Hybrid graphene plasmonic waveguide modulators.

The unique optical and electronic properties of graphene make possible the fabrication of novel optoelectronic devices. One of the most exciting graphene characteristics is the tunability by gating which allows one to realize active optical devices. While several types of graphene-based photonic modulators have already been demonstrated, the potential of combining the versatility of graphene with subwavelength field confinement of plasmonic waveguides remains largely unexplored. Here we report fabrication and study of hybrid graphene-plasmonic waveguide modulators. We consider several types of modulators and identify the most promising one for telecom applications. The modulator working at the telecom range is demonstrated, showing a modulation depth of >0.03 dB µm(-1) at low gating voltages for an active device area of just 10 µm(2), characteristics which are already comparable to those of silicon-based waveguide modulators while retaining the benefit of further device miniaturization. Our proof-of-concept results pave the way towards on-chip realization of efficient graphene-based active plasmonic waveguide devices for optical communications.

Prenatal glucocorticoid exposure programs adrenal PNMT expression and adult hypertension.

Prenatal exposure to glucocorticoids (GCs) programs for hypertension later in life. The aim of the current study was to examine the impact of prenatal GC exposure on the postnatal regulation of the gene encoding for phenylethanolamine N-methyltransferase (PNMT), the enzyme involved in the biosynthesis of the catecholamine, epinephrine. PNMT has been linked to hypertension and is elevated in animal models of hypertension. Male offspring of Wistar-Kyoto dams treated with dexamethasone (DEX) developed elevated systolic, diastolic and mean arterial blood pressure compared to saline-treated controls. Plasma epinephrine levels were also elevated in adult rats exposed to DEX in utero. RT-PCR analysis revealed adrenal PNMT mRNA was higher in DEX exposed adult rats. This was associated with increased mRNA levels of transcriptional regulators of the PNMT gene: Egr-1, AP-2, and GR. Western blot analyses showed increased expression of PNMT protein, along with increased Egr-1 and GR in adult rats exposed to DEX in utero. Furthermore, gel mobility shift assays showed increased binding of Egr-1 and GR to DNA. These results suggest that increased PNMT gene expression via altered transcriptional activity is a possible mechanism by which prenatal exposure to elevated levels of GCs may program for hypertension later in life.

Structured assessment for prospective identification of safety signals in electronic medical records: evaluation in the health improvement network.

BACKGROUND: Pharmacovigilance signal detection largely relies on individual case reports, but longitudinal health data are being explored as complementary information sources. Research to date has focused on the ability of epidemiological methods to distinguish established adverse drug reactions (ADRs) from unrelated adverse events. OBJECTIVE: The aim of this study was to evaluate a process for structured clinical and epidemiological assessment of temporally associated drugs and medical events in electronic medical records. METHODS: Pairs of drugs and medical events were selected for review on the basis of their temporal association according to a calibrated self-controlled cohort analysis in The Health Improvement Network. Six assessors trained in pharmacovigilance and/or epidemiology evaluated seven drugs each, with up to 20 medical events per drug. A pre-specified questionnaire considered aspects related to the nature of the temporal pattern, demographic features of the cohort, concomitant medicines, earlier signs and symptoms, and possible confounding by underlying disease. This informed a classification of drug-event pairs as known ADRs, meriting further evaluation, or dismissed. RESULTS: The number of temporally associated medical events per drug ranged from 11 to 307 (median 50) for the 42 selected drugs. Out of the 509 relevant drug-event combinations subjected to the assessment, 127 (25 %) were classified as known ADRs. Ninety-one (24 %) of the remaining pairs were classified as potential signals meriting further evaluation and 291 (76 %) were dismissed. Suggestive temporal patterns and lack of clear alternative explanations were the most common reasons that drug-event pairs were classified as meriting further evaluation. Earlier signs and symptoms and confounding by the underlying disease were the most common reasons that drug-event pairs were dismissed. CONCLUSIONS: Exploratory analysis of electronic medical records can detect important potential safety signals. However, effective signal detection requires that statistical signal detection be combined with clinical and epidemiological review to achieve an acceptable false positive rate.

