Vibrational Electronic-Thermofield Coupled Cluster (VE-TFCC) Theory for Quantum Simulations of Vibronic Coupling Systems at Thermal Equilibrium.

A vibrational electronic-thermofield coupled cluster (VE-TFCC) approach is developed to calculate thermal properties of non-adiabatic vibronic coupling systems. The thermofield (TF) theory and a mixed linear exponential ansatz based on second-quantized Bosonic construction operators are introduced to propagate the thermal density operator as a "pure state" in the Bogoliubov representation. Through this compact representation of the thermal density operator, the approach is basis-set-free and scales classically (polynomial) as the number of degrees of freedoms (DoF) in the system increases. The VE-TFCC approach is benchmarked with small test models and a real molecular compound (CoF4- anion) against the conventional sum over states (SOS) method and applied to calculate thermochemistry properties of a gas-phase reaction: CoF3 + F- → CoF4-. Results shows that the VE-TFCC approach, in conjunction with vibronic models, provides an effective protocol for calculating thermodynamic properties of vibronic coupling systems.

Time dependent vibrational electronic coupled cluster (VECC) theory for non-adiabatic nuclear dynamics.

A time-dependent vibrational electronic coupled-cluster (VECC) approach is proposed to simulate photo-electron/UV-VIS absorption spectra as well as time-dependent properties for non-adiabatic vibronic models, going beyond the Born-Oppenheimer approximation. A detailed derivation of the equations of motion and a motivation for the ansatz are presented. The VECC method employs second-quantized bosonic construction operators and a mixed linear and exponential ansatz to form a compact representation of the time-dependent wave-function. Importantly, the method does not require a basis set, has only a few user-defined inputs, and has a classical (polynomial) scaling with respect to the number of degrees of freedom (of the vibronic model), resulting in a favorable computational cost. In benchmark applications to small models and molecules, the VECC method provides accurate results compared to multi-configurational time-dependent Hartree calculations when predicting short-time dynamical properties (i.e., photo-electron/UV-VIS absorption spectra) for non-adiabatic vibronic models. To illustrate the capabilities, the VECC method is also successfully applied to a large vibronic model for hexahelicene with 14 electronic states and 63 normal modes, developed in the group by Aranda and Santoro [J. Chem. Theory Comput. 17, 1691, (2021)].

Creatinine standardization: a key consideration in evaluating whole blood creatinine monitoring systems for CKD screening.

Early detection of CKD using point of care creatinine and eGFR testing improves patient management outcomes. We undertook a field study to evaluate the use of a whole blood creatinine/eGFR device to screen a rural Nicaraguan population to determine the variability between creatinine methods and specimen types. All specimens including capillary and venous dried blood spots (DBS) were tested with an isotope dilution liquid chromatography mass spectrometry (ID-LCMS) gold standard method. This is to our knowledge the first time a capillary whole blood (POC) method has been directly compared to the gold standard IDMS method, through the novel approach of using dried blood spots. Capillary and venous whole blood specimens were obtained and tested directly with the BCMS method, and then, DBS samples were prepared. Venous plasma specimens were tested using three laboratory analyzer creatinine methods. DBS were sent to the site performing ID-LCMS. Control samples were also prepared to assess the stability of shipment and storage of DBS. The ID-LCMS method was aligned using primary and secondary standards. Sixty-six (66) patients participated in the study, and the CKD prevalence rate was 7.8%. While all creatinine methods showed a good correlation to ID-LCMS, there was a positive bias (mean absolute bias range: 0.21-0.63 mg/dL). All methods used were 100% sensitive, but specificity varied from 62.7 to 94.9% with PPV ranging from 25 to 62.5%. A correction factor was used to align the values from each method to ID-LCMS which improved the specificity of each method. This study used a unique DBS approach to align capillary whole blood creatinine to ID-LCMS. To ensure reliability of BCMS for identifying screened patients with CKD, it is important to establish IDMS traceability and alignment prior to undertaking CKD studies.

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes.

OBJECTIVES: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D. METHODS: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes <-3 and > 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource. RESULTS: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR. CONCLUSIONS: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Comparison of Medium-term Outcomes of Living Kidney Donors With Longitudinal Healthy Control in the United Kingdom.

