Publications by authors named "Robert Griffiths"

152 Publications

Device-related infection in de novo transvenous implantable cardioverter-defibrillator Medicare patients.

Heart Rhythm 2021 Apr 19. Epub 2021 Apr 19.

Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota; Department of Cardiovascular Disease, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

Background: Cardiac device infection is a serious complication of implantable cardioverter-defibrillator (ICD) placement and requires complete device removal with accompanying antimicrobial therapy for durable cure. Recent guidelines have highlighted the need to better identify patients at high risk of infection to assist in device selection.

Objective: To estimate the prevalence of infection in de novo transvenous (TV) ICD implants and assess factors associated with infection risk in a Medicare population.

Methods: A retrospective cohort study was conducted using 100% Medicare administrative and claims data to identify patients who underwent de novo TV-ICD implantation (July 2016-December 2017). Infection within 720 days of implantation was identified using ICD-10 codes. Baseline factors associated with infection were identified by univariable logistic regression analysis of all variables of interest, including conditions in Charlson and Elixhauser comorbidity indices, followed by stepwise selection criteria with a P ≤ .25 for inclusion in a multivariable model and a backwards, stepwise elimination process with P ≤ .1 to remain in the model. A time-to-event analysis was also conducted.

Results: Among 26,742 patients with de novo TV-ICD, 519 (1.9%) developed an infection within 720 days post implant. While more than half (54%) of infections occurred during the first 90 days, 16% of infections occurred after 365 days. Multivariable analysis revealed several significant predictors of infection: age <70 years, renal disease with dialysis, and complicated diabetes mellitus.

Conclusion: The rate of de novo TV-ICD infection was 1.9%, and identified risk factors associated with infection may be useful in device selection.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.014DOI Listing
April 2021

Climate change alters temporal dynamics of alpine soil microbial functioning and biogeochemical cycling via earlier snowmelt.

ISME J 2021 Feb 22. Epub 2021 Feb 22.

Department of Earth and Environmental Sciences, Michael Smith Building, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.

Soil microbial communities regulate global biogeochemical cycles and respond rapidly to changing environmental conditions. However, understanding how soil microbial communities respond to climate change, and how this influences biogeochemical cycles, remains a major challenge. This is especially pertinent in alpine regions where climate change is taking place at double the rate of the global average, with large reductions in snow cover and earlier spring snowmelt expected as a consequence. Here, we show that spring snowmelt triggers an abrupt transition in the composition of soil microbial communities of alpine grassland that is closely linked to shifts in soil microbial functioning and biogeochemical pools and fluxes. Further, by experimentally manipulating snow cover we show that this abrupt seasonal transition in wide-ranging microbial and biogeochemical soil properties is advanced by earlier snowmelt. Preceding winter conditions did not change the processes that take place during snowmelt. Our findings emphasise the importance of seasonal dynamics for soil microbial communities and the biogeochemical cycles that they regulate. Moreover, our findings suggest that earlier spring snowmelt due to climate change will have far reaching consequences for microbial communities and nutrient cycling in these globally widespread alpine ecosystems.
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http://dx.doi.org/10.1038/s41396-021-00922-0DOI Listing
February 2021

Towards a microbial process-based understanding of the resilience of peatland ecosystem service provisioning - A research agenda.

Sci Total Environ 2021 Mar 10;759:143467. Epub 2020 Nov 10.

Ecological Sciences, The James Hutton Institute, Craigiebuckler, Aberdeen AB15 8QH, UK.

Peatlands are wetland ecosystems with great significance as natural habitats and as major global carbon stores. They have been subject to widespread exploitation and degradation with resulting losses in characteristic biota and ecosystem functions such as climate regulation. More recently, large-scale programmes have been established to restore peatland ecosystems and the various services they provide to society. Despite significant progress in peatland science and restoration practice, we lack a process-based understanding of how soil microbiota influence peatland functioning and mediate the resilience and recovery of ecosystem services, to perturbations associated with land use and climate change. We argue that there is a need to: in the short-term, characterise peatland microbial communities across a range of spatial and temporal scales and develop an improved understanding of the links between peatland habitat, ecological functions and microbial processes; in the medium term, define what a successfully restored 'target' peatland microbiome looks like for key carbon cycle related ecosystem services and develop microbial-based monitoring tools for assessing restoration needs; and in the longer term, to use this knowledge to influence restoration practices and assess progress on the trajectory towards 'intact' peatland status. Rapid advances in genetic characterisation of the structure and functions of microbial communities offer the potential for transformative progress in these areas, but the scale and speed of methodological and conceptual advances in studying ecosystem functions is a challenge for peatland scientists. Advances in this area require multidisciplinary collaborations between peatland scientists, data scientists and microbiologists and ultimately, collaboration with the modelling community. Developing a process-based understanding of the resilience and recovery of peatlands to perturbations, such as climate extremes, fires, and drainage, will be key to meeting climate targets and delivering ecosystem services cost effectively.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143467DOI Listing
March 2021

Advancing nursing practice for improved health outcomes using the principles of perceptual control theory.

Nurs Philos 2020 Jul 27;21(3):e12301. Epub 2020 May 27.

Institute of Global Health Equity Research, University of Global Health Equity, Kigali, Rwanda.

