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Abstract Transcutaneous immunization (TCI) utilizing the TLR7 agonist imiquimod (IMQ-TCI) induces T cell-driven protective immunity upon application onto intact skin. In our present work, we combine the anti-psoriatic agent dithranol with IMQ-TCI to boost vaccination efficacy (Dithranol/IMQ-based transcutaneous vaccination (DIVA)). Using ovalbumin-derived peptides as model antigens in mice, DIVA induced superior cytolytic CD8+ T cells and CD4+ T cells with a TH1 cytokine profile in the priming as well as in the memory phase. Regarding the underlying mechanisms, dithranol induced an oxidant-dependent, monocyte-attracting inflammatory milieu in the skin boosting TLR7-dependent activation of dendritic cells and macrophages leading to superior T cell priming and protective immunity in vaccinia virus infection. In conclusion, we introduce the non-invasive vaccination method DIVA to induce strong primary and memory T cell responses upon a single local treatment. This work provides relevant insights in cutaneous vaccination approaches, paving the way for clinical development in humans.

Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism’s lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called “niche” that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

When examining the effects of a continuous variable 'x' on an outcome 'y', a researcher might choose to dichotomize on 'x', dividing the population into two sets—low 'x' and high 'x'—and testing whether these two subpopulations differ with respect to 'y'. Dichotomization has long been known to incur a cost in statistical power, but there remain circumstances in which it is appealing: an experimenter might use it to control for confounding covariates through subset selection, by carefully choosing a subpopulation of Low and a corresponding subpopulation of High that are balanced with respect to a list of control variables, and then comparing the subpopulations’ 'y' values. This “divide, select, and test” approach is used in many papers throughout the psycholinguistics literature, and elsewhere. Here we show that, despite the apparent innocuousness, these methodological choices can lead to erroneous results, in two ways. First, if the balanced subsets of Low and High are selected in certain ways, it is possible to conclude a relationship between 'x' and 'y' not present in the full population. Specifically, we show that previously published conclusions drawn from this methodology—about the effect of a particular lexical property on spoken-word recognition—do not in fact appear to hold. Second, if the balanced subsets of Low and High are selected randomly, this methodology frequently fails to show a relationship between 'x' and 'y' that is present in the full population. Our work uncovers a new facet of an ongoing research effort: to identify and reveal the implicit freedoms of experimental design that can lead to false conclusions.

The research aimed to estimate educational psychologist (EP) service provision required to deliver a "good" level of EP service within primary and secondary schools in one local authority (LA) in England. There is no current shared understanding of the level of demand for EP services, nor the required workforce to meet projected needs. Using a mixed methods design, four index schools were recruited; key staff within each school forecasted potential future commissioning of EP services. Content analysis was used to present key findings from focus groups/interviews to a working group of EPs who assessed the exact time-cost required to supply services. By extrapolation of the data, a model forecasted potential future demand for EP services across all primary and secondary schools in the LA. Findings reveal that all four schools would, with sufficient funding, commission significantly more EP time than they do currently; details and proportions are provided. The model predicts that schools across the LA would commission a fourfold increase in EP time purchased. Under the assumption that other EP service levels remain constant, the model suggests that meeting this need for increased EP services would require more than doubling of the size of the LA EP workforce.

In England, Wales and Northern Ireland, the General Certificate of Secondary Education (GCSE) has been for the last 35 years the most common qualification by which students' attainment at age 16 has been measured. The range and balance of processes by which the GCSEs' programmes of study have been assessed have varied over the decades, to include both teacher-assessed coursework and modular or end-of-programme timed written assessments (examinations). The necessary replacement in 2020 of GCSE written examinations with teacher-led assessment provided a unique opportunity to explore students' perceptions of the validity and utility of both examination and teacher-led assessment media for this high-stakes award. This research reports part of a survey that explored the experiences of GCSE candidates in 2020, with particular focus upon students' perceptions of preparing for written examinations, and then for teacher-led assessment. 216 students responded to a mixed quantitative/qualitative methods survey that invited opinion and reflection on the relative affordances and shortcomings of written examinations and teacher-led assessment, both for the individual respondent and the wider student cohort. Responses revealed a balance of both positive and negative evaluations of both assessment media, with an almost equal preference for either, albeit many respondents indicated consideration of some other assessment medium (e.g. modular assessment; combined assessment media). We re-emphasise the attested value of ongoing 'dialogue' and consultation with student stakeholders to inform planning for optimisation of assessment utility and validity.

