Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std β=-0.73; p=0.007) and posterior cingulate (Std β=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin β7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products

Determining the effect of drying time on phosphorus solubilization from three agricultural soils under climate change scenarios

Climate projections for the future indicate that the United Kingdom will experience hotter, drier summers and warmer, wetter winters, bringing longer dry periods followed by rewetting. This will result in changes in phosphorus (P) mobilization patterns that will influence the transfer of P from land to water. We tested the hypothesis that changes in the future patterns of drying–rewetting will affect the amount of soluble reactive phosphorus (SRP) solubilized from soil. Estimations of dry period characteristics (duration and temperature) under current and predicted climate were determined using data from the UK Climate Projections (UKCP09) Weather Generator tool. Three soils (sieved 25°C are predicted in some places and dry periods of 30 to 90 d extremes are predicted. Combining the frequency of projected dry periods with the SRP concentration in leachate suggests that this may result overall in increased mobilization of P; however, critical breakpoints of 6.9 to 14.5 d dry occur wherein up to 28% more SRP can be solubilized following a rapid rewetting event. The precise cause of this increase could not be identified and warrants further investigation as the process is not currently included in P transfer models

Framework, principles and recommendations for utilising participatory methodologies in the co-creation and evaluation of public health interventions

Background: Due to the chronic disease burden on society, there is a need for preventive public health interventions to stimulate society towards a healthier lifestyle. To deal with the complex variability between individual lifestyles and settings, collaborating with end-users to develop interventions tailored to their unique circumstances has been suggested as a potential way to improve effectiveness and adherence. Co-creation of public health interventions using participatory methodologies has shown promise but lacks a framework to make this process systematic. The aim of this paper was to identify and set key principles and recommendations for systematically applying participatory methodologies to co-create and evaluate public health interventions. Methods: These principles and recommendations were derived using an iterative reflection process, combining key learning from published literature in addition to critical reflection on three case studies conducted by research groups in three European institutions, all of whom have expertise in co-creating public health interventions using different participatory methodologies. Results: Key principles and recommendations for using participatory methodologies in public health intervention co-creation are presented for the stages of: Planning (framing the aim of the study and identifying the appropriate sampling strategy); Conducting (defining the procedure, in addition to manifesting ownership); Evaluating (the process and the effectiveness) and Reporting (providing guidelines to report the findings). Three scaling models are proposed to demonstrate how to scale locally developed interventions to a population level. Conclusions: These recommendations aim to facilitate public health intervention co-creation and evaluation utilising participatory methodologies by ensuring the process is systematic and reproducible

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43–57) vs 55 years (IQR 51–62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P =.0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P &lt;.0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P &lt;.0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.</p

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.5-7,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice

Calibrating a network meta-analysis of diabetes trials of sodium glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor analogues and dipeptidyl peptidase-4 inhibitors to a representative routine population : a systematic review protocol

Introduction: Participants in randomised controlled trials (trials) are generally younger and healthier than many individuals encountered in clinical practice. Consequently, the applicability of trial findings is often uncertain. To address this, results from trials can be calibrated to more representative data sources. In a network meta-analysis, using a novel approach which allows the inclusion of trials whether or not individual-level participant data (IPD) is available, we will calibrate trials for three drug classes (sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor analogues and dipeptidyl peptidase-4 (DPP4) inhibitors) to the Scottish diabetes register. Methods and analysis: Medline and EMBASE databases, the US clinical trials registry (clinicaltrials.gov) and the Chinese Clinical Trial Registry (chictr.org.cn) will be searched from 1 January 2002. Two independent reviewers will apply eligibility criteria to identify trials for inclusion. Included trials will be phase 3 or 4 trials of SGLT2 inhibitors, GLP1 receptor analogues or DPP4 inhibitors, with placebo or active comparators, in participants with type 2 diabetes, with at least one of glycaemic control, change in body weight or major adverse cardiovascular event as outcomes. Unregistered trials will be excluded. We have identified a target population from the population-based Scottish diabetes register. The chosen cohort comprises people in Scotland with type 2 diabetes who either (1) require further treatment due to poor glycaemic control where any of the three drug classes may be suitable, or (2) who have adequate glycaemic control but are already on one of the three drug classes of interest or insulin. Ethics and dissemination: Ethical approval for IPD use was obtained from the University of Glasgow MVLS College Ethics Committee (Project: 200160070). The Scottish diabetes register has approval from the Scottish A Research Ethics Committee (11/AL/0225) and operates with Public Benefit and Privacy Panel for Health and Social Care approval (1617-0147). PROSPERO registration number: CRD42020184174

