Showing papers by "David W. Johnson published in 2019"

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease

Abstract: We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Status of care for end stage kidney disease in countries and regions worldwide: International cross sectional survey

Abstract: Objective To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. Design International cross sectional survey. Setting International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. Participants Key stakeholders identified by ISN's national and regional leaders. Main outcome measures Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. Results Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world's population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management-namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold from 4 to 3392 per million population. Rwanda was the only low income country to report data on the prevalence of treated disease; 5 (<10%) of 53 African countries reported these data. Of 159 countries, 102 (64%) provided public funding for kidney replacement therapy. Sixty eight (43%) of 159 countries charged no fees at the point of care delivery and 34 (21%) made some charge. Haemodialysis was reported as available in 156 (100%) of 156 countries, peritoneal dialysis in 119 (76%) of 156 countries, and kidney transplantation in 114 (74%) of 155 countries. Dialysis and kidney transplantation were available to more than 50% of patients in only 108 (70%) and 45 (29%) of 154 countries that offered these services, respectively. Conservative kidney management was available in 124 (81%) of 154 countries. Worldwide, the median number of nephrologists was 9.96 per million population, which varied with income level. Conclusions These comprehensive data show the capacity of countries (including low income countries) to provide optimal care for patients with end stage kidney disease. They demonstrate substantial variability in the burden of such disease and capacity for kidney replacement therapy and conservative kidney management, which have implications for policy.

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.

Abstract: Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson’s disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: –13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (–9.6±6.7 vs. –3.8±4.2 points, p = 0.0108) and activities of daily living score (–6.9±5.5 vs. –1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. Conclusions: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis.

Abstract: Background: Effects of oral anticoagulation in chronic kidney disease (CKD) are uncertain.Purpose: To evaluate the benefits and harms of vitamin K antagonists (VKAs) and non-vitamin K oral anticoagulants (NOACs) in adults with CKD stages 3 to 5, including those with dialysis-dependent end-stage kidney disease (ESKD).Data Sources: English-language searches of MEDLINE, EMBASE, and Cochrane databases (inception to February 2019); review bibliographies; and ClinicalTrials. gov (25 February 2019).Study Selection: Randomized controlled trials evaluating VKAs or NOACs for any indication in patients with CKD that reported efficacy or bleeding outcomes.Data Extraction: Two authors independently extracted data, assessed risk of bias, and rated certainty of evidence.Data Synthesis: Forty-five trials involving 34 082 participants who received anticoagulation for atrial fibrillation (AF) (11 trials), venous thromboembolism (VTE) (11 trials), thromboprophylaxis (6 trials), prevention of dialysis access thrombosis (8 trials), and cardiovascular disease other than AF (9 trials) were included. All but the 8 trials involving patients with ESKD excluded participants with creatinine clearance less than 20 mL/min or estimated glomerular filtration rate less than 15 mL/min/1.73 m(2). In AF, compared with VKAs, NOACs reduced risks for stroke or systemic embolism (risk ratio [RR], 0.79 [95% CI, 0.66 to 0.93]; high-certainty evidence) and hemorrhagic stroke (RR, 0.48 [CI, 0.30 to 0.76]; moderate-certainty evidence). Compared with VKAs, the effects of NOACs on recurrent VTE or VTE-related death were uncertain (RR, 0.72 [CI, 0.44 to 1.17]; low-certainty evidence). In all trials combined, NOACs seemingly reduced major bleeding risk compared with VKAs (RR, 0.75 [CI, 0.56 to 1.01]; low-certainty evidence).Limitation: Scant evidence for advanced CKD or ESKD; data mostly from subgroups of large trials.Conclusion: In early-stage CKD, NOACs had a benefit-risk profile superior to that of VKAs. For advanced CKD or ESKD, there was insufficient evidence to establish benefits or harms of VKAs or NOACs.Primary Funding Source: None. (PROSPERO: CRD42017079709)