BACKGROUND: Understanding the outcomes and risks for live kidney donors (LD) is increasingly important; this study investigated all-cause mortality and morbidity outcomes of LD compared with a healthy cohort. METHODS: Live donor dataset was obtained from the UK Transplant Registry and a comparator nondonor cohort selected from The Health Improvement Network (THIN) database, a UK primary healthcare database. All LD from January 1, 2001, to December 31, 2013, were included, with follow-up until December 31, 2016. RESULTS: There were 9750 LD and 19 071 THIN participants. Median follow-up (interquartile range) for LD was 8.4 (6.0-11.3) years and for THIN was 5.4 (2.6-8.5) years. In up to 15 years, follow-up end-stage renal disease was observed in 1 LD versus 7 THIN (P = 0.280). Nine LD had estimated glomerular filtration rate of <30 mL/min/1.73 m versus 43 in THIN (P = 0.012), but no statistically significant difference in adjusted logistic regression analyses. Risk of diabetes mellitus, depression, and cardiovascular disease was significantly higher for THIN cohort in adjusted analyses. The risk of hypertension was higher for LD at 5 years but was not significantly different in fully adjusted analyses at 10 years. There were 68 deaths in LD and 485 in THIN over the follow-up period, with significant difference in mortality favoring LD (P < 0.001). CONCLUSIONS: The medium-term morbidity and mortality outcomes of live donors in comparison with a healthy cohort suggest that live donation is not associated with excess mortality, end-stage renal disease, or morbidity, in at least 10 years follow-up.

Phenotypic characteristics and risk factors in a multi-ethnic cohort of young adults with type 2 diabetes.

Background: Early onset of type 2 diabetes (T2DM) is associated with prolonged exposure to hyperglycaemia and increased propensity to chronic complications. The aim of this study was to characterize and compare the phenotypic characteristics and risk factors in a multi-ethnic cohort of young adults with type 2 diabetes (T2DMY). Methods: One hundred young adults (White European [WE], South Asian [SA] and African-Caribbean [AC]) diagnosed with T2DM before the age of 40 years were recruited. Demographics, family history, diabetes related complications, co-morbidities, anthropometry (body mass index [BMI], body composition), physical activity and biochemistry (HbA1c, lipid profile, liver and renal function) and autoantibodies (anti GAD, anti islet cell) were collected for all participants. Data were analysed for the most represented ethnic groups: (WE, N = 36 and SA, N = 53) using SPSS version 23. Results: Mean (± standard deviation) age at diagnosis was 32.5 ± 5.5 years and mean diabetes duration was 7.7 ± 3.8 years. Overweight/obesity was present in 95% of participants, history of maternal diabetes in 68%, deprivation 75%, low physical activity 40%, polycystic ovarian disease 29% (in females), acanthosis nigricans 12% and non-alcoholic fatty liver 11%. There was considerable clustering of risk factors within the cohort with over 75% of all subjects having three or more of the above risk factors and 52% required insulin within 3 years of diagnosis. Two-thirds of the patients had evidence of at least one diabetes related microvascular complication. Conclusion: T2DMY is characterized by a high burden of commonly associated risk factors for both the disease and its long-term complications.

Glass Slippers and Glass Cliffs: Fitting In and Falling Off.

BACKGROUND: A glass ceiling effect exists for women in male-dominated professions. Recent studies also show a glass-cliff effect where senior women can more easily fall from positions of leadership. Transplantation remains a male-dominated specialty. This study investigated gender and the perception of adverse clinical incidents in transplantation. METHODS: Prospective randomised web-based survey involving five clinical scenarios presenting two versions of episodes with errors or mistakes, with either a male or female as a randomly named protagonist (Set1 and Set2). To address unconscious bias, the study was described as examining actions following clinical adverse incidents in transplantation. Each scenario was followed by 2 closed questions: (1) clinical performance rating and (2) selection of action required. Reasoning was invited (open-text comments). Responses were analyzed using quantitative and qualitative methods. RESULTS: One hundred ninety-one invitees responded; 134 completed questionnaires. There were no statistically significant differences (P > 0.05) in responses between sets for performance ratings or recommended actions. However, for "first solo laparoscopic surgery" scenario, there was some indication that "No Action" was more likely if surgeon was male (P = 0.056). Male responses rated female performance as significantly worse (P = 0.035) for the laboratory-based scenario. One hundred two participants provided open-text comments. Thematic analysis identified 7 themes. Acceptable levels of risk theme demonstrated engendered leadership beliefs, that is, when clinical judgment proved incorrect, males described as forceful but females as needing support. In cases where things went wrong, respondents were more likely to comment females should not have decided to proceed. CONCLUSIONS: While gender may no longer be an overt issue in perceived performance of senior staff in transplantation, respondents' use of language and their choice of words display elements of unconscious (covert) engendered views.