This article describes how an empirically supported theory of human behaviour, perceptual control theory, can be used to advance nursing practice and improve health outcomes for people who are accessing nursing care. Nursing often takes a pragmatic approach to the delivery of care, with an emphasis on doing what appears to work. This focus on pragmatism can sometimes take precedence over any consideration of the underlying theoretical assumptions that inform decisions to take one particular approach over another or the mechanisms through which nursing interventions have their effects. For nursing to develop as a profession, there needs to be an increased focus on the core principles that underpin the delivery of care. In addition to understanding what works, nurses must develop their understanding of how and why particular approaches work or do not work. Understanding the fundamental principles that underpin nurses' actions will lead to more efficient and effective approaches to the delivery of nursing care. It will also enable nurses to maximize those elements of their practice that are most beneficial for people and minimize other activities that either have little effect or actually lead to worse outcomes. In this article, we will propose that the phenomenon of control is fundamental to human health. Perceptual control theory provides a coherent theoretical framework that enables us to understand the phenomenon of control through a functional model of human behaviour. People are healthy when their neurochemical, physiological, biological, psychological and social states are all controlled satisfactorily. We will explain the implications of understanding health as control throughout the paper. From this perspective, we will argue that the aim of nurses and nursing should be to support people to maintain or recover control over those aspects of their lives that are important and meaningful to them.
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http://dx.doi.org/10.1111/nup.12301DOI Listing
July 2020

Identifying Functional Mechanisms in Psychotherapy: A Scoping Systematic Review.

Front Psychiatry 2020 17;11:291. Epub 2020 Apr 17.

Centre for Remote Health, Flinders University, Alice Springs, NT, Australia.

The identification of fundamental mechanisms is an important scientific pursuit in many fields of enquiry. With regard to the development of psychological treatments, understanding the mechanisms through which change occurs such that psychological distress resolves, can enable us to develop more effective and efficient interventions. In the field of psychotherapy, mechanisms are often identified either statistically or conceptually. The most powerful and useful mechanisms, however, are functional rather than statistical or conceptual. More specifically, with regard to mechanisms relevant to psychotherapy, it is difficult to identify what any of these mechanisms actually in a mechanistic sense. That is, the mechanics of putative mechanisms are generally unspecified. In order to obtain a rigorous and comprehensive account of the current mechanisms in psychotherapy, as well as to evaluate their usefulness, a systematic scoping review was conducted. The systematic scoping review did not yield any mechanisms that were expressed in functional terms. We argue that, in order for psychotherapy to improve its effectiveness and efficiency, the standard for what is accepted as a useful mechanism needs to be substantially raised. Only functional mechanisms that express plausible actions consistent with known biological processes should be used to inform therapeutic interventions.
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http://dx.doi.org/10.3389/fpsyt.2020.00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180170PMC
April 2020

C-C Motif Chemokine Receptor 7 Exacerbates Hypertension Through Effects on T Lymphocyte Trafficking.

Hypertension 2020 03 27;75(3):869-876. Epub 2020 Jan 27.

From the Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Center, NC (Y.W., N.P.R., J.Z., X.L., J.R., R.G., S.D.C.).

Activated T lymphocytes that infiltrate blood pressure control organs make a critical contribution to the pathogenesis of hypertension. Dendritic cells act as potent antigen-presenting cells to stimulate prohypertensive T cells. However, the mechanisms that facilitate the recruitment of prohypertensive T cells and dendritic cells into the kidney's draining lymph node during hypertension require elucidation. As CCR7 (C-C motif chemokine receptor type 7) directs the homing of lymphocytes and dendritic cells into lymph nodes, we posited that dendritic cell-mediated T lymphocyte stimulation in the renal lymph node is CCR7 dependent and required for a full hypertensive response. We found that CCR7-deficient (CCR7 KO) mice had a blunted hypertensive response in our model of chronic Ang II (angiotensin II) infusion. Ang II-infused CCR7 KO animals had exaggerated accumulation of CD8 T cells in the kidney but reduced numbers of CD4 and CD8 T cells in the kidney's draining lymph node. To understand whether CCR7-dependent homing of T lymphocytes or dendritic cells into the lymph node regulates the hypertensive response, we injected CCR7 KO or wild-type T cells or dendritic cells into CCR7 KO recipients, neither of which restored the full hypertensive response to Ang II infusion. However, adoptive transfer of wild-type but not CCR7 KO T lymphocytes into RAG1 (recombination-activating gene 1)-deficient mice that lack a lymphocyte niche restored full blood pressure elevation during Ang II infusion. Thus, CCR7-dependent interactions between T lymphocytes and dendritic cells are essential for T lymphocyte stimulation and hypertension accruing from inappropriate activation of the renin-angiotensin system.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035160PMC
March 2020

Costs and complications associated with transvenous lead reoperation in cardiac implantable electronic devices.

J Cardiovasc Electrophysiol 2020 02 20;31(2):503-511. Epub 2020 Jan 20.

Economics & Quality of Life Research, Baim Institute for Clinical Research, Boston, Massachusetts.

Background: Cardiac implantable electronic device transvenous (TV) lead reoperations are projected to increase, and robust economic data are needed to assess the resulting financial impact and the cost-effectiveness of prevention and treatment strategies. This study estimates Medicare costs, and describes patterns of complications, in patients who underwent TV lead reoperation.

Methods And Results: Medicare data (2010-2014) were used to identify patients who underwent TV lead reoperation. Cumulative costs to Medicare, and rates of infection and mechanical complications were calculated from 180 days before, to 180 days after, lead reoperation. Multivariate analysis was used to estimate adjusted costs, and to examine the impact of complications on medical resource use and costs. There were 1691 patients, 63.2% of whom underwent inpatient lead reoperation. Overall, the mean age was 78.2 years, 39.6% were female, and 92.3% were white. The mean cumulative cost was $36 199 (95% confidence interval [CI], $31 864-$40 535) for TV lead repositioning, $27 701 (95% CI, $19 869-$35 534) for repair, and $54 442 (95% CI, $51 651-$57 233) for removal. Underlying infection was associated with increased odds of inpatient reoperation and of lead removal, as well as longer length of stay and higher costs.

Conclusions: The economic consequences of TV lead reoperation are substantial. Strategies aimed at reducing reoperation, particularly lead removal, are likely to result in considerable cost offsets.
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http://dx.doi.org/10.1111/jce.14337DOI Listing
February 2020

Estimated Lifetime Economic Burden of Type 1 Diabetes.