Background: Universal social and emotional learning interventions can produce significant practical improvements in children’s social skills and other outcomes. However, the UK evidence base remains limited. Objectives: To investigate the implementation, impact and cost-effectiveness of the Promoting Alternative THinking Strategies (PATHS) curriculum. Design: Cluster randomised controlled trial. Primary schools (n = 45) were randomly assigned to implement PATHS or to continue with their usual provision for 2 years. Setting: Primary schools in seven local authorities in Greater Manchester. Participants: Children (n = 5218) in Years 3–5 (aged 7–9 years) attending participating schools. Intervention: PATHS aims to promote children’s social skills via a taught curriculum, which is delivered by the class teacher, generalisation activities and techniques, and supplementary materials for parents. Schools in the usual provision group delivered the Social and Emotional Aspects of Learning programme and related interventions. Main outcome measures: Children’s social skills (primary outcome, assessed by the Social Skills Improvement System); pro-social behaviour and mental health difficulties (Strengths and Difficulties Questionnaire); psychological well-being, perceptions of peer and social support, and school environment (Kidscreen-27); exclusions, attendance and attainment (National Pupil Database records); and quality-adjusted life-years (QALYs) (Child Health Utility 9 Dimensions). A comprehensive implementation and process evaluation was undertaken, involving usual provision surveys, structured observations of PATHS lessons, interviews with school staff and parents, and focus groups with children. Results: There was tentative evidence (at a p-value of

Parametric Presburger arithmetic: logic, combinatorics, and quasi-polynomial behavior, Discrete Analysis 2017:4, 34 pp. Let $T$ be a triangle with vertices $(0,0)$, $(0,1/3)$, and $(1,0)$, and let $t$ be a positive integer. Then it is not hard to check that there are three quadratics $q_1,q_2$ and $q_3$ such that the number of integer points in $tT$ is $q_i(t)$ if $t\equiv i$ mod 3. In a situation like this, we say that the number of integer points is _quasipolynomial_ with period 3. In 1962, Ehrhart proved that if $P$ is a polytope in $\mathbb Z^d$ defined by a finite set of linear inequalities of the form $a_i.x\leq b_i$, where each of the $a_i$ belong to $\mathbb Z^d$ and $b$ belongs to $\mathbb Z$, then the number of lattice points in $tP$ is quasipolynomial with period $m$, where $m$ is the smallest integer such that the vertices of $mP$ are all lattice points. Since then, the same conclusion has been established for other families of sets $S_t\subset \mathbb Z^d$ by Chen, Li and Sam, by Calegari and Walker, and by Roune and Woods. After these results, it was tempting to wonder whether _all_ families of sets, provided that they are sufficiently nice in some appropriate sense, exhibit this quasipolynomial behaviour. The constraints would have to be reasonably strong -- for example, the number of lattice points inside the unit sphere of radius $t$ is certainly not quasipolynomial (and indeed, estimating it is a famous problem) -- but one could still hope for a general theorem that would encompass the known results and give a number of further ones. It turns out that the right behaviour to look for in general is that the size of $S_t$ should be _eventually_ quasipolynomial -- that is, it should agree with a quasipolynomial for sufficiently large $t$. Woods conjectured that eventual quasipolynomial behaviour should occur whenever the family is definable in _parametric Presburger arithmetic_. Roughly what this means (for a more precise definition, see the paper) is that the family $S_t$ of subsets of $\mathbb Z^d$ can be defined using addition, inequalities, integer constants, Boolean operations, multiplication by $t$, and quantification over $\mathbb Z$. The polytopes discussed earlier are examples. For a somewhat different kind of example, let $S_t$ be the set of positive integers $n$ such that there do not exist non-negative integers $a,b,c$ with $n=at+b(t+1)+c(t+2)$. This example involves quantification over $\mathbb Z$, but again the number of points in $S_t$ turns out to be quasipolynomial: in fact, it is $\lfloor t^2/4 \rfloor$ (the paper also discusses a quasipolynomial formula for the maximum element of $S_t$). Note that it is crucial in this definition that multiplication, except by the parameter $t$, should not be allowed, since otherwise we would have the full power of Peano arithmetic, which is undecidable. The main result of this paper is a proof of this very appealing conjecture. The proof uses a series of reductions that make the family simpler and simpler until the result can be shown using previously developed methods. One of the reductions uses the well-known technique of quantifier elimination. However, this cannot be applied straightforwardly, owing to the multiplication-by-$t$ operation, which is not part of standard Presburger arithmetic (hence the word "parametric"). The paper also discusses the power of parametric Presburger arithmetic, which, considering the necessary restrictions, is greater than one might expect. Thus, it proves eventual quasipolynomial behaviour for an extremely wide class of families and is probably the most general result one could hope for along these lines. [Image created by Georgios Barmparis, Georgios Kopidakis and Ioannis Remediakis](http://www.mdpi.com/1996-1944/9/4/301/htm)