Patient and Caregiver Priorities for Outcomes in Peritoneal Dialysis: Multinational Nominal Group Technique Study

Abstract: BACKGROUND AND OBJECTIVES: The absence of accepted patient-centered outcomes in research can limit shared decision-making in peritoneal dialysis (PD), particularly because PD-related treatments can be associated with mortality, technique failure, and complications that can impair quality of life. We aimed to identify patient and caregiver priorities for outcomes in PD, and to describe the reasons for their choices. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on PD and their caregivers were purposively sampled from nine dialysis units across Australia, the United States, and Hong Kong. Using nominal group technique, participants identified and ranked outcomes, and discussed the reasons for their choices. An importance score (scale 0-1) was calculated for each outcome. Qualitative data were analyzed thematically. RESULTS: Across 14 groups, 126 participants (81 patients, 45 caregivers), aged 18-84 (mean 54, SD 15) years, identified 56 outcomes. The ten highest ranked outcomes were PD infection (importance score, 0.27), mortality (0.25), fatigue (0.25), flexibility with time (0.18), BP (0.17), PD failure (0.16), ability to travel (0.15), sleep (0.14), ability to work (0.14), and effect on family (0.12). Mortality was ranked first in Australia, second in Hong Kong, and 15th in the United States. The five themes were serious and cascading consequences on health, current and impending relevance, maintaining role and social functioning, requiring constant vigilance, and beyond control and responsibility. CONCLUSIONS: For patients on PD and their caregivers, PD-related infection, mortality, and fatigue were of highest priority, and were focused on health, maintaining lifestyle, and self-management. Reporting these patient-centered outcomes may enhance the relevance of research to inform shared decision-making.

Fruit and Vegetable Intake and Mortality in Adults undergoing Maintenance Hemodialysis.

Abstract: Background and objectives Higher fruit and vegetable intake is associated with lower cardiovascular and all-cause mortality in the general population. It is unclear whether this association occurs in patients on hemodialysis, in whom high fruit and vegetable intake is generally discouraged because of a potential risk of hyperkalemia. We aimed to evaluate the association between fruit and vegetable intake and mortality in hemodialysis. Design, setting, participants, & measurements Fruit and vegetable intake was ascertained by the Global Allergy and Asthma European Network food frequency questionnaire within the Dietary Intake, Death and Hospitalization in Adults with ESKD Treated with Hemodialysis study, a multinational cohort study of 9757 adults on hemodialysis, of whom 8078 (83%) had analyzable dietary data. Adjusted Cox regression analyses clustered by country were conducted to evaluate the association between tertiles of fruit and vegetable intake with all-cause, cardiovascular, and noncardiovascular mortality. Estimates were calculated as hazard ratios with 95% confidence intervals (95% CIs). Results During a median follow up of 2.7 years (18,586 person-years), there were 2082 deaths (954 cardiovascular). The median (interquartile range) number of servings of fruit and vegetables was 8 (4–14) per week; only 4% of the study population consumed at least four servings per day as recommended in the general population. Compared with the lowest tertile of servings per week (0–5.5, median 2), the adjusted hazard ratios for the middle (5.6–10, median 8) and highest (>10, median 17) tertiles were 0.90 (95% CI, 0.81 to 1.00) and 0.80 (95% CI, 0.71 to 0.91) for all-cause mortality, 0.88 (95% CI, 0.76 to 1.02) and 0.77 (95% CI, 0.66 to 0.91) for noncardiovascular mortality and 0.95 (95% CI, 0.81 to 1.11) and 0.84 (95% CI, 0.70 to 1.00) for cardiovascular mortality, respectively. Conclusions Fruit and vegetable intake in the hemodialysis population is low and a higher consumption is associated with lower all-cause and noncardiovascular death.