Diabetes Technol Ther 2020 02;22(2):121-130

Boston Health Economics, LLC, Boston, Massachusetts.

The financial strain of type 1 diabetes on the United States health care system, patients, and employers underscores the importance of developing novel treatments for the disease. This study estimated the lifetime economic burden attributable to type 1 diabetes in the United States. A patient-level, Markov state/transition simulation model was developed to compare cumulative societal costs among patients with and without type 1 diabetes. For each patient type, 1 prevalent and 10 incident cohorts were constructed and followed annually over a lifetime horizon. The 1 prevalent cohort with type 1 diabetes entered in the first year of the model and at the current age of each patient, whereas the 10 incident cohorts entered in each of 10 subsequent years and at the age of diagnosis of each patient. Patients were assigned age-specific annual medical expenditures and lost wages. Model outputs included the total cumulative medical and lost productivity costs attributable to type 1 diabetes, defined as the difference in costs between patients with and without type 1 diabetes. The model consisted of 1,630,317 patients with type 1 diabetes and an equal number of patients without type 1 diabetes. The difference in lifetime costs was $813 billion (95% confidence interval: $682-$1037 billion), representing a high burden of illness compared with patients without type 1 diabetes. Sensitivity analyses demonstrated robustness in model results. Our findings suggest significant investment in research and development of novel treatments for type 1 diabetes is justified, given the high burden of illness associated with the disease.
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http://dx.doi.org/10.1089/dia.2019.0398DOI Listing
February 2020

Classical Dendritic Cells Mediate Hypertension by Promoting Renal Oxidative Stress and Fluid Retention.

Hypertension 2020 01 2;75(1):131-138. Epub 2019 Dec 2.

From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (X.L., N.P.R., J.R.P., J.R., Y.W., R.G., S.D.C.).

FLT3L (Fms-like tyrosine kinase 3 ligand) stimulates the development of classical dendritic cells (DCs). Here we tested the hypothesis that classical DCs drive blood pressure elevation by promoting renal fluid retention. FLT3L-deficient (FLT3L) mice that lack classical DCs in the kidney had mean arterial pressures similar to wild-types (WTs) at baseline but had blunted hypertensive responses during 4 weeks of chronic Ang II (angiotensin II) infusion. In FLT3L mice, the proportions of effector memory T cells in the kidney were similar to those in WTs at baseline. However, after Ang II infusion, proportions of effector memory T cells were dramatically lower in the FLT3L kidneys versus WTs, indicating that classical DCs augment the renal accumulation of effector T cells after renin-angiotensin system activation. Consistent with their lower blood pressures, the Ang II-infused FLT3L mice had attenuated cardiac hypertrophy and lower renal mRNA expression for pro-hypertensive cytokines. Moreover, the Ang II-infused FLT3L mice had lower urinary excretion of the oxidative stress marker 8-isoprostane and lower renal mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase 2. In an intraperitoneal saline challenge test at day 7 of Ang II, FLT3L mice excreted higher proportions of the injected volume and sodium than WTs. Consistent with this enhanced diuresis, mRNA expressions for the sodium chloride cotransporter and all 3 subunits of the epithelial sodium channel were diminished by >40% in FLT3L kidneys compared with the WTs. Thus, classical FLT3L-dependent DCs promote renal T-cell activation with consequent oxidative stress, fluid retention, and blood pressure elevation.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004279PMC
January 2020

Effects of acidity on dissolved organic carbon in organic soil extracts, pore water and surface litters.

Sci Total Environ 2020 Feb 18;703:135585. Epub 2019 Nov 18.

Centre for Ecology and Hydrology, Deiniol Rd, Bangor LL57 2UP, UK.

Over the past 30-40 years, dissolved organic carbon (DOC) concentrations have increased in soil solutions and surface waters in many acid-sensitive areas of Europe and North America. This has been linked to recovery from acidification in response to decreasing levels of atmospheric pollution. Evidence from radiocarbon dating suggests that DOC in surface waters is typically derived from recently photosynthesised organic matter such as plant litter and exudates, yet there is little information on the pH-sensitivity of organic matter solubility, or its decomposition, in litter layers and in different organic soils. Therefore the purpose of this study was to determine a) the sensitivity of DOC to acidity in different surface layers and soil types, in order to b) improve understanding of the key sources contributing to the increasing DOC trend. Such information is vital for understanding site specific characteristics contributing to inconsistencies in DOC release between catchments, and for improving predictions of carbon fluxes and budgets. Based on data collected at four established field pH-manipulation experiments in upland areas of the United Kingdom, we examined the sources, composition and acid-sensitivity of DOC export from the litter and organic soils. We found that litter generated nearly three times more DOC than the organic soils, consistent with radiocarbon evidence that recent plant inputs are a major source of DOC. Furthermore, litter derived DOC had lower specific ultraviolet light absorbance (SUVA) than organic soil DOC, suggesting greater biodegradability, and was not acid sensitive. In contrast, organic soil DOC concentrations were more strongly related to experimentally manipulated pH, implying that the mobility of this DOC may be subject to physicochemical rather than biotic controls. Our results suggest that physicochemically mediated controls on organic matter solubility may be a key driver behind the widely observed increases in surface water DOC in areas undergoing recovery from acidification.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135585DOI Listing
February 2020

A20 in Myeloid Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T-Cell Activation.

Circ Res 2019 12 21;125(12):1055-1066. Epub 2019 Oct 21.

From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (X.L., N.P.R., Y.W., J.R., R.G., J.R.P., B.Y., M.A.S., S.D.C.).

Rationale: The ubiquitin-editing protein A20 in dendritic cells (DCs) suppresses NF-κB (nuclear factor-κB) signaling and constrains DC-mediated T-cell stimulation, but the role of A20 in modulating the hypertensive response requires elucidation.