Graphene-protected copper and silver plasmonics.

Plasmonics has established itself as a branch of physics which promises to revolutionize data processing, improve photovoltaics, and increase sensitivity of bio-detection. A widespread use of plasmonic devices is notably hindered by high losses and the absence of stable and inexpensive metal films suitable for plasmonic applications. To this end, there has been a continuous search for alternative plasmonic materials that are also compatible with complementary metal oxide semiconductor technology. Here we show that copper and silver protected by graphene are viable candidates. Copper films covered with one to a few graphene layers show excellent plasmonic characteristics. They can be used to fabricate plasmonic devices and survive for at least a year, even in wet and corroding conditions. As a proof of concept, we use the graphene-protected copper to demonstrate dielectric loaded plasmonic waveguides and test sensitivity of surface plasmon resonances. Our results are likely to initiate wide use of graphene-protected plasmonics.

Singular phase nano-optics in plasmonic metamaterials for label-free single-molecule detection.

The non-trivial behaviour of phase is crucial for many important physical phenomena, such as, for example, the Aharonov-Bohm effect and the Berry phase. By manipulating the phase of light one can create 'twisted' photons, vortex knots and dislocations which has led to the emergence of the field of singular optics relying on abrupt phase changes. Here we demonstrate the feasibility of singular visible-light nano-optics which exploits the benefits of both plasmonic field enhancement and the peculiarities of the phase of light. We show that properly designed plasmonic metamaterials exhibit topologically protected zero reflection yielding to sharp phase changes nearby, which can be employed to radically improve the sensitivity of detectors based on plasmon resonances. By using reversible hydrogenation of graphene and binding of streptavidin-biotin, we demonstrate an areal mass sensitivity at a level of fg mm(-2) and detection of individual biomolecules, respectively. Our proof-of-concept results offer a route towards simple and scalable single-molecule label-free biosensing technologies.

Senescence rates in patients with end-stage renal disease: a critical appraisal of the Gompertz model.

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274 221; follow-up=594 767 person-years), for European patients with a functioning kidney transplant (n=61 286; follow-up=345 024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.

Variation between centres in access to renal transplantation in UK: longitudinal cohort study.

OBJECTIVE: To assess whether equity exists in access to renal transplantation in the UK after adjustment for case mix in incident patients with end stage renal disease. DESIGN: Longitudinal cohort study. SETTING: UK Renal Registry and UK Transplant Registry. PARTICIPANTS: All incident renal replacement treatment patients (n=16 202) from 65 renal centres submitting data to the UK Renal Registry between 1 January 2003 and 31 December 2005, followed until 31 December 2008 (or until transplantation or death, whichever was earliest). OUTCOME MEASURES: Proportion of incident dialysis patients at each renal centre who were registered on the national transplant list; time taken to achieve registration; and proportion of patients subsequently transplanted. RESULTS: We found that recipients' age, ethnicity, and primary renal diagnosis were associated with the likelihood of accessing the waiting list or receiving a transplant. After adjustment for case mix, significant inter-centre variability existed in access to the transplant list (change in -2LogL=89.9, df=1, P<0.001), in the time taken to register patients on the waiting list (change in -2LogL=247.4, df=64, P<0.001), in receipt of a renal transplant from a donor after brain stem death (change in -2LogL=15.1, df=1, P=0.001), and in receipt of a renal transplant from a living donor or a donor after cardiac death (change in -2LogL=46.1, df=1, P<0.001). CONCLUSIONS: Significant variation in access to renal transplantation exists between centres within the UK that cannot be explained by differences in case mix.

Validation and utility of a computerized South Asian names and group recognition algorithm in ascertaining South Asian ethnicity in the national renal registry.