White light colonoscopy is the current gold standard for early detection and treatment of colorectal cancer, but emerging data suggest that this approach is inherently limited. Even the most experienced colonoscopists, under optimal conditions, miss at least 15–25% of adenomas. There is an unmet clinical need for an adjunctive modality to white light colonoscopy with improved lesion detection and characterization. Optical molecular imaging with exogenously administered organic fluorochromes is a burgeoning imaging modality poised to advance the capabilities of colonoscopy. In this proof-of-principle clinical trial, we investigated the ability of a custom-designed fluorescent colonoscope and indocyanine green, a clinically approved fluorescent blood pool imaging agent, to visualize polyps in high risk patients with polyposis syndromes or known distal colonic masses. We demonstrate (1) the successful performance of real-time, wide-field fluorescence endoscopy using off-the-shelf equipment, (2) the ability of this system to identify polyps as small as 1 mm, and (3) the potential for fluorescence imaging signal intensity to differentiate between neoplastic and benign polyps.

Background and study aims: Biopsy sampling error can be a problem for the diagnosis of certain gastrointestinal tract diseases. Spectrally-encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technology that has the potential to overcome sampling error by imaging large regions of gastrointestinal tract tissues. The aim of this study was to test a recently developed SECM endoscopic probe for comprehensively imaging large segments of the esophagus at the microscopic level in vivo. Methods: Topical acetic acid was endoscopically applied to the esophagus of a normal living swine. The 7 mm diameter SECM endoscopic probe was transorally introduced into the esophagus over a wire. Optics within the SECM probe were helically scanned over a 5 cm length of the esophagus. Confocal microscopy data was displayed and stored in real time. Results: Very large confocal microscopy images (length = 5 cm; circumference = 2.2 cm) of swine esophagus from three imaging depths, spanning a total area of 33 cm2, were obtained in about 2 minutes. SECM images enabled the visualization of cellular morphology of the swine esophagus, including stratified squamous cell nuclei, basal cells, and collagen within the lamina propria. Conclusions: The results from this study suggest that the SECM technology can rapidly provide large, contiguous confocal microscopy images of the esophagus in vivo. When applied to human subjects, the unique comprehensive, microscopic imaging capabilities of this technology may be utilized for improving the screening and surveillance of various esophageal diseases.