A path integral methodology for obtaining thermodynamic properties of nonadiabatic systems using Gaussian mixture distributions.

We introduce a new path integral Monte Carlo method for investigating nonadiabatic systems in thermal equilibrium and demonstrate an approach to reducing stochastic error. We derive a general path integral expression for the partition function in a product basis of continuous nuclear and discrete electronic degrees of freedom without the use of any mapping schemes. We separate our Hamiltonian into a harmonic portion and a coupling portion; the partition function can then be calculated as the product of a Monte Carlo estimator (of the coupling contribution to the partition function) and a normalization factor (that is evaluated analytically). A Gaussian mixture model is used to evaluate the Monte Carlo estimator in a computationally efficient manner. Using two model systems, we demonstrate our approach to reduce the stochastic error associated with the Monte Carlo estimator. We show that the selection of the harmonic oscillators comprising the sampling distribution directly affects the efficiency of the method. Our results demonstrate that our path integral Monte Carlo method's deviation from exact Trotter calculations is dominated by the choice of the sampling distribution. By improving the sampling distribution, we can drastically reduce the stochastic error leading to lower computational cost.

Feasibility and effects of intra-dialytic low-frequency electrical muscle stimulation and cycle training: A pilot randomized controlled trial.

BACKGROUND AND OBJECTIVES: Exercise capacity is reduced in chronic kidney failure (CKF). Intra-dialytic cycling is beneficial, but comorbidity and fatigue can prevent this type of training. Low-frequency electrical muscle stimulation (LF-EMS) of the quadriceps and hamstrings elicits a cardiovascular training stimulus and may be a suitable alternative. The main objectives of this trial were to assess the feasibility and efficacy of intra-dialytic LF-EMS vs. cycling. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Assessor blind, parallel group, randomized controlled pilot study with sixty-four stable patients on maintenance hemodialysis. Participants were randomized to 10 weeks of 1) intra-dialytic cycling, 2) intra-dialytic LF-EMS, or 3) non-exercise control. Exercise was performed for up to one hour three times per week. Cycling workload was set at 40-60% oxygen uptake (VO2) reserve, and LF-EMS at maximum tolerable intensity. The control group did not complete any intra-dialytic exercise. Feasibility of intra-dialytic LF-EMS and cycling was the primary outcome, assessed by monitoring recruitment, retention and tolerability. At baseline and 10 weeks, secondary outcomes including cardio-respiratory reserve, muscle strength, and cardio-arterial structure and function were assessed. RESULTS: Fifty-one (of 64 randomized) participants completed the study (LF-EMS = 17 [77%], cycling = 16 [80%], control = 18 [82%]). Intra-dialytic LF-EMS and cycling were feasible and well tolerated (9% and 5% intolerance respectively, P = 0.9). At 10-weeks, cardio-respiratory reserve (VO2 peak) (Difference vs. control: LF-EMS +2.0 [95% CI, 0.3 to 3.7] ml.kg-1.min-1, P = 0.02, and cycling +3.0 [95% CI, 1.2 to 4.7] ml.kg-1.min-1, P = 0.001) and leg strength (Difference vs. control: LF-EMS, +94 [95% CI, 35.6 to 152.3] N, P = 0.002 and cycling, +65.1 [95% CI, 6.4 to 123.8] N, P = 0.002) were improved. Arterial structure and function were unaffected. CONCLUSIONS: Ten weeks of intra-dialytic LF-EMS or cycling improved cardio-respiratory reserve and muscular strength. For patients who are unable or unwilling to cycle during dialysis, LF-EMS is a feasible alternative.

