Unexpectedly high incidence of Kawasaki Disease in a Canadian Atlantic Province- an 11-year retrospective descriptive study.

BACKGROUND: Kawasaki Disease (KD) is the leading cause of acquired heart disease in children in developed countries with a variable incidence worldwide. Previous studies reported an unexpectedly high incidence of KD in the Canadian Atlantic Provinces. The goals of our study were to validate this finding in the province of Nova Scotia and to carefully review patients' characteristics and disease outcomes. METHODS: This was a retrospective review of all children < 16 years old from Nova Scotia diagnosed with KD between 2007-2018. Cases were identified using a combination of administrative and clinical databases. Clinical information was collected retrospectively by health record review using a standardized form. RESULTS: Between 2007-2018, 220 patients were diagnosed with KD; 61.4% and 23.2% met the criteria for complete and incomplete disease, respectively. The annual incidence was 29.6 per 100,000 children < 5 years. The male to female ratio was 1.3:1 and the median age was 3.6 years. All patients diagnosed with KD in the acute phase received intravenous immunoglobulin (IVIG); 23 (12%) were refractory to the first dose. Coronary artery aneurysms were found in 13 (6%) patients and one patient died with multiple giant aneurysms. CONCLUSION: We have confirmed an incidence of KD in our population which is higher than that reported in Europe and other regions of North America despite our small Asian population. The comprehensive method to capture patients may have contributed to the detection of the higher incidence. The role of local environmental and genetic factors also deserves further study. Increased attention to regional differences in the epidemiology of KD may improve our understanding of this important childhood vasculitis.

The resilience of postglacial hunter-gatherers to abrupt climate change.

Understanding the resilience of early societies to climate change is an essential part of exploring the environmental sensitivity of human populations. There is significant interest in the role of abrupt climate events as a driver of early Holocene human activity, but there are very few well-dated records directly compared with local climate archives. Here, we present evidence from the internationally important Mesolithic site of Star Carr showing occupation during the early Holocene, which is directly compared with a high-resolution palaeoclimate record from neighbouring lake beds. We show that-once established-there was intensive human activity at the site for several hundred years when the community was subject to multiple, severe, abrupt climate events that impacted air temperatures, the landscape and the ecosystem of the region. However, these results show that occupation and activity at the site persisted regardless of the environmental stresses experienced by this society. The Star Carr population displayed a high level of resilience to climate change, suggesting that postglacial populations were not necessarily held hostage to the flickering switch of climate change. Instead, we show that local, intrinsic changes in the wetland environment were more significant in determining human activity than the large-scale abrupt early Holocene climate events.

Combination therapy for KIT-mutant mast cells: targeting constitutive NFAT and KIT activity.

Resistant KIT mutations have hindered the development of KIT kinase inhibitors for treatment of patients with systemic mastocytosis. The goal of this research was to characterize the synergistic effects of a novel combination therapy involving inhibition of KIT and calcineurin phosphatase, a nuclear factor of activated T cells (NFAT) regulator, using a panel of KIT-mutant mast cell lines. The effects of monotherapy or combination therapy on the cellular viability/survival of KIT-mutant mast cells were evaluated. In addition, NFAT-dependent transcriptional activity was monitored in a representative cell line to evaluate the mechanisms responsible for the efficacy of combination therapy. Finally, shRNA was used to stably knockdown calcineurin expression to confirm the role of calcineurin in the observed synergy. The combination of a KIT inhibitor and a calcineurin phosphatase inhibitor (CNPI) synergized to reduce cell viability and induce apoptosis in six distinct KIT-mutant mast cell lines. Both KIT inhibitors and CNPIs were found to decrease NFAT-dependent transcriptional activity. NFAT-specific inhibitors induced similar synergistic apoptosis induction as CNPIs when combined with a KIT inhibitor. Notably, NFAT was constitutively active in each KIT-mutant cell line tested. Knockdown of calcineurin subunit PPP3R1 sensitized cells to KIT inhibition and increased NFAT phosphorylation and cytoplasmic localization. Constitutive activation of NFAT appears to represent a novel and targetable characteristic of KIT-mutant mast cell disease. Our studies suggest that combining KIT inhibition with NFAT inhibition might represent a new treatment strategy for mast cell disease.

