METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
METHODS: We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability.
RESULTS: Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified.
CONCLUSION: By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.
STUDY DESIGN: Prospective observational cohort study.
SETTING & PARTICIPANTS: 552 children and adolescents from 27 countries on maintenance HD followed up prospectively by the International Pediatric HD Network (IPHN) Registry between 2012 and 2017.
PREDICTOR: Type of vascular access: AVF, central venous catheter (CVC), or arteriovenous graft.
OUTCOME: Infectious and noninfectious vascular access complication rates, dialysis performance, biochemical and hematologic parameters, and clinical outcomes.
ANALYTICAL APPROACH: Univariate and multivariable linear mixed models, generalized linear mixed models, and proportional hazards models; cumulative incidence functions.
RESULTS: During 314 cumulative patient-years, 628 CVCs, 225 AVFs, and 17 arteriovenous grafts were placed. One-third of the children with an AVF required a temporary CVC until fistula maturation. Vascular access choice was associated with age and expectations for early transplantation. There was a 3-fold higher living related transplantation rate and lower median time to transplantation of 14 (IQR, 6-23) versus 20 (IQR, 14-36) months with CVCs compared with AVFs. Higher blood flow rates and Kt/Vurea were achieved with AVFs than with CVCs. Infectious complications were reported only with CVCs (1.3/1,000 catheter-days) and required vascular access replacement in 47%. CVC dysfunction rates were 2.5/1,000 catheter-days compared to 1.2/1,000 fistula-days. CVCs required 82% more revisions and almost 3-fold more vascular access replacements to a different site than AVFs (P<0.001).
LIMITATIONS: Clinical rather than population-based data.
CONCLUSIONS: CVCs are the predominant vascular access choice in children receiving HD within the IPHN. Age-related anatomical limitations and expected early living related transplantation were associated with CVC use. CVCs were associated with poorer dialysis efficacy, higher complication rates, and more frequent need for vascular access replacement. Such findings call for a re-evaluation of pediatric CVC use and practices.
RESEARCH QUESTION: What is the association between chitinase activity, airway fungi and clinical outcomes in bronchiectasis and bronchiectasis-COPD overlap?
STUDY DESIGN AND METHODS: A prospective cohort of 463 individuals were recruited across five hospital sites in three countries (Singapore, Malaysia, and Scotland) including individuals who were not diseased (n = 35) and who had severe asthma (n = 54), COPD (n = 90), bronchiectasis (n = 241) and BCO (n = 43). Systemic chitinase levels were assessed for bronchiectasis and BCO and related to clinical outcomes, airway Aspergillus status, and underlying pulmonary mycobiome profiles.
RESULTS: Systemic chitinase activity is elevated significantly in bronchiectasis and BCO and exceed the activity in other airway diseases. CHIT1 activity strongly predicts bronchiectasis exacerbations and is associated with the presence of at least one Aspergillus species in the airway and frequent exacerbations (≥3 exacerbations/y). Subgroup analysis reveals an association between CHIT1 activity and the "frequent exacerbator" phenotype in South-East Asian patients whose airway mycobiome profiles indicate the presence of novel fungal taxa that include Macroventuria, Curvularia and Sarocladium. These taxa, enriched in frequently exacerbating South-East Asian patients with high CHIT1 may have potential roles in bronchiectasis exacerbations.
INTERPRETATION: Systemic CHIT1 activity may represent a useful clinical tool for the identification of fungal-driven "frequent exacerbators" with bronchiectasis in South-East Asian populations.
RESEARCH QUESTION: We aim to determine if clusters of Chinese patients with COPD exist and their association with clinical outcomes and inflammation.
STUDY DESIGN AND METHODS: Chinese patients with stable COPD were prospectively recruited into two cohorts (derivation and validation) from six hospitals across three Southeast Asian countries (Singapore, Malaysia, and Hong Kong; n = 1,480). Each patient was followed more than 2 years. Clinical data (including co-morbidities) were employed in unsupervised hierarchical clustering (followed by validation) to determine the existence of patient clusters and their prognostic outcome. Accompanying systemic cytokine assessments were performed in a subset (n = 336) of patients with COPD to determine if inflammatory patterns and associated networks characterized the derived clusters.
RESULTS: Five patient clusters were identified including: (1) ex-TB, (2) diabetic, (3) low comorbidity: low-risk, (4) low comorbidity: high-risk, and (5) cardiovascular. The cardiovascular and ex-TB clusters demonstrate highest mortality (independent of Global Initiative for Chronic Obstructive Lung Disease assessment) and illustrate diverse cytokine patterns with complex inflammatory networks.
INTERPRETATION: We describe clusters of Chinese patients with COPD, two of which represent high-risk clusters. The cardiovascular and ex-TB patient clusters exhibit high mortality, significant inflammation, and complex cytokine networks. Clinical and inflammatory risk stratification of Chinese patients with COPD should be considered for targeted intervention to improve disease outcomes.
METHODS: Patients with stable COPD (n=446) and nondiseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assessed outdoor and indoor environmental allergen exposure in COPD. We identified key fungi in outdoor air and developed specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of 11 COPD patients and linked to clinical outcome.
RESULTS: High frequencies of sensitisation to a broad range of allergens occur in COPD. Fungal sensitisation associates with frequent exacerbations, and unsupervised clustering reveals a "highly sensitised fungal predominant" subgroup demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD and promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function, illustrating the importance of environmental exposures on clinical outcomes in COPD.
CONCLUSION: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD.
STUDY DESIGN: Prospective cohort study.
SETTING & PARTICIPANTS: Patients younger than 19 years at inclusion into the International Pediatric Peritoneal Dialysis Network registry, who initiated MPD between 1996 and 2017.
EXPOSURE: Region as primary exposure (Asia, Western Europe, Eastern Europe, Latin America, North America, and Oceania). Other demographic, clinical, and macroeconomic (4 income groups based on gross national income) factors also were studied.
OUTCOME: All-cause MPD mortality.
ANALYTICAL APPROACH: Patients were observed for 3 years, and the mortality rates in different regions and income groups were calculated. Cause-specific hazards models with random effects were fit to calculate the proportional change in variance for factors that could explain variation in mortality rates.
RESULTS: A total of 2,956 patients with a median age of 7.8 years at the start of KRT were included. After 3 years, the overall probability of death was 5%, ranging from 2% in North America to 9% in Eastern Europe. Mortality rates were higher in low-income countries than in high-income countries. Income category explained 50.1% of the variance in mortality risk between regions. Other explanatory factors included peritoneal dialysis modality at start (22.5%) and body mass index (11.1%).
LIMITATIONS: The interpretation of interregional survival differences as found in this study may be hampered by selection bias.
CONCLUSIONS: This study shows that the overall 3-year patient survival on pediatric MPD is high, and that country income is associated with patient survival.