Vulval dermatoses: A review of referrals to dermatology.

We undertook a retrospective observational review of patients referred to a tertiary dermatology department with vulval complaints over 12 months. The most common provisional diagnoses made by the referrer and final dermatology diagnoses were lichen sclerosus (54% and 38%), dermatitis (12.7% and 16.5%) and psoriasis (5.1% and 6.3%). Referrers may benefit from further education about skin diseases of the vulva, topical steroids for vulval complaints and the importance of clinical photography.

Agricultural ditches are hotspots of greenhouse gas emissions controlled by nutrient input.

Agricultural ditches are pervasive in agricultural areas and are potential greenhouse gas (GHG) hotspots, since they directly receive abundant nutrients from neighboring farmlands. However, few studies measure GHG concentrations or fluxes in this particular water course, likely resulting in underestimations of GHG emissions from agricultural regions. Here we conducted a one-year field study to investigate the GHG concentrations and fluxes from typical agricultural ditch systems, which included four different types of ditches in an irrigation district located in the North China Plain. The results showed that almost all the ditches were large GHG sources. The mean fluxes were 333 µmol m-2 h-1 for CH4, 7.1 mmol m-2 h-1 for CO2, and 2.4 µmol m-2 h-1 for N2O, which were approximately 12, 5, and 2 times higher, respectively, than that in the river connecting to the ditch systems. Nutrient input was the primary driver stimulating GHG production and emissions, resulting in GHG concentrations and fluxes increasing from the river to ditches adjacent to farmlands, which potentially received more nutrients. Nevertheless, the ditches directly connected to farmlands showed lower GHG concentrations and fluxes compared to the ditches adjacent to farmlands, possibly due to seasonal dryness and occasional drainage. All the ditches covered approximately 3.3% of the 312 km2 farmland area in the study district, and the total GHG emission from the ditches in this area was estimated to be 26.6 Gg CO2-eq yr-1, with 17.5 Gg CO2, 0.27 Gg CH4, and 0.006 Gg N2O emitted annually. Overall, this study demonstrated that agricultural ditches were hotspots of GHG emissions, and future GHG estimations should incorporate this ubiquitous but underrepresented water course.

Restoration impacts on rates of denitrification and greenhouse gas fluxes from tropical coastal wetlands.

Forested coastal wetlands are globally important systems sequestering carbon and intercepting nitrogen pollution from nutrient-rich river systems. Coastal wetlands that have suffered extensive disturbance are the target of comprehensive restoration efforts. Accurate assessment of restoration success requires detailed mechanistic understanding of wetland soil biogeochemical functioning across restoration chrono-sequences, which remains poorly understood for these sparsely investigated systems. This study investigated denitrification and greenhouse gas fluxes in mangrove and Melaleuca forest soils of Vietnam, using the 15N-Gas flux method. Denitrification-derived N2O was significantly higher from Melaleuca than mangrove forest soils, despite higher potential rates of total denitrification in the mangrove forest soils (8.1 ng N g-1 h-1) than the Melaleuca soils (6.8 ng N g-1 h-1). Potential N2O and CO2 emissions were significantly higher from the Melaleuca soils than from the mangrove soils. Disturbance and subsequent recovery had no significant effect on N biogeochemistry except with respect to the denitrification product ratio in the mangrove sites, which was highest from the youngest mangrove site. Potential CO2 and CH4 fluxes were significantly affected by restoration in the mangrove soils. The lowest potential CO2 emissions were observed in the mid-age plantation and potential CH4 fluxes decreased in the older forests. The mangrove system, therefore, may remove excess N and improve water quality with low greenhouse gas emissions, whereas in Melaleucas, increased N2O and CO2 emissions also occur. These emissions are likely balanced by higher carbon stocks observed in the Melaleuca soils. These mechanistic insights highlight the importance of ecosystem restoration for pollution attenuation and reduction of greenhouse gas emissions from coastal wetlands. Restoration efforts should continue to focus on increasing wetland area and function, which will benefit local communities with improved water quality and potential for income generation under future carbon trading.

Polygenic basis and biomedical consequences of telomere length variation.

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity.

Objective: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene (IL15RA) for an association with OA with radiographic severity and symptoms. Methods: Cartilage samples from donors (n = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 in vitro using explant cultures. Data from two independent Nottinghamshire-based studies (n = 795 and n = 613) were used to test genetic variants in the IL15RA gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP. Results: IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the IL15RA gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10-1.98 p < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63-0.92 p < 0.01) but not with radiographic severity. Conclusions: In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although ex vivo cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between IL15RA variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA.

Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length.

Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10-7, minor allele frequency of 0.2-0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10-6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10-4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

The method controls the story - Sampling method impacts on the detection of pore-water nitrogen concentrations in streambeds.

Biogeochemical gradients in streambeds are steep and can vary over short distances often making adequate characterisation of sediment biogeochemical processes challenging. This paper provides an overview and comparison of streambed pore-water sampling methods, highlighting their capacity to address gaps in our understanding of streambed biogeochemical processes. This work reviews and critiques available pore-water sampling techniques to characterise streambed biogeochemical conditions, including their characteristic spatial and temporal resolutions, and associated advantages and limitations. A field study comparing three commonly-used pore-water sampling techniques (multilevel mini-piezometers, miniature drivepoint samplers and diffusive equilibrium in thin-film gels) was conducted to assess differences in observed nitrate and ammonium concentration profiles. Pore-water nitrate concentrations did not differ significantly between sampling methods (p-value = 0.54) with mean concentrations of 2.53, 4.08 and 4.02 mg l-1 observed with the multilevel mini-piezometers, miniature drivepoint samplers and diffusive equilibrium in thin-film gel samplers, respectively. Pore-water ammonium concentrations, however, were significantly higher in pore-water extracted by multilevel mini-piezometers (3.83 mg l-1) and significantly lower where sampled with miniature drivepoint samplers (1.05 mg l-1, p-values <0.01). Differences in observed pore-water ammonium concentration profiles between active (suction: multilevel mini-piezometers) and passive (equilibrium; diffusive equilibrium in thin-film gels) samplers were further explored under laboratory conditions. Measured pore-water ammonium concentrations were significantly greater when sampled by diffusive equilibrium in thin-film gels than with multilevel mini-piezometers (all p-values ≤0.02). The findings of this study have critical implications for the interpretation of field-based research on hyporheic zone biogeochemical cycling and highlight the need for more systematic testing of sampling protocols. For the first time, the impact of different active and passive pore-water sampling methods is addressed systematically here, highlighting to what degree the choice of pore-water sampling methods affects research outcomes, with relevance for the interpretation of previously published work as well as future studies.

Seasonal variability of sediment controls of carbon cycling in an agricultural stream.

Streams and rivers are 'active pipelines' where high rates of carbon (C) turnover can lead to globally important emissions of carbon dioxide (CO2) and methane (CH4) from surface waters to the atmosphere. Streambed sediments are particularly important in affecting stream chemistry, with rates of biogeochemical activity, and CO2 and CH4 concentrations far exceeding those in surface waters. Despite an increase in research on CO2 and CH4 in streambed sediments there is a lack of knowledge and insight on seasonal dynamics. In this study the seasonally variable effect of sediment type (sand-dominated versus gravel-dominated) on porewater C cycling, including CO2 and CH4 concentrations, was investigated. We found high concentrations of CO2 and CH4 in the streambed of a small agricultural stream. Sand-dominated sediments were characterised by higher microbial activity and CO2 and CH4 concentrations than gravel-dominated sediments, with CH4:CO2 ratios higher in sand-dominated sediments but rates of recalcitrant C uptake highest in gravel-dominated sediments. CO2 and CH4 concentrations were unexpectedly high year-round, with little variation in concentrations among seasons. Our results indicate that small, agricultural streams, which generally receive large amounts of fine sediment and organic matter (OM), may contribute greatly to annual C cycling in freshwater systems. These results should be considered in future stream management plans where the removal of sandy sediments may perform valuable ecosystem services, reducing C turnover, CO2 and CH4 concentrations, and mitigating greenhouse gas (GHG) production.

Streambed Organic Matter Controls on Carbon Dioxide and Methane Emissions from Streams.

Greenhouse gas (GHG) emissions of carbon dioxide (CO2) and methane (CH4) from streambeds are currently understudied. There is a paucity of research exploring organic matter (OM) controls on GHG production by microbial metabolic activity in streambeds, which is a major knowledge gap given the increased inputs of allochthonous carbon to streams, especially in agricultural catchments. This study aims to contribute to closing this knowledge gap by quantifying how contrasting OM contents in different sediments affect streambed GHG production and associated microbial metabolic activity. We demonstrate, by means of an incubation experiment, that streambed sediments have the potential to produce substantial amounts of GHG, controlled by sediment OM quantity and quality. We observed streambed CO2 production rates that can account for 35% of total stream evasion estimated in previous studies, ranging between 1.4 and 86% under optimal conditions. Methane production varied stronger than CO2 between different geologic backgrounds, suggesting OM quality controls between streambed sediments. Moreover, our results indicate that streambed sediments may produce much more CO2 than quantified to date, depending on the quantity and quality of the organic matter, which has direct implications for global estimates of C fluxes in stream ecosystems.