Characterization of a factor H mutation that perturbs the alternative pathway of complement in a family with membranoproliferative GN.

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.

Global differences in dialysis modality mix: the role of patient characteristics, macroeconomics and renal service indicators.

BACKGROUND: An increase in the dialysis programme expenditure is expected in most countries given the continued rise in the number of people with end-stage renal disease (ESRD) globally. Since chronic peritoneal dialysis (PD) therapy is relatively less expensive compared with haemodialysis (HD) and because there is no survival difference between PD and HD, identifying factors associated with PD use is important. METHODS: Incidence counts for the years 2003-05 were available from 36 countries worldwide. We studied associations of population characteristics, macroeconomic factors and renal service indicators with the percentage of patients on PD at Day 91 after starting dialysis. With linear regression models, we obtained relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: The median percentage of incident patients on PD was 12% (interquartile range: 7-26%). Determinants independently associated with lower percentages of patients on PD were as follows: patients with diabetic kidney disease (per 5% increase) (RR 0.93; 95% CI 0.89-0.97), health expenditure as % gross domestic product (per 1% increase) (RR 0.93; 95% CI 0.87-0.98), private-for-profit share of HD facilities (per 1% increase) (RR 0.996; 95% CI 0.99-1.00; P = 0.04), costs of PD consumables relative to staffing (per 0.1 increase) (RR 0.97; 95% CI 0.95-0.99). CONCLUSIONS: The factors associated with a lower percentage of patients on PD include higher diabetes prevalence, higher healthcare expenditures, larger share of private-for-profit centres and higher costs of PD consumables relative to staffing. Whether dialysis modality mix can be influenced by changing healthcare organization and funding requires additional studies.

A new reconstructive technique for posterior vaginal wall defects, a case report.

INTRODUCTION: Post-partum vaginal laxity is a problem encountered by many women. More uncommon is a resulting vaginal defect. In most cases of laxity, a period of extensive physiotherapy can strengthen the pelvic muscles enough for symptoms to be minimized. However, this is not the case once there is a tissue defect. AIM: To present a new reconstructive method for patients with posterior vaginal wall defects. METHODS: We present a case of a 38-year-old female who, 12 years prior to presentation, had a vaginal delivery. Due to complications during the delivery, she sustained pelvic trauma and developed a posterior vaginal wall defect. She had a sizable soft tissue defect, causing sexual, urinary, and confidence problems. Fat was harvested from the patient's abdomen and injected into the defect after more conservative treatment options were exhausted. RESULTS: The defect was corrected successfully using the minimally invasive Coleman fat grafting technique. DISCUSSION/CONCLUSION: This is to our knowledge the first case in the literature where a posterior vaginal defect has been corrected using Coleman fat grafting, and we believe that this treatment method may be of benefit to more patients.

Exploring the association between macroeconomic indicators and dialysis mortality.

BACKGROUND AND OBJECTIVES: Mortality on dialysis varies greatly worldwide, with patient-level factors explaining only a small part of this variation. The aim of this study was to examine the association of national-level macroeconomic indicators with the mortality of incident dialysis populations and explore potential explanations through renal service indicators, incidence of dialysis, and characteristics of the dialysis population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Aggregated unadjusted survival probabilities were obtained from 22 renal registries worldwide for patients starting dialysis in 2003-2005. General population age and health, macroeconomic indices, and renal service organization data were collected from secondary sources and questionnaires. Linear modeling with log-log transformation of the outcome variable was applied to establish factors associated with survival on dialysis. RESULTS: Two-year survival on dialysis ranged from 62.3% in Iceland to 89.8% in Romania. A higher gross domestic product per capita (hazard ratio=1.02 per 1000 US dollar increase), a higher percentage of gross domestic product spent on healthcare (1.10 per percent increase), and a higher intrinsic mortality of the dialysis population (i.e., general population-derived mortality risk of the dialysis population in that country standardized for age and sex; hazard ratio=1.04 per death per 10,000 person years) were associated with a higher mortality of the dialysis population. The incidence of dialysis and renal service indicators were not associated with mortality on dialysis. CONCLUSIONS: Macroeconomic factors and the intrinsic mortality of the dialysis population are associated with international differences in the mortality on dialysis. Renal service organizational factors and incidence of dialysis seem less important.