Logging and soil nutrients independently explain plant trait expression in tropical forests

Abstract: Plant functional traits regulate ecosystem functions but little is known about how co-occurring gradients of land use and edaphic conditions influence their expression. We test how gradients of logging disturbance and soil properties relate to community-weighted mean traits in logged and old-growth tropical forests in Borneo. We studied 32 physical, chemical and physiological traits from 284 tree species in eight 1 ha plots and measured long-term soil nutrient supplies and plant-available nutrients. Logged plots had greater values for traits that drive carbon capture and growth, whilst old-growth forests had greater values for structural and persistence traits. Although disturbance was the primary driver of trait expression, soil nutrients explained a statistically independent axis of variation linked to leaf size and nutrient concentration. Soil characteristics influenced trait expression via nutrient availability, nutrient pools, and pH. Our finding, that traits have dissimilar responses to land use and soil resource availability, provides robust evidence for the need to consider the abiotic context of logging when predicting plant functional diversity across human-modified tropical forests. The detection of two independent axes was facilitated by the measurement of many more functional traits than have been examined in previous studies.

Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients

Abstract: The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852.

Regional variation in the treatment and prevention of peritoneal dialysis-related infections in the Peritoneal Dialysis Outcomes and Practice Patterns Study.

Abstract: BACKGROUND Peritoneal dialysis (PD)-related infections lead to significant morbidity. The International Society for Peritoneal Dialysis (ISPD) guidelines for the prevention and treatment of PD-related infections are based on variable evidence. We describe practice patterns across facilities participating in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS). METHODS PDOPPS, a prospective cohort study, enrolled nationally representative samples of PD patients in Australia/New Zealand (ANZ), Canada, Thailand, Japan, the UK and the USA. Data on PD-related infection prevention and treatment practices across facilities were obtained from a survey of medical directors'. RESULTS A total of 170 centers, caring for >11 000 patients, were included. The proportion of facilities reporting antibiotic administration at the time of PD catheter insertion was lowest in the USA (63%) and highest in Canada and the UK (100%). Exit-site antimicrobial prophylaxis was variably used across countries, with Japan (4%) and Thailand (28%) having the lowest proportions. Exit-site mupirocin was the predominant exit-site prophylactic strategy in ANZ (56%), Canada (50%) and the UK (47%), while exit-site aminoglycosides were more common in the USA (72%). Empiric Gram-positive peritonitis treatment with vancomycin was most common in the UK (88%) and USA (83%) compared with 10-45% elsewhere. Empiric Gram-negative peritonitis treatment with aminoglycoside therapy was highest in ANZ (72%) and the UK (77%) compared with 10-45% elsewhere. CONCLUSIONS Variation in PD-related infection prevention and treatment strategies exist across countries with limited uptake of ISPD guideline recommendations. Further work will aim to understand the impact these differences have on the wide variation in infection risk between facilities and other clinically relevant PD outcomes.

Quality of life of children and adolescents with chronic kidney disease: a cross-sectional study

Abstract: Objective The aim was to compare quality of life (QoL) among children and adolescents with different stages of chronic kidney disease (CKD) and determine factors associated with changes in QoL Design Cross-sectional Setting The Kids with CKD study involved five of eight paediatric nephrology units in Australia and New Zealand Patients There were 375 children and adolescents (aged 6–18 years) with CKD, on dialysis or transplanted, recruited between 2013 and 2016 Main outcome measures Overall and domain-specific QoL were measured using the Health Utilities Index 3 score, with a scale from −036 (worse than dead) to 1 (perfect health) QoL scores were compared between CKD stages using the Mann-Whitney U test Factors associated with changes in QoL were assessed using multivariable linear and ordinal logistic regression Results QoL for those with CKD stages 1–2 (n=106, median 088, IQR 063–096) was higher than those on dialysis (n=43, median 067, IQR 039–091, p Conclusions The overall QoL and domains such as pain and emotion are substantially worse in children on dialysis compared with earlier stage CKD and those with kidney transplants

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Abstract: The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Association Between Duration of Delayed Graft Function, Acute Rejection, and Allograft Outcome After Deceased Donor Kidney Transplantation.