Thermal sensitivity of CO2 and CH4 emissions varies with streambed sediment properties.

Globally, rivers and streams are important sources of carbon dioxide and methane, with small rivers contributing disproportionately relative to their size. Previous research on greenhouse gas (GHG) emissions from surface water lacks mechanistic understanding of contributions from streambed sediments. We hypothesise that streambeds, as known biogeochemical hotspots, significantly contribute to the production of GHGs. With global climate change, there is a pressing need to understand how increasing streambed temperatures will affect current and future GHG production. Current global estimates assume linear relationships between temperature and GHG emissions from surface water. Here we show non-linearity and threshold responses of streambed GHG production to warming. We reveal that temperature sensitivity varies with substrate (of variable grain size), organic matter (OM) content and geological origin. Our results confirm that streambeds, with their non-linear response to projected warming, are integral to estimating freshwater ecosystem contributions to current and future global GHG emissions.

Bidirectional association between disturbed sleep and neuropathic pain symptoms: a prospective cohort study in post-total joint replacement participants.

BACKGROUND: Disturbed sleep is strongly correlated with chronic pain. The aim of this study was to examine the association between sleep disturbance and incident joint pain focusing on neuropathic-like pain symptoms. METHODS: A total of 423 individuals who had undergone total joint replacement (TJR) for osteoarthritis were assessed at the mean time of 3.6 years post-surgery and again at 5.9 years post-TJR, using the Medical Outcomes Survey sleep subscale, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and painDETECT questionnaire instruments. Cox hazard ratios (HRs) and 95% confidence intervals (CIs) were computed adjusting for age, body mass index, sex, and use of hypnotic and analgesic medication. RESULTS: The presence of neuropathic pain symptoms predicted incidence of disturbed sleep after adjustment for covariates and pain severity (adjusted HR [aHR] 2.01, 95% CI: 1.00-4.10; p<0.05). There was no association between joint pain and incidence of disturbed sleep when individuals with neuropathic pain symptoms at the baseline visit were excluded (aHR 1.11, 95% CI: 0.47-2.67). Disturbed sleep at baseline predicted incident neuropathic joint pain symptoms (aHR 2.75, 95% CI: 1.21-6.26; p<0.016) but had no effect on incidence of joint pain when all types of pain were considered together (aHR 0.63, 95% CI: 0.30-1.39). CONCLUSION: These data suggest a causal bidirectional link between sleep disturbance and joint pain with neuropathic features but not with other types of joint pain.

Neuropathic pain-like symptoms and pre-surgery radiographic severity contribute to patient satisfaction 4.8 years post-total joint replacement.

AIM: To investigate a comprehensive range of factors that contribute to long-term patient satisfaction post-total joint replacement (TJR) in people who had undergone knee or hip replacement for osteoarthritis. METHODS: Participants (n = 1151) were recruited from Nottinghamshire post-total hip or knee replacement. Questionnaire assessment included medication use, the pain-DETECT questionnaire (PDQ) to assess neuropathic pain-like symptoms (NP) and TJR satisfaction measured on average 4.8 years post-TJR. Individual factors were tested for an association with post-TJR satisfaction, before incorporating all factors into a full model. Data reduction was carried out using LASSO and receiver operator characteristic (ROC) curve analysis was used to quantify the contribution of variables to post-TJR satisfaction. RESULTS: After data reduction, the best fitting model for post-TJR satisfaction included various measures of pain, history of revision surgery, smoking, pre-surgical X-ray severity, WOMAC function scores and various comorbidities. ROC analysis of this model gave AUC = 0.83 (95%CI: 0.80-0.85). PDQ scores were found to capture much of the variation in post-TJR satisfaction outcomes: AUC = 0.79 (0.75-0.82). Pre-surgical radiographic severity was associated with higher post-TJR satisfaction: ORsatisfied = 2.06 (95%CI: 1.15-3.69), P = 0.015. CONCLUSION: These results highlight the importance of pre-surgical radiographic severity, post-TJR function, analgesic medication use and NP in terms of post-TJR satisfaction. The PDQ appears to be a useful tool in capturing factors that contribute to post-TJR satisfaction.

Opening Opportunities for High-Resolution Isotope Analysis - Quantification of δ15NNO3 and δ18ONO3 in Diffusive Equilibrium in Thin-Film Passive Samplers.

