Determinants of change in arterial stiffness over 5 years in early chronic kidney disease

BackgroundArterial stiffness is an established and potentially modifiable risk factor for cardiovascular disease, associated with chronic kidney disease. There have been few studies to evaluate progression of arterial stiffness over time or factors that contribute to this, particularly in early chronic kidney disease. We therefore investigated arterial stiffness over 5 years in an elderly population with chronic kidney disease stage 3, cared for in primary care.Methods1741 persons with estimated GFR 30-59mL/min/1.73m2 underwent detailed clinical and biochemical assessment at baseline, year 1 and 5. Carotid to femoral pulse wave velocity (PWV) was measured to assess arterial stiffness using a Vicorder™ device.Results970 participants had PWV assessments at baseline and 5 years. PWV increased significantly by a mean of 1.1 m/s (from 9.7±1.9 to 10.8±2.1m/s). Multivariable linear regression analysis identified the following independent determinants of ΔPWV at year 5: baseline age, diabetes status, baseline systolic and diastolic blood pressure (BP), baseline PWV, ΔPWV at one year, Δ systolic BP over 5 years and Δ serum bicarbonate over 5 years (R2=0.38 for equation).ConclusionsWe observed a clinically significant increase in PWV over 5 years in a cohort with early chronic kidney disease despite reasonably well controlled hypertension. Measures of blood pressure were identified as the most important modifiable determinant of change in PWV suggesting that interventions to prevent arterial disease should focus on improved control of blood pressure, particularly in those who evidence an early increase in PWV. These hypotheses should now be tested in prospective trials

Associations of fibroblast growth factor 23, vitamin D and parathyroid hormone with 5-year outcomes in a prospective primary care cohort of people with chronic kidney disease stage 3

Objectives Vitamin D deficiency, elevated fibroblast growth factor 23 (FGF23) and elevated parathyroid hormone (PTH) have each been associated with increased mortality in people with chronic kidney disease (CKD). Previous studies have focused on the effects of FGF23 in relatively advanced CKD. This study aims to assess whether FGF23 is similarly a risk factor in people with early CKD, and how this risk compares to that associated with vitamin D deficiency or elevated PTH. Design Prospective cohort study. Setting Thirty-two primary care practices. Participants One thousand six hundred and sixty-four people who met Kidney Disease: Improving Global Outcomes (KDIGO) definitions for CKD stage 3 (two measurements of estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 at least 90 days apart) prior to study recruitment. Outcome measures All-cause mortality over the period of study follow-up and progression of CKD defined as a 25% fall in eGFR and a drop in GFR category, or an increase in albuminuria category. Results Two hundred and eighty-nine participants died during the follow-up period. Vitamin D deficiency (HR 1.62, 95% CI 1.01 to 2.58) and elevated PTH (HR 1.42, 95% CI 1.09 to 1.84) were independently associated with all-cause mortality. FGF23 was associated with all-cause mortality in univariable but not multivariable analysis. Fully adjusted multivariable models of CKD progression showed no association with FGF23, vitamin D status or PTH. Conclusions In this cohort of predominantly older people with CKD stage 3 and low risk of progression, vitamin D deficiency and elevated PTH were independent risk factors for all-cause mortality but elevated FGF23 was not. While FGF23 may have a role as a risk marker in high-risk populations managed in secondary care, our data suggest that it may not be as important in CKD stage 3, managed in primary care

Chronic kidney disease in primary care: outcomes after five years in a prospective cohort study

Background Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance. Methods and Findings In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5–33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity. Conclusions Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD

Incidence of cytological abnormalities within 24 months of a normal cervical smear in Soweto, South Africa

BACKGROUND: A screening programme for cervical cancer has been implemented in South Africa (SA) with intervals of 10 years after a normal cytological result. There are no studies that evaluate repeat screening at a shorter interval in SA. OBJECTIVES: (i) To find the incidence of cytological abnormalities on a repeat test after a report of normal cytology or an inadequate Pap smear; and (ii) to explore the factors associated with an abnormal cytology on repeat testing. METHODS: This was a secondary data analysis of a randomised controlled trial of diaphragm, lubricant gel and condoms v. condoms in the prevention of HIV infection. HIV-negative women were recruited between November 2003 and December 2005, with a normal Pap smear at entry. Observation time was from the first Pap smear to the date of the repeat Pap smear. Explanatory variables used were baseline, excepting any new HIV infection. RESULTS: The incidence of cytological abnormalities was 6.48% yearly in women with a previously normal Pap smear and 11.71% yearly in women with an inadequate smear result (p=0.03). The incidence of high-grade squamous intra-epithelial lesions (HSILs) was <0.5%. Factors associated with abnormal cytology were a history of ectopic pregnancy (odds ratio (OR) 9.25; confidence interval (CI) 1.78 - 48.02; p=0.01), number of male partners (OR 1.12; CI 1.03 - 1.22; p=0.01), history of vaginal discharge (OR 13.95; CI 1.18 - 164.47; p=0.04), and incident HIV infection (OR 6.56; CI 1.14 - 38.16; p=0.04). CONCLUSION: The incidence of HSILs is low in the first 2 years after a normal or inadequate Pap smear, even in a setting with a high prevalence of cytological abnormalities

