Medically unexplained symptoms (MUS) account for 3-50% of all General Practitioner (GP) consultations and are difficult to diagnose due to their unknown aetiology, symptom overlap between conditions, ...and lack of effective treatment options. MUS patients' and primary care clinicians frequently face challenges during consultations, with GPs reporting difficulty identifying and classifying MUS, whilst patients report stigma and feeling illegitimised by clinicians. Communication interventions have been proposed as a method to facilitate the doctor-patient relationship and aid the management of MUS. This systematic review aims to evaluate the effectiveness of primary care based communication interventions at improving MUS patients' and/or clinician outcomes. Four electronic databases were searched from inception to November 2021. Two researchers independently undertook screening, data extraction and quality appraisal. Given the heterogeneous nature of the studies identified, narrative syntheses were conducted, along with meta-analyses where possible to pool data. 9 papers from 10 Randomised Controlled Trials were included. The included studies displayed considerable risk of bias and poor reporting. Some limited evidence suggests that communication interventions tailored to MUS and not following a pre-specified model (such as reattribution) could improve pain, mental and physical functioning whilst reattribution training may improve clinician confidence treating MUS. However, methodological limitations mean that these findings should be interpreted with caution. A range of interventions for improving communication with MUS patients in primary care have been evaluated. However, the heterogeneous nature of existing evidence and poor study quality mean we cannot conclude whether these interventions are effective. Before considering further randomised controlled trials researchers should focus on developing a new or modified communication intervention for MUS patients and their clinicians.
DUBs are dysregulated in cancer and other diseases, but there is much that is unknown about the specific substrates and pathways that individual DUBs regulate and their clinical utility remains ...incompletely explored. In this work, I present characterization of the functions and therapeutic potential of DUBs in oncology through pharmacological and genetic studies coupled with analysis of publicly available datasets. First, I used phenotypic screens using early small molecule DUB inhibitors and target deconvolution to identify promising DUB targets in acute myeloid leukemia (AML) and breast cancer (chapter II). Specifically, I identify USP10 as the DUB responsible for stabilizing the oncoprotein, FMS-like receptor tyrosine kinase-3 (FLT3), in AML, and I identify USP7 as a DUB with selective proliferative effects based on subtype in breast cancer. Next, I used targeted studies with USP7 inhibitors to understand the functions of USP7 important for transcription and proliferation as well as characterize the polypharmacology of commonly used USP7 inhibitors. (chapter III). I conclude that p53 is central to the impact of USP7 on both proliferation and the transcriptome, but additional USP7 functions also impact proliferation to a lesser extent. Finally, I used parallel experimental and computational approaches with pharmacological and genetic tools coupled with multiple, publicly available omics datasets to systematically interrogate the function and therapeutic potential of each DUB (chapter IV), and these results comprise the majority of the work presented here. I use this multi-omics approach to identify candidate functions and interactors essential for proliferation for 35 DUBs and investigate the transcriptional impacts of DUB knock out and inhibition. Overall, in this thesis, I present novel insights into both well studied DUBs as well as understudied DUBs, identify promising therapeutic contexts for many individual DUBs, and create a resource of integrated omics datasets for further exploration of DUB function. For example, I determine that copy number loss of USPL1 is predictive of sensitivity to USPL1 loss and the role of USPL1 in the Little Elongation Complex is central to its impact on cancer cell proliferation and transcription.
This review investigates whether the distribution of recruitment to multicentre randomised controlled trials (RCTs) fits the “Pareto Principle”, i.e. 80% of participants are recruited by 20% of ...sites, or Price's Law, i.e. 50% of participants are recruited by the square root of the total number of sites.
A review of HTA reports published between 2017 and 2019.
40 RCTs conducted face-to-face recruitment, five recruited via mail-outs and one used both methods. For face-to-face recruitment (n = 41 studies), 80% of participants were recruited by the top recruiting 42.6% of sites; for mail-out methods (n = 6 studies) this was 52.0%. From the square root of sites, 51.3% and 31.8% of participants were recruited for the two recruitment approaches, respectively. Specifically, 3 (7.3%, 95% CI 2.5% to 19.4%) and 20 (48.8%, 95% CI 34.3% to 63.5%) RCTs that recruited face-to-face followed Pareto Principle and Price's Law, respectively. One mail-out recruitment study followed one of these principles, Price's Law. Chief Investigator (CI) sites (n = 24) in face-to-face recruitment studies recruited 18.1% of participants.