Abstract: Prolonged duration of delayed graft function (DGF) may be associated with adverse allograft outcomes, but the association between threshold duration of DGF, acute rejection and long-term allograft loss remains undefined. We aimed to determine the impact of DGF duration on allograft outcomes and to assess whether this association was mediated by acute rejection. Using data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, Cox proportional modelling was used to determine the association between quartiles of DGF duration, acute rejection at 6 months and death-censored graft loss (DCGL). Mediation analysis was conducted to determine whether acute rejection was a causal intermediate between DGF and DCGL. Of 7668 deceased donor kidney transplants between 1997-2014, 1497 (19.5%) recipients experienced DGF requiring dialysis. The median (interquartile range) duration of DGF was 7(9) days, with 25% requiring dialysis for ≥14 days. Among recipients who had experienced DGF duration of 1-4 days, the adjusted HR for duration of 5-7, 8-13 and ≥14 days were 1.13 (95%CI 0.83-1.55;p=0.43), 1.44 (1.08-1.91;p=0.013), and 1.99 (1.50-2.65;p There was a direct dose-dependent effect between DGF duration and DCGL, with acute rejection explaining <10% of the effects between DGF duration and DCGL. Future research identifying other potential modifiable mediators that lies in the causal pathway between DGF duration and allograft loss is essential.

Relationships between plant traits, soil properties and carbon fluxes differ between monocultures and mixed communities in temperate grassland

Abstract: The use of plant traits to predict ecosystem functions has been gaining growing attention. Above-ground plant traits, such as leaf nitrogen (N) content and specific leaf area (SLA), have been shown to strongly relate to ecosystem productivity, respiration and nutrient cycling. Furthermore, increasing plant functional trait diversity has been suggested as a possible mechanism to increase ecosystem carbon (C) storage. However, it is uncertain whether below-ground plant traits can be predicted by above-ground traits, and if both above- and below-ground traits can be used to predict soil properties and ecosystem-level functions. Here, we used two adjacent field experiments in temperate grassland to investigate if above- and below-ground plant traits are related, and whether relationships between plant traits, soil properties and ecosystem C fluxes (i.e. ecosystem respiration and net ecosystem exchange) measured in potted monocultures could be detected in mixed field communities. We found that certain shoot traits (e.g. shoot N and C, and leaf dry matter content) were related to root traits (e.g. root N, root C:N and root dry matter content) in monocultures, but such relationships were either weak or not detected in mixed communities. Some relationships between plant traits (i.e. shoot N, root N and/or shoot C:N) and soil properties (i.e. inorganic N availability and microbial community structure) were similar in monocultures and mixed communities, but they were more strongly linked to shoot traits in monocultures and root traits in mixed communities. Structural equation modelling showed that above- and below-ground traits and soil properties improved predictions of ecosystem C fluxes in monocultures, but not in mixed communities on the basis of community-weighted mean traits. Synthesis. Our results from a single grassland habitat detected relationships in monocultures between above- and below-ground plant traits, and between plant traits, soil properties and ecosystem C fluxes. However, these relationships were generally weaker or different in mixed communities. Our results demonstrate that while plant traits can be used to predict certain soil properties and ecosystem functions in monocultures, they are less effective for predicting how changes in plant species composition influence ecosystem functions in mixed communities.

Soil microbes drive phylogenetic diversity-productivity relationships in a subtropical forest.

Abstract: The relationship between plant diversity and productivity and the mechanisms underpinning that relationship remain poorly resolved in species-rich forests. We combined extensive field observations and experimental manipulations in a subtropical forest to test how species richness (SR) and phylogenetic diversity (PD) interact with putative root-associated pathogens and how these interactions mediate diversity-productivity relationships. We show that (i) both SR and PD were positively correlated with biomass for both adult trees and seedlings across multiple spatial scales, but productivity was best predicted by PD; (ii) significant positive relationships between PD and productivity were observed in nonsterile soil only; and (iii) root fungal diversity was positively correlated with plant PD and SR, while the relative abundance of putative pathogens was negatively related to plant PD. Our findings highlight the key role of soil pathogenic fungi in tree diversity-productivity relationships and suggest that increasing PD may counteract negative effects of plant-soil feedback.