Objective: Here, we tested the hypothesis that A20 in CD11c-expressing myeloid cells mitigates Ang II (angiotensin II)-induced hypertension by limiting renal T-cell activation.

Methods And Results: Mice with heterozygous deletion of A20 in CD11c-expressing myeloid cells (DC ACT[ ]) have spontaneous DC activation but have normal baseline blood pressures. In response to low-dose chronic Ang II infusion, DC ACT mice compared with WT (wild type) controls had an exaggerated hypertensive response and augmented proportions of CD62LCD44 effector memory T lymphocytes in the kidney lymph node. After 10 days of Ang II, DC ACT kidneys had increased numbers of memory effector CD8, but not CD4 T cells, compared with WTs. Moreover, the expressions of TNF-α (tumor necrosis factor-α) and IFN-γ (interferon-γ) were upregulated in the DC ACT renal CD8 T cells but not CD4 T cells. Saline challenge testing revealed enhanced renal fluid retention in the DC ACT mice. DC ACT kidneys showed augmented protein expression of γ-epithelial sodium channel and NHE3 (sodium-hydrogen antiporter 3). DC ACT mice also had greater reductions in renal blood flow following acute injections with Ang II and enhanced oxidant stress in the vasculature as evidenced by higher circulating levels of malondialdehyde compared with WT controls. To directly test whether enhanced T-cell activation in the DC ACT cohort was responsible for their exaggerated hypertensive response, we chronically infused Ang II into lymphocyte-deficient DC ACT Rag1 (recombination activating protein 1)-deficient () mice and WT (- ) Rag1 controls. The difference in blood pressure elevation accruing from DC activation was abrogated on the Rag1 strain.

Conclusions: Following stimulation of the renin-angiotensin system, A20 suppresses DC activation and thereby mitigates T-cell-dependent blood pressure elevation.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006714PMC
December 2019

Opposing actions of renal tubular- and myeloid-derived porcupine in obstruction-induced kidney fibrosis.

Kidney Int 2019 12 31;96(6):1308-1319. Epub 2019 Jul 31.

Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; Durham Veterans Affairs Medical Center, Durham, North Carolina, USA. Electronic address:

Wnt/β-catenin signaling is essential in the pathogenesis of renal fibrosis. We previously reported inhibition of the Wnt O-acyl transferase porcupine, required for Wnt secretion, dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Here, we investigated the tissue-specific contributions of porcupine to renal fibrosis and inflammation in ureteral obstruction using mice with porcupine deletion restricted to the kidney tubular epithelium or infiltrating myeloid cells. Obstruction of the ureter induced the renal mRNA expression of porcupine and downstream targets, β-catenin, T-cell factor, and lymphoid enhancer factor in wild type mice. Renal tubular specific deficiency of porcupine reduced the expression of collagen I and other fibrosis markers in the obstructed kidney. Moreover, kidneys from obstructed mice with tubule-specific porcupine deficiency had reduced macrophage accumulation with attenuated expression of myeloid cytokine and chemokine mRNA. In co-culture with activated macrophages, renal tubular cells from tubular-specific porcupine knockout mice had blunted induction of fibrosis mediators compared with wild type renal tubular cells. In contrast, macrophages from macrophage-specific porcupine deficient mice in co-culture with wild type renal tubular cells had markedly enhanced expression of pro-fibrotic cytokines compared to wild type macrophages. Consequently, porcupine deletion specifically within macrophages augmented renal scar formation following ureteral obstruction. Thus, our experiments suggest a benefit of interrupting Wnt secretion specifically within the kidney epithelium while preserving Wnt O-acylation in infiltrating myeloid cells during renal fibrogenesis.
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http://dx.doi.org/10.1016/j.kint.2019.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875628PMC
December 2019

The transition distribution of a sample from a Wright-Fisher diffusion with general small mutation rates.

J Math Biol 2019 12 17;79(6-7):2315-2342. Epub 2019 Sep 17.

School of Mathematics, Monash University, Melbourne, Australia.

The transition distribution of a sample taken from a Wright-Fisher diffusion with general small mutation rates is found using a coalescent approach. The approximation is equivalent to having at most one mutation in the coalescent tree of the sample up to the most recent common ancestor with additional mutations occurring on the lineage from the most recent common ancestor to the time origin if complete coalescence occurs before the origin. The sampling distribution leads to an approximation for the transition density in the diffusion with small mutation rates. This new solution has interest because the transition density in a Wright-Fisher diffusion with general mutation rates is not known.
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http://dx.doi.org/10.1007/s00285-019-01430-8DOI Listing
December 2019

Quantum measurements and contextuality.

Philos Trans A Math Phys Eng Sci 2019 Nov 16;377(2157):20190033. Epub 2019 Sep 16.

Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.

In quantum physics, the term 'contextual' can be used in more than one way. One usage, here called 'Bell contextual' since the idea goes back to Bell, is that if , and are three quantum observables, with compatible (i.e. commuting) with and also with , whereas and are incompatible, a measurement of might yield a different result (indicating that quantum mechanics is contextual) depending upon whether is measured along with (the {, } context) or with (the {, } context). An analysis of what projective quantum measurements measure shows that quantum theory is Bell non-contextual: the outcome of a particular measurement when is measured along with would have been exactly the same if had, instead, been measured along with . A different definition, here called 'globally (non)contextual' refers to whether or not there is (non-contextual) or is not (contextual) a single joint probability distribution that simultaneously assigns probabilities in a consistent manner to the outcomes of measurements of a certain collection of observables, not all of which are compatible. A simple example shows that such a joint probability distribution can exist even in a situation where the measurement probabilities cannot refer to properties of a quantum system, and hence lack physical significance, even though mathematically well defined. It is noted that the quantum sample space, a projective decomposition of the identity, required for interpreting measurements of incompatible properties in different runs of an experiment using different types of apparatus, has a tensor product structure, a fact sometimes overlooked. This article is part of the theme issue 'Contextuality and probability in quantum mechanics and beyond'.
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http://dx.doi.org/10.1098/rsta.2019.0033DOI Listing
November 2019

Corrigendum to "A coalescent dual process for a Wright-Fisher diffusion with recombination and its application to haplotype partitioning" [Theor. Popul. Biol. 112 (2016) 126-138].