BACKGROUND: The UK Renal Registry (UKRR) reports on equity and quality of renal replacement therapy (RRT). Ethnic origin is a key variable, but it is only recorded for 76% patients overall in the UKRR and there is wide variation in the degree of its completeness between renal centres. Most South Asians have distinctive names. AIM: To test the relative performance of a computerized name recognition algorithm (SANGRA) in identifying South Asian names using the UKRR database. DESIGN: Cross-sectional study of patients (n = 27 832) starting RRT in 50 renal centres in England and Wales from 1997 to 2005. METHODS: Kappa statistics were used to assess the degree of agreement of SANGRA coding with existing ethnicity information in UKRR centres. RESULTS: In 12 centres outside London (number of patients = 7555) with 11% (n = 747) self-ascribed South Asian ethnicity, the level of agreement between SANGRA and self-ascribed ethnicity was high (kappa=0.91, 95% CI 0.90-0.93). In two London centres (n = 779) with 21% (n = 165) self-ascribed South Asian ethnicity, SANGRA's agreement with self-ascribed ethnicity was lower (kappa=0.60, 95% CI 0.54-0.67), primarily due to difficulties in distinguishing between South Asian ethnicity and other non-White ethnic minorities. Use of SANGRA increased numbers defined as South Asian from 1650 to 2076 with no overall change in percentage of South Asians. Kappa values showed no obvious association with degree of missing data returns to the UKRR. CONCLUSION: SANGRA's use, taking into account its lower validity in London, allows increased power and generalizability for both ethnic specific analyses and for analyses where adjustment for ethnic origin is important.

Patients with diabetic nephropathy on renal replacement therapy in England and Wales.

BACKGROUND: The incidence of patients with diabetic nephropathy (DN) who start renal replacement therapy (RRT) is increasing. AIM: To describe the characteristics and survival of patients with DN starting RRT in the UK. DESIGN: Retrospective cohort study. METHODS: We analysed data for incident patients on RRT in centres participating in the Renal Association UK Renal Registry (UKRR), 1997 -2004, comparing DN vs. non-DN patients with regard to survival, social deprivation, ethnicity, gender, and age, using Cox regression models. RESULTS: DN was the most common renal disease (19%) in the 20 532 patients starting RRT. The majority of patients with DN (77%) were Caucasian. Within the Caucasian population, DN patients were more likely to be from a socially deprived area (p < 0.0001). About 20% were referred <3 months before starting RRT. The difference in crude survival was greatest in younger patients (5-year survival was 56% (DN) vs. 85% (non-DN) in patients aged 18-54 years, and 17% (DN) vs. 28% (non-DN) in patients aged >or=65 years). Despite adjusting for gender, age, treatment modality, social deprivation, referral and co-morbidities, the long-term prognosis for DN patients aged 18-54 years was worse (adjusted hazard ratio 2.13, 95%CI 1.23-3.67) than for older age groups. DISCUSSION: Patients with DN starting RRT are more likely to come from socially deprived areas. Relative risk of death is greatest in working-age DN patients and is not fully explained by recorded co-morbidity. This emphasizes the need for focused diabetes care in poorer areas, and assessment of quality of care of diabetic patients on RRT.

Chronic renal failure in kidney transplant recipients. Do they receive optimum care?: data from the UK renal registry.

We report the prevalence of chronic kidney disease (CKD) and related complications in a national cohort of RTR (n=9542), and compare this with dialysis patients. The majority of RTR were classified as having CKD stage 2T (21.6%) or 3T (57.5%) with 15.7% classified as CKD stage 4T and 3.1% as stage 5T. Only 2.1% of RTR were in CKD stage 1T. The proportion of patients with stage 4T and 5T CKD who lost their graft in the following year was 8% and 49%, respectively. The prevalence of anemia (hemoglobin <11 g/dL) increased from 4.4% in stage 1T to 51.5% in stage 5T and compared with 30% in dialysis patients (p<0.0001). Hypertension, hyperphosphatemia, elevated Ca x PO(4), raised iPTH and hypoalbuminemia rose with increasing CKD stage. For many variables, the achievement of standards was lower in stage 5T RTR than in dialysis patients. There were center differences in median estimated glomerular filtration rate and percentage of patients with hemoglobin <11 g/dL (p<0.0001). In conclusion, many patients in stage 4T-5T have CKD-related complications that fall below targets established for nontransplant CKD patients. They are at increased risk of graft loss. More attention needs to be paid to managing these complications and preparing these patients for a return to dialysis and/or retransplantation.