Effects of Exotic Spartina alterniflora Invasion on Soil Phosphorus and Carbon Pools and Associated Soil Microbial Community Composition in Coastal Wetlands

Soil microorganisms can be altered by plant invasion into wetland ecosystems and comprise an important linkage between phosphorus (P) availability and soil carbon (C) chemistry; however, the intrinsic mechanisms of P and C transformation associated with microbial community and function are poorly understood in coastal wetland. In this study, we used a sequential fractionation method and 13C nuclear magnetic resonance (NMR) spectroscopy to capture the changes in soil P pools and C chemical composition with bare flats (BF), native Phragmites australis(PA), and invasive Spartina alterniflora(SA), respectively. The responses of the soil microbial community using phospholipid fatty acid (PLFA) profiling and function indicated by nine enzyme activities associated with C, nitrogen (N), and P cycles were also investigated. Compared to PA and BF, SA invasion significantly (P < 0.05) changed P pools and mainly increased the available P by 17.5 and 37.0%, respectively. The presence of the plants (SA and PA) significantly (P < 0.05) altered the soil C chemical composition mainly by affecting the aliphatic functional groups, resulting in a lower alkyl C/O-alkyl C ratio value. Compared to BF and SA, PA significantly (P < 0.05) increased arbuscular mycorrhizal fungi (AMF) abundance. Soil enzyme activity, especially for the P and C cycle enzymes, was also affected by plant species with the highest geometric mean enzyme and hydrolase activity for the PA zone. We also found that soil C compositions and P pools were associated with microbial community structure and enzyme activity, respectively. However, little interaction between C and P was found on either soil microbial composition or soil enzyme activity variation. Further, microbial community composition was tightly correlated with the soil P compared to soil C chemistry, while enzyme activity showed more response with soil C chemistry compared to soil P pool changes

An agricultural practise with climate and food security benefits: Claying with kaolinitic clay subsoil decreased soil carbon priming and mineralisation in sandy cropping soils

As the agricultural sector seeks to feed a growing global population, climate-smart agriculture offers opportunities to concurrently mitigate climate change by reducing greenhouse gas emissions and/or increasing carbon storage in soils. This study examined the potential for clay addition to reduce CO2 emissions from plant residues and soil organic matter in a sandy soil. Soils were sourced from a 15-year-old field trial where claying (200 t ha−1) had already demonstrated improvements in water infiltration, grain yield and profits. Isotopically labelled plant residues (wheat, canola, or pea) were used to separate residue-derived and soil-derived CO2 sources from a nil-clay control, a historically clayed, and two freshly created soils with either high (10%) or low (3%) subsoil clay additions. Laboratory incubations demonstrated that historically clayed soils released less CO2 from plant residues and soil organic matter. Clay addition also decreased the priming effect of adding fresh residue to soils. The results from clay experimentally added in the laboratory varied. Differences in chemical and biological indicators (pH, microbial biomass C and N, extractable organic C and N, NO3−, NH4+, abundance of bacterial, archaeal, fungal, LMCO, GH48 and CbhI genes) did not correlate with patterns of CO2 emissions across treatments. While claying practices have previously demonstrated benefits to crop productivity, this research demonstrates long-term changes in carbon-cycling that could promote greater carbon sequestration