Theor Popul Biol 2019 Dec 5;130:203. Epub 2019 Aug 5.

Département de Mathématiques et de Statistique, Université de Montréal, Montréal, Canada.

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http://dx.doi.org/10.1016/j.tpb.2019.08.001DOI Listing
December 2019

Zones of influence for soil organic matter dynamics: A conceptual framework for data and models.

Glob Chang Biol 2019 Dec 28;25(12):3996-4007. Epub 2019 Aug 28.

Centre for Ecology & Hydrology, Environment Centre Wales, Bangor, Gwynedd, UK.

Soil organic matter (SOM) is an indicator of sustainable land management as stated in the global indicator framework of the United Nations Sustainable Development Goals (SDG Indicator 15.3.1). Improved forecasting of future changes in SOM is needed to support the development of more sustainable land management under a changing climate. Current models fail to reproduce historical trends in SOM both within and during transition between ecosystems. More realistic spatio-temporal SOM dynamics require inclusion of the recent paradigm shift from SOM recalcitrance as an 'intrinsic property' to SOM persistence as an 'ecosystem interaction'. We present a soil profile, or pedon-explicit, ecosystem-scale framework for data and models of SOM distribution and dynamics which can better represent land use transitions. Ecosystem-scale drivers are integrated with pedon-scale processes in two zones of influence. In the upper vegetation zone, SOM is affected primarily by plant inputs (above- and belowground), climate, microbial activity and physical aggregation and is prone to destabilization. In the lower mineral matrix zone, SOM inputs from the vegetation zone are controlled primarily by mineral phase and chemical interactions, resulting in more favourable conditions for SOM persistence. Vegetation zone boundary conditions vary spatially at landscape scales (vegetation cover) and temporally at decadal scales (climate). Mineral matrix zone boundary conditions vary spatially at landscape scales (geology, topography) but change only slowly. The thicknesses of the two zones and their transport connectivity are dynamic and affected by plant cover, land use practices, climate and feedbacks from current SOM stock in each layer. Using this framework, we identify several areas where greater knowledge is needed to advance the emerging paradigm of SOM dynamics-improved representation of plant-derived carbon inputs, contributions of soil biota to SOM storage and effect of dynamic soil structure on SOM storage-and how this can be combined with robust and efficient soil monitoring.
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http://dx.doi.org/10.1111/gcb.14787DOI Listing
December 2019

KLF4 in Macrophages Attenuates TNF-Mediated Kidney Injury and Fibrosis.

J Am Soc Nephrol 2019 10 23;30(10):1925-1938. Epub 2019 Jul 23.

Division of Nephrology,

Background: Polarized macrophage populations can orchestrate both inflammation of the kidney and tissue repair during CKD. Proinflammatory M1 macrophages initiate kidney injury, but mechanisms through which persistent M1-dependent kidney damage culminates in fibrosis require elucidation. Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor that suppresses inflammatory signals, is an essential regulator of macrophage polarization in adipose tissues, but the effect of myeloid KLF4 on CKD progression is unknown.

Methods: We used conditional mutant mice lacking KLF4 or TNF (KLF4's downstream effector) selectively in myeloid cells to investigate macrophage KLF4's role in modulating CKD progression in two models of CKD that feature robust macrophage accumulation, nephrotoxic serum nephritis, and unilateral ureteral obstruction.

Results: In these murine CKD models, KLF4 deficiency in macrophages infiltrating the kidney augmented their M1 polarization and exacerbated glomerular matrix deposition and tubular epithelial damage. During the induced injury in these models, macrophage-specific KLF4 deletion also exacerbated kidney fibrosis, with increased levels of collagen 1 and -smooth muscle actin in the injured kidney. CD11bLy6C myeloid cells isolated from injured kidneys expressed higher levels of TNF mRNA versus wild-type controls. In turn, mice bearing macrophage-specific deletion of TNF exhibited decreased glomerular and tubular damage and attenuated kidney fibrosis in the models. Moreover, treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters.

Conclusions: These data indicate that macrophage KLF4 ameliorates CKD by mitigating TNF-dependent injury and fibrosis.
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http://dx.doi.org/10.1681/ASN.2019020111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779357PMC
October 2019

Twist1 in Infiltrating Macrophages Attenuates Kidney Fibrosis Matrix Metallopeptidase 13-Mediated Matrix Degradation.

J Am Soc Nephrol 2019 09 17;30(9):1674-1685. Epub 2019 Jul 17.

Divisions of Nephrology and

Background: Following an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs). In macrophages, Twist1 can influence patterns of cytokine generation, but the role of macrophage Twist1 in renal fibrogenesis remains undefined.

Methods: To study Twist1 functions in different macrophage subsets during kidney scar formation, we used two conditional mutant mouse models in which was selectively ablated either in infiltrating, inflammatory macrophages or in resident tissue macrophages. We assessed fibrosis-related parameters, matrix metallopeptidase 13 (MMP13, or collagen 3, which catalyzes collagen degradation), inflammatory cytokines, and other factors in these Twist1-deficient mice compared with wild-type controls after subjecting the animals to unilateral ureteral obstruction. We also treated wild-type and Twist1-deficient mice with an MMP13 inhibitor after unilateral ureteral obstruction.