Social deprivation and survival on renal replacement therapy in England and Wales.

This study examines the association between social deprivation and patient characteristics and outcomes in a nationally representative cohort of incident renal replacement therapy (RRT) patients. All Caucasian patients reported to the UK Renal Registry between 1997 and 2004 by centers in England and Wales with high data completeness were included. Social deprivation was assessed using the Townsend index. Socially deprived patients were more likely to be referred late. They were less likely to receive peritoneal dialysis (25.1 vs 34.8% on day 1, P trend <0.0001) or a renal transplant (5.3 vs 12.4% at 1 year, P trend <0.0001), and were less likely to attain UK Renal Association standards for hemoglobin and phosphate at 1 year. Crude survival decreased significantly with increasing deprivation for patients under the age of 65 years, but not for those aged 65 years and above (likelihood ratio for age-social deprivation interaction P<0.0001). Social deprivation was significantly associated with poorer survival after adjustment for age, gender, and cause of renal failure. After adjusting for baseline co-morbidity, social deprivation was no longer associated with poorer survival. Baseline differences in co-morbidity seem to explain poorer crude survival in incident Caucasian RRT patients from socially deprived areas in England and Wales. Differences also exist in some processes of care and intermediate outcomes, which may be amenable to intervention.

Equity of access to dialysis facilities in Wales.

BACKGROUND: Demand for dialysis, particularly, in-centre haemodialysis (HD), is growing, and more units will be needed. Travel time to treatment is consistently a major area of concern for patients. AIM: To analyse access to current dialysis facilities in Wales, and use the data to help plan for new dialysis units. METHODS: We analysed a combination of UK Renal Registry, Welsh population census data, the Welsh Index of Multiple Deprivation 2005 (WIMD), travel time and geographical information systems. RESULTS: Prevalence of HD fell significantly with increasing travel time from units. This was not influenced by the WIMD. Prior to the opening of a new HD unit in Aberystwyth, prevalence in the surrounding area was significantly lower than for Wales as whole, but within 2 years, prevalence had risen to approximate national levels. In Haverfordwest, an area >30 min drive from any current facility, prevalence is consistently and significantly lower than for Wales as a whole, and has not shown the growth seen elsewhere in the country. DISCUSSION: The ability to combine data has enabled modelling of the likely immediate impact of opening a new unit in Haverfordwest, and also provided an estimate of its required capacity. This multidisciplinary approach to demand analysis should help to highlight areas of under-provision, and facilitate the planning of the sites and sizes of new dialysis units in Wales.

Current chronic kidney disease practice patterns in the UK: a national survey.

BACKGROUND: There is an increasing focus on improving the detection and management of patients with chronic kidney disease (CKD). Data on CKD prevalence based on population sampling are now available, but there are few data about CKD patients attending nephrology services or how such services are organized. AIM: To survey services for CKD patients nationally. METHODS: A pre-piloted questionnaire was sent to all 72 renal units in the UK, referring to the situation in June 2004. RESULTS: Seventy units (97%) responded. The median ratio of prevalent CKD patients/prevalent renal replacement therapy (RRT) patients in the 25 units with data was 3.7 (IQR 2.7-5.7) and the median ratio of CKD stage 4 and 5 patients/prevalent RRT patients was 0.6 (IQR 0.4-1.1). This gives an estimated 140 000 CKD patients under the care of UK nephrologists, with 23 000 at CKD stage 4 or 5 (excluding those on RRT). Very few units had a full complement of the recommended multi-skilled renal team. Counsellors and psychologist were the most common perceived shortages. Of 70 responding units, 50 (74%) were using low clearance clinics for management of advanced CKD patients. Elective dialysis access services often had long delays, with median waiting time for vascular access ranging between 1 and 36 weeks, and for Tenchkoff catheter, between 0 and 12 weeks. DISCUSSION: CKD patients are a significant workload for UK nephrologists. Current provision of service is variable, and services need to be re-designed to cope with the expected future increase of referral of CKD patients.