The impact of pediatric emergency department crowding on patient and health care system outcomes: a multicentre cohort study

Abstract: BACKGROUND: Emergency department overcrowding has been associated with increased odds of hospital admission and mortality after discharge from the emergency department in predominantly adult cohorts. The objective of this study was to evaluate the association between crowding and the odds of several adverse outcomes among children seen at a pediatric emergency department. METHODS: We conducted a retrospective cohort study involving all children visiting 8 Canadian pediatric emergency departments across 4 provinces between 2010 and 2014. We analyzed the association between mean departmental length of stay for each index visit and hospital admission within 7 days or death within 14 days of emergency department discharge, as well as hospital admission at index visit and return visits within 7 days, using mixed-effects logistic regression modelling. RESULTS: A total of 1 931 465 index visits occurred across study sites over the 5-year period, with little variation in index visit hospital admission or median length of stay. Hospital admission within 7 days of discharge and 14-day mortality were low across provinces (0.8%–1.5% and INTERPRETATION: Emergency department crowding was not significantly associated with hospital admission within 7 days of the emergency department visit or mortality in children. However, it was associated with increased hospital admission at the index visit for the sickest children, and with return visits to the emergency department for those less sick.

Using plant, microbe and soil fauna traits to improve the predictive power of biogeochemical models

Abstract: ELF is supported by the NERC Soil Security Programme (NE/P013708/1); JRD and BGJ by the UK Biotechnology and Biological Sciences Research Council (BBSRC) (Grants BB/I009000/2 and BB/I009183/1) DJ receives partial support from the N8 AgriFood programme This work was supported by a BBSRC International Partnering award (BB/L026759/1) to EB, DJ, RB and PS

Chinese herbal medicine for diabetic kidney disease: a systematic review and meta-analysis of randomised placebo-controlled trials.

Abstract: Objectives To provide a broad evaluation of the efficacy and safety of oral Chinese herbal medicine (CHM) as an adjunctive treatment for diabetic kidney disease (DKD), including mortality, progression to end-stage kidney disease (ESKD), albuminuria, proteinuria and kidney function. Design A systematic review and meta-analysis. Methods Randomised controlled trials (RCTs) comparing oral CHM with placebo as an additional intervention to conventional treatments were retrieved from five English (Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Allied and Complementary Medicine Database and Cumulative Index of Nursing and Allied Health Literature) and four Chinese databases (China BioMedical Literature, China National Knowledge Infrastructure, Chonqing VIP and Wanfang) from inception to May 2018. RCTs recruiting adult DKD patients induced by primary diabetes were considered eligible, regardless of the form and ingredients of oral CHM. Mean difference (MD) or standardised mean difference (SMD) was used to analyse continuous variables and RR for dichotomous data. Results From 7255 reports retrieved, 20 eligible studies involving 2719 DKD patients were included. CHM was associated with greater reduction of albuminuria than placebo, regardless of whether renin–angiotensin system (RAS) inhibitors were concurrently administered (SMD −0.56, 95% CI [−1.04 to –0.08], I2=64%, p=0.002) or not (SMD −0.92, 95% CI [−1.35 to –0.51], I2=87%, p Conclusions Based on moderate to low quality evidence, CHM may have beneficial effects on renal function and albuminuria beyond that afforded by conventional treatment in adults with DKD. Further well-conducted, adequately powered trials with representative DKD populations are warranted to confirm the long-term effect of CHM, particularly on clinically relevant outcomes. PROSPERO registration number CRD42015029293.