Results: Twist1 in infiltrating inflammatory macrophages but not in resident macrophages limited kidney fibrosis after ureteral obstruction by driving extracellular matrix degradation. Moreover, deletion of Twist1 in infiltrating macrophages attenuated the expression of MMP13 in CD11bLy6C myeloid cells. Inhibition of MMP13 abrogated the protection from renal fibrosis afforded by macrophage Twist1.

Conclusions: Twist1 in infiltrating myeloid cells mitigates interstitial matrix accumulation in the injured kidney by promoting MMP13 production, which drives extracellular matrix degradation. These data highlight the complex cell-specific actions of Twist1 in the pathogenesis of kidney fibrosis.
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http://dx.doi.org/10.1681/ASN.2018121253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727252PMC
September 2019

To Mix or Not To Mix? A Meta-Method Approach to Rethinking Evaluation Practices for Improved Effectiveness and Efficiency of Psychological Therapies Illustrated With the Application of Perceptual Control Theory.

Front Psychol 2019 26;10:1445. Epub 2019 Jun 26.

Greater Manchester Mental Health NHS Foundation Trust, Manchester, United Kingdom.

Progress in the development of more effective and efficient psychological therapies could be accelerated with innovative and nuanced approaches to research methodology. Therapy development has been dominated by a mono-methodology attitude with randomized controlled trials (RCTs) regarded as a "gold standard" despite the concept of a single methodology being ascribed gold standard status having been called into question. Rather than one particular methodology being considered superior to all others, the gold standard approach should be matching appropriate methodologies to important research questions. The way in which that matching should occur, however, is far from clear. Moving from a mono-methodological approach to mixed-method designs has not been straightforward. The ways in which methods should be mixed, to arrive at robust and persuasive answers to genuine research questions, is not entirely clear. In this paper, we argue that attention to the meta-methods underpinning all research designs will improve research precision and provide greater clarity about the contribution of any particular program of research to scientific progress in that field. From a meta-method perspective, the matter of changed can be delineated from or these changes occurred. Different methods and different types of mixing can be justified for each meta question. A meta-method approach should make explicit the assumptions that guide the development of research designs and also promote the articulation of putative mechanisms that might be relevant. By paying greater attention to assumptions such as how causality occurs, and important mechanisms of change, the mixing of methodologies that are still not mainstream in this area such as routine outcome monitoring and evaluation and functional model building, can occur. By adopting methodologies that focus on learning about a program's strengths and weaknesses rather than presiding over judgments of whether or not the program is deemed to be effective, we will move much closer to a position of being able to understand what programs under which conditions people find most helpful for their purposes.
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http://dx.doi.org/10.3389/fpsyg.2019.01445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607441PMC
June 2019

Method of levels therapy for first-episode psychosis: The feasibility randomized controlled Next Level trial.

J Clin Psychol 2019 10 25;75(10):1756-1769. Epub 2019 Jun 25.

Division of Psychology and Mental Health, School of Psychological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Objective: We aimed to determine the feasibility and acceptability of Method of Levels (MOL) for people experiencing first-episode psychosis (FEP) to inform decision making about the therapy's suitability for further testing in a larger clinical trial.

Method: A parallel group randomized controlled trial design was used. Participants (N = 36) were allocated to receive either treatment as usual (TAU) or TAU plus MOL. Recruitment and retention in the trial and the acceptability of the MOL intervention were the primary outcomes.

Results: The recruitment target was met within the planned time frame. Retention in the trial at final follow-up was 97%, substantially higher than the 80% threshold prespecified as a successful feasibility outcome. Participant feedback provided initial evidence of the acceptability of the study design and intervention for this population.

Conclusion: Results support progressing to a larger trial of MOL for FEP. Recommendations for the design of future trials are provided.
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http://dx.doi.org/10.1002/jclp.22820DOI Listing
October 2019

Stimulating Type 1 Angiotensin Receptors on T Lymphocytes Attenuates Renal Fibrosis.

Am J Pathol 2019 05 15;189(5):981-988. Epub 2019 Apr 15.

Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina; Department of Medicine, Durham Veterans Affairs Medical Centers, Durham, North Carolina. Electronic address:

Most forms of chronic kidney disease culminate in renal fibrosis that heralds organ failure. In contrast to the protective effects of globally blocking type 1 angiotensin (AT) receptors throughout the body, activating AT receptors directly on immune cells may serve protective functions. However, the effects of stimulating the T-cell AT receptor on the progression of renal fibrosis remain unknown. In this study, mice with T-cell-specific deletion of the dominant murine AT receptor isoform Lck-Cre Agtra [total knockout (TKO)] and wild-type (WT) controls were subjected to the unilateral ureteral obstruction model of kidney fibrosis. Compared with WT controls, obstructed kidneys from TKO mice at day 14 had increased collagen 1 deposition. CD4 T cells, CD11bLy6C myeloid cells, and mRNA levels of Th1 inflammatory cytokines are elevated in obstructed TKO kidneys, suggesting that augmented Th1 responses in the TKO mice may exaggerate renal fibrosis by driving proinflammatory macrophage differentiation. In turn, T-bet deficient (T-bet knockout) mice lacking Th1 responses have attenuated collagen deposition after unilateral ureteral obstruction. We conclude that activating the AT receptor on T cells mitigates renal fibrogenesis by inhibiting Th1 differentiation and renal accumulation of profibrotic macrophages.
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http://dx.doi.org/10.1016/j.ajpath.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521889PMC
May 2019

Divergent national-scale trends of microbial and animal biodiversity revealed across diverse temperate soil ecosystems.

Nat Commun 2019 03 7;10(1):1107. Epub 2019 Mar 7.

School of Natural Sciences, Bangor University, Deiniol Road, Bangor, LL57 2UW, Gwynedd, UK.