Trends in adult renal replacement therapy in the UK: 1982-2002.

BACKGROUND: Following the introduction of dialysis and transplantation for the treatment of established renal failure (ERF) 40 years ago, the UK failed to match the achievements of many other countries. AIM: To review progress with treatment for ERF in the UK in the past 20 years. DESIGN: Review of four cross-sectional national studies, and 1997-2002 annual UK Renal Registry data. METHODS: Data on UK patients on renal replacement treatment (RRT) were collated from three sources: European Registry reports for 1982-1990, surveys carried out within the UK in 1993, 1996, 1998 and 2002, and the UK Renal Registry database (1997-2002). Trends in acceptance and prevalence rates, median age, cause of ERF, and treatment modality were analysed and compared with current data from other countries. RESULTS: The UK annual acceptance rate for RRT increased from 20 per million population (pmp) in 1982 to 101 pmp in 2002. This growth was largely in those aged over 65 years, and in those with co-morbidity. Annual acceptance rates for ERF due to diabetes rose from 1.6 to 18 pmp. The prevalence of RRT increased from 157 pmp in 1982 to 626 pmp in 2002. Hospital haemodialysis has become the main modality, and is increasingly being provided in satellite units. Although rising, UK acceptance and prevalence rates are still lower than in many developed countries. DISCUSSION: Despite significant expansion in RRT services for adults in the UK over the last 20 years, there is evidence of unmet need, and need is expected to rise, due to demographic changes and trends in type 2 diabetes. Continuing growth in the already substantial investment in RRT will be needed, unless efforts to prevent the occurrence of ERF are successful.

Evaluating Chicago's success in reaching the Healthy People 2000 goal of reducing health disparities.

OBJECTIVE: This study was designed to assess Chicago's progress from 1980 to 1998 in addressing the Healthy People 2000 goal of reducing health disparities. METHODS: Chicago vital statistics and surveillance data were used to calculate black:white rate ratios of mortality and morbidity for 1980-1998. Mortality and morbidity rate ratios were also used to compare people living in areas with the lowest median household income with those living in the highest for 1979-1981, 1991-1993, and 1996-1998. The health measures included mortality associated with leading causes of death; all-cause mortality, incidence rates for two communicable diseases; and two birth outcomes. RESULTS: Both black:white and low-income:high-income rate ratios monotonically increased for virtually all measures of mortality and morbidity. Almost all of the rate ratios and linear trends were statistically significant. From 1980 to 1998, the black:white rate ratio for all-cause mortality increased by 57% to 2.03. From 1979-1981 to 1996-1998, the low-income:high-income rate ratio for all-cause mortality increased by 56% to 2.68. CONCLUSIONS: These findings provide clear evidence that disparities in health did not decrease in Chicago. Instead, racial and economic disparities increased for almost all measures of mortality and morbidity used in this study. The fact that the Healthy People 2000 campaign to reduce and then eliminate health disparities was not effective must serve as a stimulus for improved strategies.

Management of anaemia in United Kingdom renal units: a report from the UK Renal Registry.

BACKGROUND: Morbidity and mortality of patients undergoing renal replacement therapy is influenced by the adequacy of correction of renal anaemia. The Renal Association has set standards for attainment of a target haemoglobin of 10 g/dl. This study compared the management of anaemia in dialysis patients in nine renal units in the UK. METHODS: A cross-sectional analysis was carried out on data submitted electronically to the UK Renal Registry. There were 1449 haemodialysis patients and 741 peritoneal dialysis patients in the nine renal centres analysed. Individual patient data were collected on haemoglobin, ferritin, erythropoietin prescription, and pre- and post-dialysis urea concentrations. RESULTS: None of the centres achieved the standard of more than 80% of haemodialysis patients with a haemoglobin of greater than 10 g/dl. Three centres achieved this standard for peritoneal dialysis. There was wide variation between centres in the percentage reaching the target. Differences in ferritin, erythropoietin prescription, and dialysis doses between centres could not entirely explain the variations between centres. Females had lower haemoglobin than males despite a greater proportion being treated with erythropoietin. There was a trend of increasing haemoglobin concentration during the study period in haemodialysis but not in peritoneal dialysis patients. CONCLUSIONS: The Renal Association standards for management of anaemia are not being met. The data allow renal centres to compare their practices with others to identify areas that might be improved. Further analysis may allow a benchmark to be determined of what it is possible to achieve by best practice.