Drought decreases incorporation of recent plant photosynthate into soil food webs regardless of their trophic complexity

Abstract: Theory suggests that more complex food webs promote stability and can buffer the effects of perturbations, such as drought, on soil organisms and ecosystem functions. Here, we tested experimentally how soil food web trophic complexity modulates the response to drought of soil functions related to carbon cycling and the capture and transfer below-ground of recent photosynthate by plants. We constructed experimental systems comprising soil communities with one, two or three trophic levels (microorganisms, detritivores and predators) and subjected them to drought. We investigated how food web trophic complexity in interaction with drought influenced litter decomposition, soil CO2 efflux, mycorrhizal colonization, fungal production, microbial communities and soil fauna biomass. Plants were pulse-labelled after the drought with 13 C-CO2 to quantify the capture of recent photosynthate and its transfer below-ground. Overall, our results show that drought and soil food web trophic complexity do not interact to affect soil functions and microbial community composition, but act independently, with an overall stronger effect of drought. After drought, the net uptake of 13 C by plants was reduced and its retention in plant biomass was greater, leading to a strong decrease in carbon transfer below-ground. Although food web trophic complexity influenced the biomass of Collembola and fungal hyphal length, 13 C enrichment and the net transfer of carbon from plant shoots to microbes and soil CO2 efflux were not affected significantly by varying the number of trophic groups. Our results indicate that drought has a strong effect on above-ground-below-ground linkages by reducing the flow of recent photosynthate. Our results emphasize the sensitivity of the critical pathway of recent photosynthate transfer from plants to soil organisms to a drought perturbation, and show that these effects may not be mitigated by the trophic complexity of soil communities, at least at the level manipulated in this experiment.

The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation

Abstract: VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.

Infection-Related Mortality in Recipients of a Kidney Transplant in Australia and New Zealand

Abstract: Background and objectives The burden of infectious disease is high among kidney transplant recipients because of concomitant immunosuppression. In this study the incidence of infectious-related mortality and associated factors were evaluated. Design, setting, participants, & measurements In this registry-based retrospective, longitudinal cohort study, recipients of a first kidney transplant in Australia and New Zealand between 1997 and 2015 were included. Cumulative incidence of infectious-related mortality was estimated using competing risk regression (using noninfectious mortality as a competing risk event), and compared with age-matched, populated-based data using standardized incidence ratios. Results Among 12,519 patients, (median age 46 years, 63% men, 15% diabetic, 6% Indigenous ethnicity), 2197 (18%) died, of whom 416 (19%) died from infection. The incidence of infection-related mortality during the study period (1997–2015) was 45.8 (95% confidence interval [95% CI], 41.6 to 50.4) per 10,000 patient-years. The incidence of infection-related mortality reduced from 53.1 (95% CI, 45.0 to 62.5) per 10,000 person-years in 1997–2000 to 43.9 (95% CI, 32.5 to 59.1) per 10,000 person-years in 2011–2015 (P Conclusions Infection-related mortality in kidney transplant recipients is significantly higher than the general population, but has reduced over time. Risk factors include older age, female sex, Indigenous ethnicity, T cell–depleting therapy, and deceased donor transplantation. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_08_27_CJN03200319.mp3

Catheter type, placement and insertion techniques for preventing catheter-related infections in chronic peritoneal dialysis patients