The effect of an interdisciplinary science course on student perceptions of computer programming

Interdisciplinary courses are being offered and recommended by many academic institutions as part of a science degree. In one such first year interdisciplinary science course with a large enrollment we measured attitudes to and perceptions of computer programming at the start and end of semester. For those students with prior computer programming experience, there was a significant positive change in their attitudes to and perceptions of computer programming. The aspects of the course that effected this change were examined. Most students reported that the regular tutorials and the summative assignment, each of which integrated scientific modelling, communication and computer programming, had a positive effect on their attitudes to and perceptions of computer programming. This suggests that an interdisciplinary course can be an effective way to introduce skills such as computer programming

A novel MC4R mutation associated with childhood-onset obesity: A case report

The melanocortin-4-receptor gene (MC4R) is a key regulator of energy homeostasis, food intake and body weight. MC4R gene mutations are associated with early-onset severe obesity. Most patients are heterozygotes, with some reports of homozygotes and compound het-erozygotes. The authors report a case involving an eight-year-old girl with progressive weight gain from infancy, body mass index 44 kg/m: (\u3e97th percentile), hyperphagia, hvperinsulinemia and increased linear growth. There was no phenotvpe of morbid obesity in the parents or sibling. Coding regions and intron-exon boundaries of the genes encoding leptin, Ieptin receptor, pro-opiomelanocortin and MC4R were analyzed. Two heterozygous coding mutations in the MCR4 gene (S94N and C293R) were detected, of which the second has not been previously reported. The mutations were on opposite chromosomes, confirming compound heterozygosity. The molecular findings and clinical features associated with this novel MC4R mutation are described. The authors emphasize that rare mutations can be found in some patients with severe childhood-onset obesity

Megasequence architecture of Taranaki, Wanganui, and King Country basins and Neogene progradation of two continental margin wedges across western New Zealand.

Taranaki, Wanganui and King Country basins (formerly North Wanganui Basin) have been regarded as discrete basins, but they contain a very similar Neogene sedimentary succession and much of their geological history is held in common. Analysis of the stratigraphic architecture of the fill of each basin reveals the occurrence of four 2nd order megasequences of tectonic origin. The oldest is the early-early Miocene (Otaian Stage) Mahoenui Group/megasequence, followed by the late-early Miocene (Altonian Stage) Mokau Group/megasequence (King Country Basin), both of which correspond to the lower part of the Manganui Formation in Taranaki Basin. The third is the middle to late Miocene Whangamomona Group/megasequence, and the fourth is the latest Miocene-Pleistocene Rangitikei Supergroup/megasequence, both represented in the three basins. Higher order sequences (4th, 5th, 6th), having a eustatic origin, are evident in the Whangamomona and Rangitikei megasequences, particularly those of 5th order with 41 ka periodicity. The distribution of the megasequences are shown in a series of cross-section panels built-up from well -to-well correlations, complemented by time-stratigraphic cross-sections. The base of each megasequence is marked by marine flooding and represents a discrete phase in basin development. For the first megasequence this corresponded to rapid subsidence of the King Country Basin in a compressional setting and basement overthrusting on the Taranaki Fault, with the rapid introduction of terrigenous sediment during transgression. The Mahoenui megasequence accumulated mostly at bathyal depths; no regressive deposits are evident, having been eroded during subsequent uplift. The second (Mokau) megasequence accumulated during reverse movement on the Ohura Fault, formation of the Tarata Thrust Zone, and onlap of the basement block between the Taranaki Fault and the Patea-Tongaporutu-Herangi High (PTH). The Whangamomona megasequence accumulated during extensive reflooding of King Country Basin, onlap of the PTH High and of basement in the Wanganui Basin. This is an assymetrical sequence with a thin transgressive part (Otunui Formation) and a thick regressive part (Mount Messenger to Matemateaonga Formations). It represents the northward progradation of a continental margin wedge with bottom-set, slope-set and top-set components through Wanganui and King Country basins, with minor progradation over the PTH High and into Taranaki Basin. The Rangitikei megasequence is marked by extensive flooding at its base (Tangahoe Mudstone) and reflects the pull-down of the main Wanganui Basin depocentre. This megasequence comprises a second progradational margin wedge, which migrated on two fronts, one northward through Wanganui Basin and into King Country Basin, and a second west of the PTH High, through the Toru Trough and into the Central and Northern Grabens of Taranaki Basin and on to the Western Platform as the Giant Foresets Formation, thereby building up the modern shelf and slope. Fifth and 6th order sequences are well expressed in the shelf deposits (top-sets) of the upper parts of the Whangamomona and Rangitikei megasequences. They typically have a distinctive sequence architecture comprising shellbed (TST), siltstone (HST) and sandstone (RST) beds. Manutahi-1, which was continuously cored, provides calibration of this sequence architecture to wireline log character, thereby enabling shelf deposits to be mapped widely in the subsurface via the wireline data for hydrocarbon exploration holes. Similar characterization of slope-sets and bottom-sets is work ongoing. The higher order (eustatic) sequences profoundly influenced the local reservoir architecture and seal properties of formations, whereas the megasequence progradation has been responsible for the regional hydrocarbon maturation and migration. Major late tilting, uplift and erosion affected all three basins and created a regional high along the eastern Margin of Taranaki Basin, thereby influencing the migration paths of hydrocarbons sourced deeper in the basin and allowing late charge of structural and possibly stratigraphic traps