Ready or not: assessing youths' preparedness for independent living.

This article discusses the utility of the Ansell-Casey Life Skills Assessment (ACLSA) in assessing life skills necessary for living successfully in the community upon emancipation from out-of-home care. ACLSA, completed by youths and their caregivers, identifies skills that have been mastered and those yet to be learned. Assessment information can be used for goal setting, strength identification, and relationship building, as well as to direct program planning and training in self-sufficiency services.

Development of a reverse transcription polymerase chain reaction procedure for the detection of marine caliciviruses with potential application for nucleotide sequencing.

A reverse transcription polymerase chain reaction (RT-PCR) procedure is described for the detection of marine caliciviruses including vesicular exanthema of swine virus (VESV), San Miguel sea lion virus (SMSV), bovine Tillamook virus (BCV Bos-1) and caliciviruses (CV) isolated from dolphin (Cetacean CV), gorilla (Primate CV) and rattlesnake (Reptile CV) using primers (1F and 1R) designed from the capsid-coding region of the viral genome. These primers were compared with those described by Neill, J.D. and Seal, B.S., 1995: Development of PCR primers for specific amplification of two distinct regions of the genomes of San Miguel sea lion and vesicular exanthema of swine viruses, Mol. Cell. Probes 9, 33-38 (Hel1/Hel2), which had been designed from the 2C-like region of the calicivirus genome. Both sets proved to be extremely useful diagnostic tools for all of the known marine calicivirus serotypes with the exception of three: SMSV-8 and -12 and mink CV suggesting that these three caliciviruses may belong to a different group. Neither of the two primer sets reacted with strains of the vesicular disease viruses of foot-and-mouth disease (FMD), swine vesicular disease (SVD) or vesicular stomatitis (VS) nor with two feline caliciviruses (FCV). The 1F/1R primer set has the advantage over the Hel1/Hel2 set in that it generates a larger PCR product for nucleotide sequence investigations and so provides greater opportunity for identifying molecular differences between the viruses.

Monoclonal antibodies, against O1 serotype foot-and-mouth disease virus, from a natural bovine host, recognize similar antigenic features to those defined by the mouse.

Eight neutralizing and two non-neutralizing anti-foot-and-mouth disease virus (FMDV) bovine IgG1 and IgG2 monoclonal antibodies (BMAbs) recognize conformationally dependent epitopes. The majority of those shown to neutralize virus passively protected mice from virus challenge, regardless of isotype. Well-characterized anti-FMDV mouse MAbs, representing five independent neutralizing epitopes on O1 serotype virus, were examined with each of the ten BMAbs in a competition-based ELISA. Five of the neutralizing BMAbs (C48, C65, C74, C83 and MH6) were shown to be directed against epitopes on, or in close proximity to, that previously defined as neutralizing antigenic site 2. Another neutralizing BMAb, MH5, bound to an epitope on, or in close proximity to antigenic site 3. Two neutralizing BMAbs (C2 and C96) simultaneously abrogated the binding of mouse antibodies to sites 2 and 4, contesting the autonomous nature of these two regions. None of the BMAbs were shown to be directed towards the immunodominant antigenic site 1. Sequence analyses of neutralization escape mutants supported the competition ELISA results, and included changes at site 2 (VP2 aa C78Y), site 3 (VP1 N46S) and site 4 (VP3 E58K). Additionally, a substitution at a previously unrecorded location (VP2 aa T1881) prevented the binding of site 2 (C48) and sites 2 and 4 (C2) directed BMAbs. Although the bovine and murine anti-FMDV repertoires may not be identical these results support the recognition of similar antigenic features. This is the first report characterizing anti-FMDV MAbs produced from a natural target host, the cow.