Face-to-face recruitment to HTA-funded RCTs fits more closely to Price's Law than the Pareto Principle, with the CI's site recruiting nearly a fifth of participants. Since we focussed on HTA-funded RCTs with ≥9 recruiting sites and for which the recruitment method and number recruited by site were known, our findings are limited in their generalisability. However, this trend could be used as a guide to aid in estimating how many sites RCTs need. More accurate estimation may prevent the need for recruitment extensions.
•Recruitment in half of the face-to-face recruitment studies follows Price's Law.•80% of participants are recruited, on average, by the top recruiting 50% of sites.•Recruitment to multicentre RCTs does not follow the Pareto Principle (80/20 rule).•The Chief Investigator's site enrols almost one-fifth of participants, on average.•These trends could predict how many recruiting sites a RCT will need.
Insufficient and delayed fracture healing remain significant public health problems with limited therapeutic options. Phosphoinositide 3-kinase (PI3K) signaling, a major pathway involved in ...regulation of fracture healing, promotes proliferation, migration, and differentiation of osteoprogenitors. We have recently reported that knock-in mice with a global increase in PI3K signaling (gCbl.sup.YF) show enhanced femoral fracture healing characterized by an extraordinary periosteal response to injury. Interestingly, of all growth factor receptors involved in fracture healing, PI3K directly binds only to PDGFR. Given these findings, we hypothesized a PDGFR-PI3K interaction is necessary for mediating robust periosteal cell activation following fracture. In this study, we isolated primary periosteal cells from gCbl.sup.YF mice to analyze cross-talk between the PDGFRbeta and PI3K signaling pathways. We found PDGFRbeta signaling contributes to robust Akt phosphorylation in periosteal cells in comparison with other growth factor signaling pathways. Additionally, we performed femoral fractures on gCbl.sup.YF mice with a conditional removal of PDGFRbeta in mesenchymal progenitors using inducible alpha smooth muscle actin (alphaSMA) CreER.sup.T2 mice. Our studies showed that depletion of PDGFRbeta signaling within these progenitors in the early phase of fracture healing significantly abrogates PI3K-mediated periosteal activation and proliferation three days after fracture. Combined, these results suggest that PDGFRbeta signaling through PI3K is necessary for robust periosteal activation in the earliest phases of fracture healing.
Purpose: The quantity and quality of maternal language input in early childhood carry long-term implications for children's language development. This includes not only the quantity (e.g., total ...number of words) but also the quality of maternal language input (e.g., complexity and diversity of vocabulary and grammar use). One central qualitative aspect of maternal language use involves prosody. Prosody is a perceptually salient aspect of spoken language that conveys meaning, emphasis (i.e., via linguistic stress patterns), and emotion through changes in pitch (fundamental frequency (fo) modulation) and timing (rate, pausing). Prosody of a child’s main communication partner, often mothers, has been shown to play an important role in the language development of the child. There are numerous contexts in which language interactions can take place between a mother and child. Mother-child shared book reading (hereafter referred to as “shared reading”) is known to provide especially rich opportunities for language input and exposure, yet the contributions of oral reading expressiveness have yet to be specified. Initial evidence suggests that more expressive presentation of a storybook (through digital manipulation of fo mean) has a positive impact on children’s comprehension of the storybook text. Yet, it remains unclear whether maternal oral reading expressiveness is associated with children’s emerging language abilities in early childhood, particularly in toddlerhood, a critical developmental window for the early identification of late talkers. This work seeks to delineate the associations of maternal oral reading expressiveness on a child’s overall concurrent and subsequent language abilities. Procedure: 44 mother-child dyads with children classified as either late talkers (n = 21) or typical controls (n=23) were selected from an ongoing larger longitudinal study of language delay in collaboration with researchers at Northwestern University. Maternal oral reading expressiveness during shared reading of the same children’s book was quantified through prosodic transcription and acoustic analysis in Praat yielding mean fundamental frequency (fo) and rate of speech as primary variables. Child language abilities were measured concurrently at the two-year time point and subsequently at the three-year time point using the Mullen Scales of Early Learning. Maternal socioeconomic status (SES) variables were assessed via family income-to-needs ratio and maternal education level. First, independent two sample t-tests were employed to determine whether late talker and typical control groups significantly differed in maternal oral reading expressiveness (as indicated by mean fo and speech rate) or SES. Thereafter, correlation analyses were employed to examine maternal oral reading expressiveness in relation to concurrent child language abilities at age two, and subsequent child language abilities at age three. Finally, multiple regression analyses were conducted to examine