The fate of nitrate transported across groundwater-surface water interfaces has been intensively studied in recent decades. The interfaces between aquifers and rivers or lakes have been identified as biogeochemical hotspots with steep redox gradients. However, a detailed understanding of the spatial heterogeneity and potential temporal variability of these hotspots, and the consequences for nitrogen processing, is still hindered by a paucity of adequate measurement techniques. A novel methodology is presented here, using Diffusive Equilibrium in Thin-film (DET) gels as high-spatial-resolution passive-samplers of δ15NNO3 and δ18ONO3 to investigate nitrogen cycling. Fractionation of δ15NNO3 and δ18ONO3 during diffusion of nitrate through the DET gel was determined using varying equilibrium times and nitrate concentrations. This demonstrated that nitrate isotopes of δ15NNO3 and δ18ONO3 do not fractionate when sampled with a DET gel. δ15NNO3 values from the DET gels ranged between 2.3 ± 0.2 and 2.7 ± 0.3‰ for a NO3- stock solution value of 2.7 ± 0.4‰, and δ18ONO3 values ranged between 18.3 ± 1.0 and 21.5 ± 0.8‰ for a NO3- stock solution of 19.7 ± 0.9‰. Nitrate recovery and isotope values were independent of equilibrium time and nitrate concentration. Additionally, an in situ study showed that nitrate concentration and isotopes provide unique, high-resolution data that enable improved understanding of nitrogen cycling in freshwater sediments.

Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene.

Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score >12 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant single-nucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N=908) and in individuals from the Rotterdam Study (N=212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs887797 mapping to the protein kinase C alpha (PRKCA) gene odds ratio (OR)possNP=2.41 (95% CI 1.74-3.34, P=1.29 × 10-7). This SNP has been found to be associated with multiple sclerosis and encodes a functional variant affecting splicing and expression of the PRKCA gene. The PRKCA gene has been associated with long-term potentiation, synaptic plasticity, chronic pain and memory in the literature, making this a biologically relevant finding.

Genetic association studies in osteoarthritis: is it fairytale?

PURPOSE OF REVIEW: Osteoarthritis is a common complex disorder with a strong genetic component. Other identified risk factors such as increasing age and overweight do not fully explain the risk of osteoarthritis. Here, we highlight the main findings from genetic association studies on osteoarthritis to date. RECENT FINDINGS: Currently, genetic association studies have identified 21 independent susceptibility loci for osteoarthritis. Studies have focused on hip, knee and hand osteoarthritis, as well as posttotal joint replacement and minimum joint space width, a proxy for cartilage thickness. Four distinct loci have recently been identified in a genome-wide association scan on minimum joint space width. The role of mitochondrial DNA variants has been the focus of a recent meta-analysis. Findings have previously been mixed, however, this study suggests a plausible involvement of mitochondrial DNA in the progression of radiographic knee osteoarthritis. SUMMARY: Identifying genetic locations of interest provides a framework upon which to base future studies, for example replication analysis and functional work. Genetic association studies have shaped and will continue to shape research in this field. Improving the understanding of osteoarthritis could improve the diagnosis and treatment of the disease and improve quality of life for many individuals.

Use of prescription analgesic medication and pain catastrophizing after total joint replacement surgery.

OBJECTIVE: To survey the use of analgesic medication 4.8 years after total joint replacement (TJR) surgery and assess the determinants of medication usage. PATIENTS AND METHODS: Of 852 patients who had undergone TJR for osteoarthritis were recruited from secondary care. Participants (mean age, 73.7 years) responded to a questionnaire on medication use, physical function and pain (WOMAC, VAS and body pain), pain catastrophizing and illness behaviour (somatization). RESULTS: Only 37% of study participants were not on any pain relief medication, 25.1% were taking opioids, 6.9% were taking prescription NSAIDs and 25.9% were taking only non-prescription analgesics. Use of NSAIDs correlated with presence of back pain, body pain and high illness behaviour. The strongest associations with use of opioids were severe joint pain, high pain catastrophizing, body and back pain. After adjustment for covariates plus presence of pain, catastrophizing remained significantly associated with higher risk of opioid use (OR = 1.66, 95% CI: 1.13-2.43, p < 0.009) and of other prescription medication that can be used to treat pain (anti-depressants, anti-epileptics and hypnotics) (OR = 2.52, 95% CI: 1.61-3.95, p < 0.0005). CONCLUSIONS: Use of opioid medication 4 years post-TJR is very high in our study population. In addition to joint, back and body pain, a major contributor to opioid use is pain catastrophizing. Our data suggest that current opioid and other analgesic prescribing patterns may benefit from considering the catastrophizing characteristics of patients.