Abstract: Background Peritonitis is one of the limiting factors for the growth of peritoneal dialysis (PD) worldwide and is a major cause of technique failure. Several studies have examined the effectiveness of various catheter-related interventions for lowering the risk of PD-related peritonitis. This is an update of a review first published in 2004. Objectives To evaluate the role of different catheter implantation techniques and catheter types in lowering the risk of PD-related peritonitis in PD patients. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 15 January 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Studies comparing different catheter insertion techniques, catheter types, use of immobilisation techniques and different break-in periods were included. Studies of different PD sets were excluded. Data collection and analysis Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and the results expressed as risk ratio (RR) with 95% confidence intervals (CI). Main results Forty-two studies (3144 participants) were included: 18 evaluated techniques of catheter implantation, 22 examined catheter types, one assessed an immobiliser device, and one examined break-in period. In general, study quality was variable and almost all aspects of study design did not fulfil CONSORT standards for reporting.Catheter insertion by laparoscopy compared with laparotomy probably makes little or no difference to the risks of peritonitis (RR 0.90, 95% CI 0.59 to 1.35; moderate certainty evidence), exit-site/tunnel infection (RR 1.00, 95% CI 0.43 to 2.31; low certainty evidence), catheter removal/replacement (RR 1.20, 95% CI 0.77 to 1.86; low certainty evidence), technique failure (RR 0.71, 95% CI 0.47 to 1.08; low certainty evidence), and death (all causes) (RR 1.26, 95% CI 0.72 to 2.20; moderate certainty evidence). It is uncertain whether subcutaneous burying of catheter increases peritonitis (RR 1.16, 95% CI 0.37 to 3.60; very low certainty evidence). Midline insertion compared to lateral insertion probably makes little or no difference to the risks of peritonitis (RR 0.65, 95% CI 0.32 to 1.33; moderate certainty evidence) and may make little or no difference to exit-site/tunnel infection (RR 0.56, 95% CI 0.12 to 2.58; low certainty evidence). Percutaneous insertion compared with open surgery probably makes little or no difference to the exit-site/tunnel infection (RR 0.16, 95% CI 0.02 to 1.30; moderate certainty evidence).Straight catheters probably make little or no difference to the risk of peritonitis (RR 1.04, 95% CI 0.82 to 1.31; moderate certainty evidence), peritonitis rate (RR 0.91, 95% CI 0.68 to 1.21; moderate certainty evidence), risk of exit-site infection (RR 1.12, 95% CI 0.94 to 1.34; moderate certainty evidence), and exit-site infection rate (RR 1.05, 95% CI 0.77 to 1.43; moderate certainty evidence) compared to coiled catheter. It is uncertain whether straight catheters prevent catheter removal or replacement (RR 1.11, 95% CI 0.73 to 1.66; very low certainty evidence) but straight catheters probably make little or no difference to technique failure (RR 0.82, 95% CI 0.51 to 1.31; moderate certainty evidence) and death (all causes) (RR 0.95, 95% CI 0.62 to 1.46; low certainty evidence) compared to coiled catheter. Tenckhoff catheter with artificial curve at subcutaneous tract compared with swan-neck catheter may make little or no difference to peritonitis (RR 1.29, 95% CI 0.85 to 1.96; low certainty evidence) and incidence of exit-site/tunnel infection (RR 0.96, 95% CI 0.77 to 1.21; low certainty evidence) but may slightly improve exit-site infection rate (RR 0.67, 95% CI 0.50 to 0.90; low certainty evidence). Authors' conclusions There is no strong evidence that any catheter-related intervention, including the use of different catheter types or different insertion techniques, reduces the risks of PD peritonitis or other PD-related infections, technique failure or death (all causes). However, the numbers and sizes of studies were generally small and the methodological quality of available studies was suboptimal, such that the possibility that a particular catheter-related intervention might have a beneficial effect cannot be completely ruled out with confidence.

Safety of corticosteroids in young children with acute respiratory conditions: a systematic review and meta-analysis