A function $g$, with domain the natural numbers, is a quasi-polynomial if there exists a period $m$ and polynomials $p_0,p_1,\ldots,p_m-1$ such that $g(t)=p_i(t)$ for $t\equiv i\bmod m$. Quasi-polynomials classically – and ``reasonably'' – appear in Ehrhart theory and in other contexts where one examines a family of polyhedra, parametrized by a variable t, and defined by linear inequalities of the form $a_1x_1+⋯+a_dx_d≤ b(t)$. Recent results of Chen, Li, Sam; Calegari, Walker; and Roune, Woods show a quasi-polynomial structure in several problems where the $a_i$ are also allowed to vary with $t$. We discuss these ``unreasonable'' results and conjecture a general class of sets that exhibit various (eventual) quasi-polynomial behaviors: sets $S_t$ that are defined with quantifiers $(\forall , ∃)$, boolean operations (and, or, not), and statements of the form $a_1(t)x_1+⋯+a_d(t)x_d ≤ b(t)$, where $a_i(t)$ and $b(t)$ are polynomials in $t$. These sets are a generalization of sets defined in the Presburger arithmetic. We prove several relationships between our conjectures, and we prove several special cases of the conjectures.

Schools have been identified as well placed to support students' wellbeing and encouraging the active participation of children and young people in school life is in line with current English legislation. Student-led research has the potential to create a positive, long-lasting impact. This evaluative systematic literature review (SLR) sought to identify the?features of?effective student?participation?in the co-production?of?whole-school?wellbeing?strategies, with a focus on Participatory Action Research (PAR) projects. Ten papers published between 2011 and 2021 were identified using the PRISMA framework and evaluated for methodological quality and appropriateness of focus. Several factors were identified as impacting on the success of PAR, including group composition, power balance, and sustainability. The paper concludes that carefully planned PAR projects can result in successful collaboration with students to develop whole-school strategies for a range of issues/topic areas. Further research evaluating the long-term impact of such projects on whole-school practice is warranted.

The classic algorithms of Needleman-Wunsch and Smith-Waterman find a maximum a posteriori probability alignment for a pair hidden Markov model (PHMM). To process large genomes that have undergone complex genome rearrangements, almost all existing whole genome alignment methods apply fast heuristics to divide genomes into small pieces that are suitable for Needleman-Wunsch alignment. In these alignment methods, it is standard practice to fix the parameters and to produce a single alignment for subsequent analysis by biologists. As the number of alignment programs applied on a whole genome scale continues to increase, so does the disagreement in their results. The alignments produced by different programs vary greatly, especially in non-coding regions of eukaryotic genomes where the biologically correct alignment is hard to find. Parametric alignment is one possible remedy. This methodology resolves the issue of robustness to changes in parameters by finding all optimal alignments for all possible parameters in a PHMM. Our main result is the construction of a whole genome parametric alignment of Drosophila melanogaster and Drosophila pseudoobscura. This alignment draws on existing heuristics for dividing whole genomes into small pieces for alignment, and it relies on advances we have made in computing convex polytopes that allow us to parametrically align non-coding regions using biologically realistic models. We demonstrate the utility of our parametric alignment for biological inference by showing that cis-regulatory elements are more conserved between Drosophila melanogaster and Drosophila pseudoobscura than previously thought. We also show how whole genome parametric alignment can be used to quantitatively assess the dependence of branch length estimates on alignment parameters.

The development of integrated care through the promotion of ‘partnership working’ is a key policy objective of the Scottish Executive, the administration responsible for health services in Scotland. This paper considers the extent to which this goal is being achieved in mental health services, particularly those for people with severe and enduring mental illness. Distinguishing between the horizontal and vertical integration of services, exploratory research was conducted to assess progress towards this objective by examining how far a range of functional activities in Primary Care Trusts (PCTs) and their constituent Local Health Care Co-operatives (LHCCs) were themselves becoming increasingly integrated. All PCTs in Scotland were surveyed by postal questionnaire, and followed up by detailed telephone interviews. Six LHCC areas were selected for detailed case study analysis. A Reference Group was used to discuss and review emerging themes from the fieldwork. The report suggests that faster progress is being made in the horizontal integration of services between health and social care organisations than is the case for vertical integration between primary health care and specialist mental health care services; and that there are significant gaps in the extent to which functional activities within Trusts are changing to support the development of integrated care. A number of models are briefly considered, including the idea of ‘intermediate care’ that might speed the process of integration.