Volcanic ash layers illuminate the resilience of Neanderthals and early modern humans to natural hazards.

Marked changes in human dispersal and development during the Middle to Upper Paleolithic transition have been attributed to massive volcanic eruption and/or severe climatic deterioration. We test this concept using records of volcanic ash layers of the Campanian Ignimbrite eruption dated to ca. 40,000 y ago (40 ka B.P.). The distribution of the Campanian Ignimbrite has been enhanced by the discovery of cryptotephra deposits (volcanic ash layers that are not visible to the naked eye) in archaeological cave sequences. They enable us to synchronize archaeological and paleoclimatic records through the period of transition from Neanderthal to the earliest anatomically modern human populations in Europe. Our results confirm that the combined effects of a major volcanic eruption and severe climatic cooling failed to have lasting impacts on Neanderthals or early modern humans in Europe. We infer that modern humans proved a greater competitive threat to indigenous populations than natural disasters.

Translating chronic kidney disease epidemiology into patient care--the individual/public health risk paradox.

BACKGROUND: Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6-year follow-up (≈ 13,000 patient-years). METHODS: A cohort had previously been identified with CKD-sustained reduced eGFR over at least 3 months and case note review. Six-year (13,339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex-specific mortality rates were compared to the general population. RESULTS: Of 3414 individuals (most Stage 3b-5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15-25 and 75-85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15-45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient-years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15-45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning. CONCLUSIONS: The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome.

Measuring the population burden of chronic kidney disease: a systematic literature review of the estimated prevalence of impaired kidney function.

BACKGROUND: Internationally, there have been substantial efforts to improve the early identification of chronic kidney disease (CKD), with a view to improving survival, reducing progression and minimizing cardiovascular morbidity and mortality. In 2002, a new and globally adopted definition of CKD was introduced. The burden of kidney function impairment in the population is unclear and widely ranging prevalence estimates have been reported. METHODS: We conducted a systematic literature review, searching databases to June 2009. We included all adult population screening studies and studies based on laboratory or clinical datasets where the denominator was clear. Studies reporting prevalence estimates based on at least one eGFR <60 mL/min/1.73m(2) or elevated creatinine above a stated threshold were included. Study design and quality were explored as potential factors leading to heterogeneity. RESULTS: We identified 43 eligible studies (57 published reports) for inclusion. Substantial heterogeneity was observed with estimated prevalence (0.6-42.6%). The included studies demonstrated significant variation in methodology and quality that impacted on the comparability of their findings. From the higher quality studies, the six studies measuring impaired kidney function (iKF) using estimated glomerular filtration rate in community screening samples reported a prevalence ranging from 1.7% in a Chinese study to 8.1% in a US study, with four reporting an estimated prevalence of 3.2-5.6%. Heterogeneity was driven by the measure used, study design and study population. CONCLUSION: In the general population, estimated iKF, particularly eGFR 30-59 mL/min/1.73m(2) was common with prevalence similar to diabetes mellitus. Appropriate care of patients poses a substantial global health care challenge.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts.

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Global variation in renal replacement therapy for end-stage renal disease.

BACKGROUND: Incidence rates of renal replacement therapy (RRT) for end-stage renal disease vary considerably worldwide. This study examines the independent association between the general population, health care system and renal service characteristics and RRT incidence rates. METHODS: RRT incidence data (2003-2005) were obtained from renal registries; general population age and health and macroeconomic indices were collected from secondary sources. Renal service organization and resource data were obtained through interviews and questionnaires. Linear regression models were built to establish the factors independently associated with RRT incidence, stratified by the Human Development Index where required. False discovery rate (FDR) correction was adjusted for multiple testing. RESULTS: Across the 46 countries (population 1.25 billion), RRT incidence rates ranged from 12 to 455 (median 130) per million population. Gross domestic product (GDP) per capita [incidence rate ratio (IRR): 1.02 per $1000 increase, P(FDR) = 0.047], percentage of GDP spent on health care (IRR: 1.11 per % increase, P(FDR) = 0.006) and dialysis facility reimbursement rate relative to GDP (IRR: 0.76 per GDP per capita-sized increase in reimbursement rate, P(FDR) = 0.007) were independently associated with RRT incidence. In more developed countries, the private for-profit share of haemodialysis facilities was also associated with higher incidence (IRR: 1.009 per % increase, P(FDR) = 0.003). CONCLUSIONS: Macroeconomic and renal service factors are more often associated with RRT incidence rates than measured demographic or general population health status factors.