Soil biota accounts for ~25% of global biodiversity and is vital to nutrient cycling and primary production. There is growing momentum to study total belowground biodiversity across large ecological scales to understand how habitat and soil properties shape belowground communities. Microbial and animal components of belowground communities follow divergent responses to soil properties and land use intensification; however, it is unclear whether this extends across heterogeneous ecosystems. Here, a national-scale metabarcoding analysis of 436 locations across 7 different temperate ecosystems shows that belowground animal and microbial (bacteria, archaea, fungi, and protists) richness follow divergent trends, whereas β-diversity does not. Animal richness is governed by intensive land use and unaffected by soil properties, while microbial richness was driven by environmental properties across land uses. Our findings demonstrate that established divergent patterns of belowground microbial and animal diversity are consistent across heterogeneous land uses and are detectable using a standardised metabarcoding approach.
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http://dx.doi.org/10.1038/s41467-019-09031-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405921PMC
March 2019

'It was me answering my own questions': Experiences of method of levels therapy amongst people with first-episode psychosis.

Int J Ment Health Nurs 2019 Jun 31;28(3):721-734. Epub 2019 Jan 31.

School of Psychological Sciences, The University of Manchester, Manchester, UK.

In this study, we aimed to understand how people with first-episode psychosis experienced a transdiagnostic cognitive therapy called method of levels (MOL). Semistructured interviews were conducted with 12 individuals who were participants of a feasibility randomized controlled trial of MOL for first-episode psychosis. Interviews were analysed using thematic analysis. Four superordinate themes were identified: 'The therapist's approach'; 'I was in control'; 'Thinking and talking'; and 'Looking at problems from a different perspective'. Our findings suggest that therapy was experienced as most helpful when participants perceived themselves to have control over the process of therapy, could explore and express a wide range of difficulties, and were able to generate new perspectives on their problems. MOL and its associated system of client-led appointment scheduling were predominantly perceived to be helpful and appear suitable for further testing in a larger clinical trial.
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http://dx.doi.org/10.1111/inm.12576DOI Listing
June 2019

Soil parameters, land use, and geographical distance drive soil bacterial communities along a European transect.

Sci Rep 2019 01 24;9(1):605. Epub 2019 Jan 24.

Agroécologie, AgroSup Dijon, INRA, Univ. Bourgogne, Univ. Bourgogne Franche-Comté, F-21000, Dijon, France.

To better understand the relationship between soil bacterial communities, soil physicochemical properties, land use and geographical distance, we considered for the first time ever a European transect running from Sweden down to Portugal and from France to Slovenia. We investigated 71 sites based on their range of variation in soil properties (pH, texture and organic matter), climatic conditions (Atlantic, alpine, boreal, continental, Mediterranean) and land uses (arable, forest and grassland). 16S rRNA gene amplicon pyrosequencing revealed that bacterial communities highly varied in diversity, richness, and structure according to environmental factors. At the European scale, taxa area relationship (TAR) was significant, supporting spatial structuration of bacterial communities. Spatial variations in community diversity and structure were mainly driven by soil physicochemical parameters. Within soil clusters (k-means approach) corresponding to similar edaphic and climatic properties, but to multiple land uses, land use was a major driver of the bacterial communities. Our analyses identified specific indicators of land use (arable, forest, grasslands) or soil conditions (pH, organic C, texture). These findings provide unprecedented information on soil bacterial communities at the European scale and on the drivers involved; possible applications for sustainable soil management are discussed.
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http://dx.doi.org/10.1038/s41598-018-36867-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345909PMC
January 2019

Treatment patterns, survival, and hospitalization in adult patients with acute lymphoblastic leukemia: an observational cohort study using SEER Medicare data.

Leuk Lymphoma 2019 08 11;60(8):2015-2024. Epub 2019 Jan 11.

a Outcomes Insights, Inc , Westlake Village , CA , USA.

There is little evidence about whether additional risk stratification for adult patients with acute lymphoblastic leukemia age 65 and older is warranted. Using the Surveillance, Epidemiology, and End Results data linked to Medicare claims, we examined the effects of age, comorbid conditions, and mobility limitations on treatment and survival in a cohort of 795 patients diagnosed with ALL between 1 January 2000 and 31 December 2009. In the cohort, 54% received chemotherapy within the first 90 days, of whom 74% were hospitalized during the first chemotherapy administration. Unadjusted median survival was 172 days (95% CI = 244-379) for the overall cohort, 325 days (95% CI = 244-379) for those age 65-69, but only 59 days (95% CI = 45-76) for those age ≥80. In multivariate analyses, older age groups (70-74, 75-79, and ≥80) and comorbidity score ≥2 were independently associated with poorer survival. Treatment and outcomes vary considerably among subgroups of older patients suggesting that further risk stratification may be useful.
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http://dx.doi.org/10.1080/10428194.2018.1555329DOI Listing
August 2019

The stationary distribution of a sample from the Wright-Fisher diffusion model with general small mutation rates.

J Math Biol 2019 03 13;78(4):1211-1224. Epub 2018 Nov 13.

Department of Statistics, University of Oxford, Oxford, UK.

The stationary distribution of a sample taken from a Wright-Fisher diffusion with general small mutation rates is found using a coalescent approach. The approximation is equivalent to having at most one mutation in the coalescent tree to the first order in the rates. The sample probabilities characterize an approximation for the stationary distribution from the Wright-Fisher diffusion. The approach is different from Burden and Tang (Theor Popul Biol 112:22-32, 2016; Theor Popul Biol 113:23-33, 2017) who use a probability flux argument to obtain the same results from a forward diffusion generator equation. The solution has interest because the solution is not known when rates are not small. An analogous solution is found for the configuration of alleles in a general exchangeable binary coalescent tree. In particular an explicit solution is found for a pure birth process tree when individuals reproduce at rate [Formula: see text].
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http://dx.doi.org/10.1007/s00285-018-1306-yDOI Listing
March 2019

Stationary distribution of a 2-island 2-allele Wright-Fisher diffusion model with slow mutation and migration rates.