Abstract: Objective Adverse events (AEs) associated with short-term corticosteroid use for respiratory conditions in young children. Design Systematic review of primary studies. Data sources Medline, Cochrane CENTRAL, Embase and regulatory agencies were searched September 2014; search was updated in 2017. Eligibility criteria Children Data extraction and synthesis One reviewer extracted with another reviewer verifying data. Study selection and methodological quality (McHarm scale) involved duplicate independent reviews. We extracted AEs reported by study authors and used a categorisation model by organ systems. Meta-analyses used Peto ORs (pORs) and DerSimonian Laird inverse variance method utilising Mantel-Haenszel Q statistic, with 95% CI. Subgroup analyses were conducted for respiratory condition and dose. Results Eighty-five studies (11 505 children) were included; 68 were randomised trials. Methodological quality was poor overall due to lack of assessment and inadequate reporting of AEs. Meta-analysis (six studies; n=1373) found fewer cases of vomiting comparing oral dexamethasone with prednisone (pOR 0.29, 95% CI 0.17 to 0.48; I2=0%). The mean difference in change-from-baseline height after one year between inhaled corticosteroid and placebo was 0.10 cm (two studies, n=268; 95% CI −0.47 to 0.67). Results from five studies with heterogeneous interventions, comparators and measurements were not pooled; one study found a smaller mean change in height z-score with recurrent high-dose inhaled fluticasone over one year. No significant differences were found comparing systemic or inhaled corticosteroid with placebo, or between corticosteroids, for other AEs; CIs around estimates were often wide, due to small samples and few events. Conclusions Evidence suggests that short-term high-dose inhaled or systemic corticosteroids use is not associated with an increase in AEs across organ systems. Uncertainties remain, particularly for recurrent use and growth outcomes, due to low study quality, poor reporting and imprecision.

Transition between different renal replacement modalities : gaps in knowledge and care : the INTEGRATED Research Initiative

Abstract: Patients with end-stage kidney disease (ESKD) have different options to replace the function of their failing kidneys. The “integrated care” model considers treatment pathways rather than individua...

Towards more predictive and interdisciplinary climate change ecosystem experiments

Abstract: Despite great advances, experiments concerning the response of ecosystems to climate change still face considerable challenges, including the high complexity of climate change in terms of environmental variables, constraints in the number and amplitude of climate treatment levels, and the limited scope of responses and interactions covered. Drawing on the expertise of researchers from a variety of disciplines, this Perspective outlines how computational and technological advances can help in designing experiments that can contribute to overcoming these challenges, and also outlines a first application of such an experimental design.

Fish oil and aspirin effects on arteriovenous fistula function: Secondary outcomes of the randomised omega-3 fatty acids (Fish oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) trial.

Abstract: Background Arteriovenous fistulas (AVF) for haemodialysis often experience early thrombosis and maturation failure requiring intervention and/or central venous catheter (CVC) placement. This secondary and exploratory analysis of the FAVOURED study determined whether omega-3 fatty acids (fish oils) or aspirin affected AVF usability, intervention rates and CVC requirements. Methods In 567 adult participants planned for AVF creation, all were randomised to fish oil (4g/d) or placebo, and 406 to aspirin (100mg/d) or placebo, starting one day pre-surgery and continued for three months. Outcomes evaluated within 12 months included AVF intervention rates, CVC exposure, late dialysis suitability failure, and times to primary patency loss, abandonment and successful cannulation. Results Final analyses included 536 participants randomised to fish oil or placebo (mean age 55 years, 64% male, 45% diabetic) and 388 randomised to aspirin or placebo. Compared with placebo, fish oil reduced intervention rates (0.82 vs 1.14/1000 patient-days, incidence rate ratio [IRR] 0.72, 95% confidence interval [CI] 0.54–0.97), particularly interventions for acute thrombosis (0.09 vs 0.17/1000 patient-days, IRR 0.53, 95% CI 0.34–0.84). Aspirin significantly reduced rescue intervention rates (IRR 0.45, 95% CI 0.27–0.78). Neither agent significantly affected CVC exposure, late dialysis suitability failure or time to primary patency loss, AVF abandonment or successful cannulation. Conclusion Although fish oil and low-dose aspirin given for 3 months reduced intervention rates in newly created AVF, they had no significant effects on CVC exposure, AVF usability and time to primary patency loss or access abandonment. Reduction in access interventions benefits patients, reduces costs and warrants further study.