The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: A prospective cohort study

BackgroundTissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause mortality (ACM), but data at earlier stages of chronic kidney disease (CKD) are inconclusive. We investigated SAF as a risk factor for CVEs and ACM in a prospective study of persons with CKD stage 3.Methods and findingsParticipants with estimated glomerular filtration rate (eGFR) 59 to 30 mL/min/1.73 m2 on two consecutive previous blood tests were recruited from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. SAF was measured in participants with CKD stage 3 at baseline, 1, and 5 years using an AGE reader (DiagnOptics). Data on hospital admissions with CVEs (based on international classification of diseases [ICD]-10 coding) and deaths were obtained from NHS Digital. Cox proportional hazards models were used to investigate baseline variables associated with CVEs and ACM. A total of 1,707 of 1,741 participants with SAF readings at baseline were included in this analysis: The mean (± SD) age was 72.9 ± 9.0 years; 1,036 (60.7%) were female, 1,681 (98.5%) were of white ethnicity, and mean (±SD) eGFR was 53.5 ± 11.9 mL/min/1.73 m2. We observed 319 deaths and 590 CVEs during a mean of 6.0 ± 1.5 and 5.1 ± 2.2 years of observation, respectively. Higher baseline SAF was an independent risk factor for CVEs (hazard ratio [HR] 1.12 per SD, 95% CI 1.03-1.22, p = 0.01) and ACM (HR 1.16, 95% CI 1.03-1.30, p = 0.01). Additionally, increase in SAF over 1 year was independently associated with subsequent CVEs (HR 1.11 per SD, 95% CI 1.00-1.22; p = 0.04) and ACM (HR 1.24, 95% CI 1.09-1.41, p = 0.001). We relied on ICD-10 codes to identify hospital admissions with CVEs, and there may therefore have been some misclassification.ConclusionsWe have identified SAF as an independent risk factor for CVE and ACM in persons with early CKD. These findings suggest that interventions to reduce AGE accumulation, such as dietary AGE restriction, may reduce cardiovascular risk in CKD, but this requires testing in prospective randomised trials. Our findings may not be applicable to more ethnically diverse or younger populations

Megasequence architecture of Taranaki, Wanganui, and King Country basins and Neogene progradation of two continental margin wedges across western New Zealand.