Intermittent versus continuous renal replacement therapy for acute renal failure in adults

It brings information about the treatment of acute renal failure in adults by using renal replacement therapy, comparing the efficacy of its application intermittently and continuously.

The EVEREST study: an international collaboration.

Rates of initiation of renal replacement therapy (RRT), use of home modalities of treatment and patient outcomes vary considerably between countries. This paper reports the methods and baseline characteristics of countries participating in the EVEREST study (n = 46), a global collaboration examining the association between medical and non-medical factors and RRT incidence, modality mix and survival. Numbers of incident and prevalent patients were collected for current (2003-05) and historic (1983-85, 1988-90, 1993-95 and 1998-2000) periods stratified, where available, by age, gender, treatment modality and cause of end stage renal disease (diabetic versus non-diabetic). General population age and health indicators and national-level macroeconomic data were collected from secondary data sources. National experts provided primary data on renal service funding, resources and organization. The median (inter quartile range) RRT incidence per million of the population (pmp) was 130 pmp (102-167 pmp). The general population life expectancy at 60 was 22.1 years (19.7-23.1 years) and 6.9% had diabetes mellitus (5.4-9.0%). Healthcare spending as a percentage of gross domestic product was 8.1% (5.6-9.3%). Countries averaged nine dialysis facilities pmp (4-12 pmp), with 69.0% (43.9-99.0%) owned by the public or private not-for-profit sector. The number of nephrologists ranged from 0.5 to 48 pmp (median 12 pmp). The heterogeneity of EVEREST countries will enable modelling to examine the independent association between medical and non-medical factors on RRT epidemiology.

Systematic review of antimicrobials for the prevention of haemodialysis catheter-related infections.

BACKGROUND: Almost 30% of chronic haemodialysis (HD) patients are dependent on central venous catheters (CVCs) for their vascular access, and catheter-related bacteraemia (CRB) is the major reason for catheter loss and has been associated with substantial morbidity, including meta-static infections. This systematic review evaluates the benefits and harms of antimicrobial interventions for the prevention of catheter-related infections (CRIs). METHODS: MEDLINE (1950-May 2009), EMBASE (1980-May 2009) CENTRAL (up to May 2009) and bibliographies of retrieved articles were searched for relevant RCTs. Analysis was by a random effects model and results expressed as rate ratio, relative risk (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI). RESULTS: A total of 29 trials with 2886 patients and 3005 catheters were included. Antimicrobial catheter locks (AMLs) significantly reduced the rates of CRBs (rate ratio, 0.33, 95% CI 0.24-0.45) and exit-site infections (ESIs) (rate ratio 0.67, 95% CI 0.47-0.96). Exit-site antimicrobial application also significantly reduced the rates of CRBs (rate ratio 0.21, 95% CI 0.12-0.36) and ESIs (rate ratio 0.22, 95% CI 0.10-0.47). Antimicrobial coating of HD catheters and the use of peri-operative antimicrobials did not result in significant reduction in rates of CRBs and ESIs. CONCLUSION: The use of AMLs and exit-site antimicrobials are useful measures in the reduction of CRIs, whereas antimicrobial impregnated catheters and peri-operative systemic antimicrobial administration have not been found to be beneficial. Further head-to-head trials of various AMLs and exit-site antimicrobials are needed to know about their comparative clinical efficacy.

Survival and dialysis initiation: comparing British Columbia and Scotland registries.