the extent to which maternal oral reading expressiveness may predict subsequent child language abilities approximately one year later (at age three) when controlling for SES. Results: Preliminary findings revealed no group differences in measures of maternal oral reading expressiveness (i.e., mean fo, speech rate) between mothers of late talkers versus controls. However, at the whole-group level (among all dyads), correlational analyses revealed that maternal oral reading expressiveness (e.g., mean fo) is positively associated with child receptive and expressive language abilities at both two and three years. Furthermore, through a multiple regression model, maternal oral reading expressiveness was found to significantly contribute to the variance in child language abilities at both two years and longitudinally at three years when SES factors (i.e., parent education level, income-to-need ratio) were held constant. Conclusions: Preliminary results suggest that maternal oral reading expressiveness is significantly associated with children’s emerging language abilities in toddlerhood. These findings highlight the need for further investigation into the variable of maternal oral reading expressiveness as a possible modifiable environmental factor with the potential to facilitate positive language outcomes for children. Future and ongoing work will be necessary to obtain a more fine-grained characterization of variation in maternal oral reading expressiveness and examine maternal oral reading expressiveness in conjunction with other quantitative and qualitative indicators of maternal language input. Findings of this work carry implications for targeting reading expressiveness in parent-focused early intervention programs.
The aspiring young undergraduate scientists envision fieldwork as a romantic escape from the office cubicle, classroom desk, and seemingly endless pile of homework. Working alongside experts in their ...field, they anticipate working in the wildest regions of the world: dense tropical forests, remote mountain ranges, and distant glacial rivers. They see themselves on the forefront of groundbreaking discoveries: truly shattering the scientific community with a cure for Malaria, discovery of a new species, or theory of planetary evolution.
Background
Effective and efficient conduct of randomised controlled trials (RCTs) ensures accurate, timely results and prevents research waste. There is however limited evidence available to inform ...the design, conduct and reporting of RCTs. A self-contained, randomised Study Within A Trial (SWAT), embedded within a host RCT or cohort study, offers an opportunity to fill this evidence gap. While SWATs are generally easy to implement, a range of challenges to undertaking SWATs have also been identified, however there is limited detail regarding practical solutions to tackle these.
Methods
Information and observations collected from PROMETHEUS members and participating trials, focusing on SWATs across a wide range of questions and settings, was reviewed to identify the challenges and solutions of delivery of a programme of SWATs.
Results
A range of challenges to undertaking SWATs (e.g., obtaining governance approvals) were identified along with potential solutions to these, which were implemented accordingly during programme delivery. Central to the solutions to resolve SWAT challenges is education to develop knowledge and understanding in the wider research community on the importance, purpose, and key methodological principles in relation to SWATs. In addition, the sharing of experience, best practice or resources to prevent or help negotiate the barriers to undertaking SWAT evaluation is also recommended.
Conclusions
Potential solutions to the barriers experienced in the design, conduct and implementation of a programme of SWATs have been identified. As more SWATs are completed, this will further develop evidence to support the mitigation or removal of barriers and in doing so this should increase the efficiency of randomised controlled trials.
Mutations in the Janus Kinase 2 (JAK2) gene resulting in constitutive kinase activation represent the most common genetic event in myeloproliferative neoplasms (MPN), a group of diseases involving ...overproduction of one or more kinds of blood cells, including red cells, white cells, and platelets. JAK2 kinase inhibitors, such as ruxolitinib, provide clinical benefit, but inhibition of wild-type (wt) JAK2 limits their clinical utility due to toxicity to normal cells, and small molecule inhibition of mutated JAK2 kinase activity can lead to drug resistance. Here, we present a strategy to target mutated JAK2 for degradation, using the cell's intracellular degradation machinery, while sparing non-mutated JAK2. We employed a chemical genetics screen, followed by extensive selectivity profiling and genetic studies, to identify the deubiquitinase (DUB), JOSD1, as a novel regulator of mutant JAK2. JOSD1 interacts with and stabilizes JAK2-V617F, and inactivation of the DUB leads to JAK2-V617F protein degradation by increasing its ubiquitination levels, thereby shortening its protein half-life. Moreover, targeting of JOSD1 leads to the death of JAK2-V617F-positive primary acute myeloid leukemia (AML) cells. These studies provide a novel therapeutic approach to achieving selective targeting of mutated JAK2 signaling in MPN.
Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function ...mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.
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