies each data set using independent observables, thereby assigning each data set to the correct location in conformational space. This procedure is illustrated using two independent observables, unit-cell parameters and intensities, to cluster mixed-state data from chymotrypsinogen (ChTg) crystals. It is observed that the data populate an arc of the reaction trajectory as ChTg is converted into chymotrypsin.

Huntington’s disease (HD) mouse models suggest that cardiovascular exercise may enhance neuroplasticity and delay disease signs, however, the effects of exercise on neuroplasticity in people with HD are unknown. Using a repeated-measures experimental design, we compared the effects of a single bout of high-intensity exercise, moderate-intensity exercise, or rest, on motor cortex synaptic plasticity in 14 HD CAG-expanded participants (9 premanifest & 5 early manifest) and 20 CAG-healthy control participants, using transcranial magnetic stimulation. Measures of cortico-motor excitability, short-interval intracortical inhibition and intracortical facilitation were obtained before and after a 20-minute bout of either high-intensity interval exercise, moderate-intensity continuous exercise, or rest, and again after intermittent theta burst stimulation (iTBS). HD participants showed less inhibition at baseline compared to controls. Whereas the control group showed increased excitability and facilitation following high-intensity exercise and iTBS, the HD group showed no differences in neuroplasticity responses following either exercise intensity or rest, with follow-up Bayesian analyses providing consistent evidence that these effects were absent in the HD group. These findings indicate that exercise-induced synaptic plasticity mechanisms in response to acute exercise may be attenuated in HD, and demonstrate the need for future research to further investigate exercise and plasticity mechanisms in people with HD.

AimsIn many low-income countries, fasting glucose is the primary measure of glycaemic control used for treatment titration, as HbA1c is often unavailable or unaffordable. Many patients in these countries walk long distances to the clinic, but the impact of walking on fasting glucose in type 2 diabetes is unknown. We aimed to determine whether this prolonged walking affects the reliability of fasting plasma glucose as a measure of glycaemic control.MethodsIn a randomised crossover trial, the change in glucose from baseline in the fasting state was compared between walking on a treadmill at a predetermined speed of 4.5 km/hour for 1 hour and not walking (resting) in people with type 2 diabetes. The pre-specified primary outcome was glucose at 1 and 2 hours.Results45 participants were enrolled and all completed both visits. 21/45 (46.7%) were female, and the median age was 51. Glucose during and after walking was similar to glucose while at rest; glucose difference (walking minus rest) was -0.15 (95% CI: -0.55, 0.26) and -0.10 (95% CI: - 0.50, 0.31) mmol/L at 1 and 2 hours respectively, p>0.4 for both).ConclusionsFasting plasma glucose is not meaningfully affected by prolonged walking in participants with type 2 diabetes; therefore, the reliability of fasting glucose for monitoring glycaemic burden is unlikely to be altered in patients who walk to the clinic.Research in contextWhat is already known about this subject?Fasting glucose is widely used to assess glycaemic control in people living with diabetes in low income countries, as HbA1c and home glucose monitoring are unaffordable. In these settings people living with diabetes will often walk long distances to receive healthcare.Little is known on the impact of walking on fasting glucose in people living with diabetes.What is the key question?Is fasting plasma glucose measure affected by a single bout of exercise such as walking in individuals with type 2 diabetes (T2D)?What are the new findings?There was no significant change in fasting glucose at the end of the walking exercise.There was no meaningful change in fasting glucose observed at any point up to 3 hours after commencing exercise.How might this impact on clinical practice in the foreseeable future?Fasting plasma glucose is not meaningfully affected by prolonged walking in participants with type 2 diabetes; therefore, the reliability of fasting glucose for monitoring glycaemic burden is unlikely to be altered in patients who walk to the clinic.

The Follower algorithm was developed to examine the properties of continuous functions and to verify their computer implementations. In particular, we studied measures for distances between unit cells.

With synthetic cannabinoid receptor agonist (SCRA) use still prevalent across Europe and structurally advanced generations emerging, it is imperative that drug detection methods advance in parallel. SCRAs are a chemically diverse and evolving group, which makes rapid detection challenging. We have previously shown that fluorescence spectral fingerprinting (FSF) has the potential to provide rapid assessment of SCRA presence directly from street material with minimal processing and in saliva. Enhancing the sensitivity and discriminatory ability of this approach has high potential to accelerate the delivery of a point-of-care technology that can be used confidently by a range of stakeholders, from medical to prison staff. We demonstrate that a range of structurally distinct SCRAs are photochemically active and give rise to distinct FSFs after irradiation. To explore this in detail, we have synthesized a model series of compounds which mimic specific structural features of AM-694. Our data show that FSFs are sensitive to chemically conservative changes, with evidence that this relates to shifts in the electronic structure and cross-conjugation. Crucially, we find that the photochemical degradation rate is sensitive to individual structures and gives rise to a specific major product, the mechanism and identification of which we elucidate through density-functional theory (DFT) and time-dependent DFT. We test the potential of our hybrid "photochemical fingerprinting"approach to discriminate SCRAs by demonstrating SCRA detection from a simulated smoking apparatus in saliva. Our study shows the potential of tracking photochemical reactivity via FSFs for enhanced discrimination of SCRAs, with successful integration into a portable device.

Background In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence. Methods We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson’s correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines – the Ludwig Melbourne melanoma (LM-MEL) cell line panel – we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies. Results Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, −221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro. Conclusions This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation. Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0554-y) contains supplementary material, which is available to authorized users.