BACKGROUND: Outcomes are a major metric for evaluating effectiveness of dialysis. Comparisons between different populations reveal significant variation. In addition, the question of optimal timing of dialysis start lacks robust data from which to generate conclusions. METHODS: This study compares dialysis survival in two geographically similar areas, Scotland and British Columbia, Canada (BC). The effect of eGFR at dialysis start on survival was also measured. Incident adult dialysis populations of Scotland (n = 3372) and BC (n = 3927), 2000-05 were compared. Mortality Hazard ratios (HR) were calculated using a Cox proportional hazards model. Multivariate analysis included pre-dialysis eGFR, registry, age, sex, dialysis modality, year of start, pre-dialysis haemoglobin and primary renal diagnosis. RESULTS: Median survival times from start of dialysis were 38 (35-40) and 44 (42-47) months in Scotland and BC, respectively, giving an unadjusted mortality HR, Scotland versus BC, of 1.20 (95% C.I. 1.12-1.29). BC patients started dialysis at a higher eGFR (8.9 ml/min/1.73 m(2)) than Scotland (7.5 ml/min/1.73 m(2)), and prior to modelling higher starting eGFR was associated with higher mortality (1 ml/min/1.73 m(2) increase, HR = 1.028; 95% C.I. 1.021-1.035). BC patients were also older and had more diabetic renal disease. In multivariate analysis, lower starting eGFR was associated with better survival, and Scotland had greater mortality than BC. General population mortality and transplantation rate had only minor influence. CONCLUSIONS: Concepts of 'late' versus 'early' start dialysis based on eGFR alone may need modification given the complexity and confounding reasons for dialysis initiation.

Automated vs continuous ambulatory peritoneal dialysis: a systematic review of randomized controlled trials.

BACKGROUND: A systematic review of randomized controlled trials (RCTs) comparing continuous ambulatory peritoneal dialysis (CAPD) with all forms of automated peritoneal dialysis (APD) was performed to assess their comparative clinical effectiveness. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, were searched for relevant RCTs. Analysis was by a random effects model and results expressed as relative risk (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI). RESULTS: Three trials (139 patients) were identified. APD when compared to CAPD was found to have significantly lower peritonitis rates (two trials, 107 patients, rate ratio 0.54, 95% CI 0.35-0.83) and hospitalization rates (one trial, 82 patients, rate ratio 0.60, 95% CI 0.39-0.93) but not exit-site infection rates (two trials, 107 patients, rate ratio 1.00, 95% CI 0.56-1.76). However no differences were detected between APD and CAPD in respect to risk of mortality (RR 1.49, 95% CI 0.51-4.37), peritonitis (RR 0.75, 95% CI 0.50-1.11), switching from the original peritoneal dialysis (PD) modality to a different dialysis modality including an alternative form of PD (RR 0.50, 95% CI 0.25-1.02), PD catheter removal (RR 0.64, 95% CI 0.27-1.48) and hospital admissions (RR 0.96, 95% CI 0.43-2.17). Patients on APD were found to have significantly more time for work, family and social activities. CONCLUSIONS: APD appears to be more beneficial than CAPD, in terms of reducing peritonitis rates and with respect to certain social issues that impact on patients' quality of life. Further, adequately powered trials are required to confirm the benefits for APD found in this review and detect differences with respect to other clinically important outcomes that may have been missed by the trials included in this review due to their small size and short follow-up periods.

A prospective national study of acute renal failure treated with RRT: incidence, aetiology and outcomes.

BACKGROUND: Acute renal failure (ARF) is a diverse condition with no standardized definition and is managed in several sub-specialty areas within hospitals. Its incidence and aetiology are unknown and studies show a wide range of incidences. ARF is becoming more common as the population ages leading to the hypothesis that the incidence is much higher than previous estimates. METHODS: This prospective population study investigated the incidence, aetiology and outcomes of ARF based on a standardized classification of ARF treated by renal replacement therapy (RRT) in all sub-specialty areas within hospitals where such treatment takes place. Data were collected prospectively on all patients starting RRT for ARF within three 12-week periods in 2002. RESULTS: Two hundred eighty-six adults per million population (pmp) per year received RRT for ARF. The incidence increased with age and pre-existing comorbid illness. Two hundred twelve adults pmp per year had no evidence of pre-existing chronic kidney disease (CKD) and the remainder had acute on CKD. The median age was 67 years. Fifty-one percent of the patients received their first RRT treatment in a critical care setting. Sepsis was the most common aetiological insult contributing to ARF in 48% of the patients. Mortality was high with 48% dying within 90 days of starting RRT. Age, comorbidity, sepsis and recent surgery were independent risk factors for death in those with no pre-existing CKD. DISCUSSION: This is the first national study to describe ARF treated with RRT in all hospital locations. The hypothesis that ARF occurs more frequently than previously thought has been confirmed. This study provides data upon which to base effective decision making for prevention, patient care and resource planning for patients with ARF.