Taranaki, Wanganui and King Country basins (formerly North Wanganui Basin) have been regarded as discrete basins, but they contain a very similar Neogene sedimentary succession and much of their geological history is held in common. Analysis of the stratigraphic architecture of the fill of each basin reveals the occurrence of four 2nd order megasequences of tectonic origin. The oldest is the early-early Miocene (Otaian Stage) Mahoenui Group/megasequence, followed by the late-early Miocene (Altonian Stage) Mokau Group/megasequence (King Country Basin), both of which correspond to the lower part of the Manganui Formation in Taranaki Basin. The third is the middle to late Miocene Whangamomona Group/megasequence, and the fourth is the latest Miocene-Pleistocene Rangitikei Supergroup/megasequence, both represented in the three basins. Higher order sequences (4th, 5th, 6th), having a eustatic origin, are evident in the Whangamomona and Rangitikei megasequences, particularly those of 5th order with 41 ka periodicity. The distribution of the megasequences are shown in a series of cross-section panels built-up from well -to-well correlations, complemented by time-stratigraphic cross-sections. The base of each megasequence is marked by marine flooding and represents a discrete phase in basin development. For the first megasequence this corresponded to rapid subsidence of the King Country Basin in a compressional setting and basement overthrusting on the Taranaki Fault, with the rapid introduction of terrigenous sediment during transgression. The Mahoenui megasequence accumulated mostly at bathyal depths; no regressive deposits are evident, having been eroded during subsequent uplift. The second (Mokau) megasequence accumulated during reverse movement on the Ohura Fault, formation of the Tarata Thrust Zone, and onlap of the basement block between the Taranaki Fault and the Patea-Tongaporutu-Herangi High (PTH). The Whangamomona megasequence accumulated during extensive reflooding of King Country Basin, onlap of the PTH High and of basement in the Wanganui Basin. This is an assymetrical sequence with a thin transgressive part (Otunui Formation) and a thick regressive part (Mount Messenger to Matemateaonga Formations). It represents the northward progradation of a continental margin wedge with bottom-set, slope-set and top-set components through Wanganui and King Country basins, with minor progradation over the PTH High and into Taranaki Basin. The Rangitikei megasequence is marked by extensive flooding at its base (Tangahoe Mudstone) and reflects the pull-down of the main Wanganui Basin depocentre. This megasequence comprises a second progradational margin wedge, which migrated on two fronts, one northward through Wanganui Basin and into King Country Basin, and a second west of the PTH High, through the Toru Trough and into the Central and Northern Grabens of Taranaki Basin and on to the Western Platform as the Giant Foresets Formation, thereby building up the modern shelf and slope. Fifth and 6th order sequences are well expressed in the shelf deposits (top-sets) of the upper parts of the Whangamomona and Rangitikei megasequences. They typically have a distinctive sequence architecture comprising shellbed (TST), siltstone (HST) and sandstone (RST) beds. Manutahi-1, which was continuously cored, provides calibration of this sequence architecture to wireline log character, thereby enabling shelf deposits to be mapped widely in the subsurface via the wireline data for hydrocarbon exploration holes. Similar characterization of slope-sets and bottom-sets is work ongoing. The higher order (eustatic) sequences profoundly influenced the local reservoir architecture and seal properties of formations, whereas the megasequence progradation has been responsible for the regional hydrocarbon maturation and migration. Major late tilting, uplift and erosion affected all three basins and created a regional high along the eastern Margin of Taranaki Basin, thereby influencing the migration paths of hydrocarbons sourced deeper in the basin and allowing late charge of structural and possibly stratigraphic traps

Cervical intra-epithelial neoplasia in HIV-positive women after excision of the transformation zone – does the grade change?

Objective. After previously reporting the presence of disease by cytology findings after treatment for cervical intra-epithelial neoplasia (CIN) in 64.6% of HIV-infected women and in 13.0% of HIV-negative women, we aimed to determine the severity of cytological disease after treatment in HIV-infected women.Methods. We studied HIV-infected (N=571) women treated at the Colposcopy Clinic at Chris Hani Baragwanath Hospital, Gauteng, between April 2003 and December 2006. We compared the initial histology results with Pap smears .6 months later, and evaluated factors associated with reduction in the grade of disease.Results. Mean age was 36.68 (SD+7.33) years; mean parity was 2 (SD+1.46); mean CD4+ count was 242.70 cells/&#402;&#202;l (SD+187.56); 262 (45.80%) were receiving antiretroviral treatment. Persistent disease was detected on the repeat Pap smear in 199 (65.03%); of these, 223 (72.88%) were of a lesser grade than in the original histology results. Of the 152 with histologically confirmed CIN3, 67 (44.08%) had improved to a lesser grade, and 54 (44.63%) had normal cytology results. Among the latter two subject groups (n=141) who had CIN2 histologically, 91 (64.53%) had improved, 29 (20.57%) remained unchanged, and 20 (14.88%) had CIN3; 13 (4.25%) patients with CIN1 returned for follow-up; 11 (84.62%) of these had normal Pap smears and 2 (15.38%) had CIN3.Conclusion. Recurrences were of a lesser degree than initial histology results. This reduction in the grade of disease was related to CD4+ count, complete excision and parity. Antiretroviral therapy use did not improve outcome, perhaps owing to low initial CD4 counts