Theor Popul Biol 2018 12 9;124:70-80. Epub 2018 Oct 9.

Department of Statistics, University of Oxford, UK. Electronic address:

The stationary distribution of the diffusion limit of the 2-island, 2-allele Wright-Fisher with small but otherwise arbitrary mutation and migration rates is investigated. Following a method developed by Burden and Tang (2016, 2017) for approximating the forward Kolmogorov equation, the stationary distribution is obtained to leading order as a set of line densities on the edges of the sample space, corresponding to states for which one island is bi-allelic and the other island is non-segregating, and a set of point masses at the corners of the sample space, corresponding to states for which both islands are simultaneously non-segregating. Analytic results for the corner probabilities and line densities are verified independently using the backward generator and for the corner probabilities using the coalescent.
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http://dx.doi.org/10.1016/j.tpb.2018.09.004DOI Listing
December 2018

Quality of diabetes care in breast, colorectal, and prostate cancer.

J Cancer Surviv 2018 12 6;12(6):803-812. Epub 2018 Oct 6.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Primary Care Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford, 0X2 6GG, UK.

Purpose: Overlooking other medical conditions during cancer treatment and follow-up could result in excess morbidity and mortality, thereby undermining gains associated with early detection and improved treatment of cancer. We compared the quality of care for diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer to matched, diabetic non-cancer controls.

Methods: Longitudinal cohort study using primary care records from the Clinical Practice Research Datalink, United Kingdom. Patients with pre-existing diabetes were followed for up to 5 years after cancer diagnosis, or after an assigned index date (non-cancer controls). Quality of diabetes care was estimated based on Quality and Outcomes Framework indicators. Mixed effects logistic regression analyses were used to compare the unadjusted and adjusted odds of meeting quality measures between cancer patients and controls, overall and stratified by type of cancer.

Results: 3382 cancer patients and 11,135 controls contributed 44,507 person-years of follow-up. In adjusted analyses, cancer patients were less likely to meet five of 14 quality measures, including: total cholesterol ≤ 5 mmol/L (odds ratio [OR] = 0.82; 95% confidence interval [CI], 0.75-0.90); glycosylated hemoglobin ≤ 59 mmol/mol (adjusted OR = 0.77; 95% CI, 0.70-0.85); and albumin creatinine ratio testing (adjusted OR = 0.83; 95% CI, 0.75-0.91). However, cancer patients were as likely as their matched controls to meet quality measures for other diabetes services, including retinal screening, foot examination, and dietary review.

Conclusions: Although in the short-term, cancer patients were less likely to achieve target thresholds for cholesterol and HbA1c, they continued to receive high-quality diabetes primary care throughout 5 years post diagnosis.

Implications For Cancer Survivors: These findings are important for cancer survivors with pre-existing diabetes because they indicate that high-quality diabetes care is maintained throughout the continuum of cancer diagnosis, treatment, and follow-up.
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http://dx.doi.org/10.1007/s11764-018-0717-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244927PMC
December 2018

Land use driven change in soil pH affects microbial carbon cycling processes.

Nat Commun 2018 09 4;9(1):3591. Epub 2018 Sep 4.

Centre for Ecology and Hydrology, Wallingford, OX10 8BB, UK.

Soil microorganisms act as gatekeepers for soil-atmosphere carbon exchange by balancing the accumulation and release of soil organic matter. However, poor understanding of the mechanisms responsible hinders the development of effective land management strategies to enhance soil carbon storage. Here we empirically test the link between microbial ecophysiological traits and topsoil carbon content across geographically distributed soils and land use contrasts. We discovered distinct pH controls on microbial mechanisms of carbon accumulation. Land use intensification in low-pH soils that increased the pH above a threshold (~6.2) leads to carbon loss through increased decomposition, following alleviation of acid retardation of microbial growth. However, loss of carbon with intensification in near-neutral pH soils was linked to decreased microbial biomass and reduced growth efficiency that was, in turn, related to trade-offs with stress alleviation and resource acquisition. Thus, less-intensive management practices in near-neutral pH soils have more potential for carbon storage through increased microbial growth efficiency, whereas in acidic soils, microbial growth is a bigger constraint on decomposition rates.
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http://dx.doi.org/10.1038/s41467-018-05980-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123395PMC
September 2018

Method of levels therapy for first-episode psychosis: rationale, design and baseline data for the feasibility randomised controlled Next Level study.

BJPsych Open 2018 Sep 14;4(5):339-345. Epub 2018 Aug 14.

Senior Lecturer in Clinical Psychology, School of Psychological Sciences, The University of Manchester, UK.

Background: Method of levels (MOL) is an innovative transdiagnostic cognitive therapy with potential advantages over existing psychological treatments for psychosis.

Aims: The Next Level study is a feasibility randomised controlled trial (RCT) of MOL for people experiencing first-episode psychosis. It aims to determine the suitability of MOL for further testing in a definitive trial (trial registration ISRCTN13359355).

Method: The study uses a parallel group non-masked feasibilityRCT design with two conditions: (a) treatment as usual (TAU) and (b) TAU plus MOL. Participants ( = 36) were recruited from early intervention in psychosis services. Outcome measures are completed at baseline, 10 and 14 months. The primary outcomes are recruitment and retention.

Results: Participants' demographic and clinical characteristics are presented along with baseline data.

Conclusions: Next Level has recruited to target, providing evidence that it is feasible to recruit to a RCT of MOL for first-episode psychosis.

Declaration Of Interest: None.
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http://dx.doi.org/10.1192/bjo.2018.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094182PMC
September 2018
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