Obstructive Sleep Apnea and Retinopathy in Patients with Type 2 Diabetes. A Longitudinal Study.

RATIONALE: Obstructive sleep apnea (OSA) is associated with several pathophysiological deficits found in diabetic retinopathy (DR). Hence, it's plausible that OSA could play a role in the pathogenesis of sight-threatening DR (STDR). OBJECTIVES: To assess the relationship between OSA and DR in patients with type 2 diabetes and to assess whether OSA is associated with its progression. METHODS: A longitudinal study was conducted in diabetes clinics within two U.K. hospitals. Patients known to have any respiratory disorder (including OSA) were excluded. DR was assessed using two-field 45-degree retinal images for each eye. OSA was assessed using a home-based multichannel cardiorespiratory device. MEASUREMENTS AND MAIN RESULTS: A total of 230 patients were included. STDR and OSA prevalence rates were 36.1% and 63.9%, respectively. STDR prevalence was higher in patients with OSA than in those without OSA (42.9% vs. 24.1%; P = 0.004). After adjustment for confounders, OSA remained independently associated with STDR (odds ratio, 2.3; 95% confidence interval, 1.1-4.9; P = 0.04). After a median (interquartile range) follow-up of 43.0 (37.0-51.0) months, patients with OSA were more likely than patients without OSA to develop preproliferative/proliferative DR (18.4% vs. 6.1%; P = 0.02). After adjustment for confounders, OSA remained an independent predictor of progression to preproliferative/proliferative DR (odds ratio, 5.2; 95% CI confidence interval, 1.2-23.0; P = 0.03). Patients who received continuous positive airway pressure treatment were significantly less likely to develop preproliferative/proliferative DR. CONCLUSIONS: OSA is associated with STDR in patients with type 2 diabetes. OSA is an independent predictor for the progression to preproliferative/proliferative DR. Continuous positive airway pressure treatment was associated with reduction in preproliferative/proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on STDR.

Prevalence and Associations of Obstructive Sleep Apnea in South Asians and White Europeans with Type 2 Diabetes: A Cross-Sectional Study.

STUDY OBJECTIVES: To assess and compare obstructive sleep apnea (OSA) prevalence in South Asians and White Europeans with type 2 diabetes mellitus (T2DM). Secondary aims included exploring possible causes for observed ethnic differences. METHODS: A cross-sectional study of patients with T2DM recruited from secondary care diabetes clinics. OSA was defined as an apnea-hypopnea index (AHI) ≥ 5 events/h using home-based, multi-channel respiratory monitoring. RESULTS: Two hundred thirty-four patients (105 South Asian and 129 White Europeans) were studied. The prevalence of mild, moderate, and severe OSA in South Asians was 36.2% (n = 38/105), 9.5% (n = 10/105), and 5.7% (n = 6/105) respectively. After adjustment, OSA was associated with a higher body mass index in South Asians. OSA was significantly less common in South Asians compared to White Europeans (51.4% [54/105] versus 75.2% [97/129], P < .001). OSA was also less severe in South Asians compared to White Europeans (median [interquartile range]: AHI 5.1 [1.4-11.5] versus 8.5 [5.0-20.7] events/h, P < .001; time spent with oxygen saturations < 90% 0.5 [0.0-2.9]% versus 4.0 [0.7-14.4]%, P < .001). Logistic regression showed that only obesity measures explained the ethnic differences in OSA. CONCLUSIONS: South Asians with T2DM are at considerable risk of OSA. OSA in South Asians was associated with obesity. However, OSA prevalence was lower in South Asians than in White Europeans. Obesity measures accounted for the observed ethnic differences. Examining factors contributing to ethnic differences will be important to inform screening and treatment strategies.

The relationship between obstructive sleep apnea and intra-epidermal nerve fiber density, PARP activation and foot ulceration in patients with type 2 diabetes.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased nitrosative stress, endothelial dysfunction, and peripheral neuropathy in patients with type 2 diabetes. We hypothesized that OSA is associated with Poly ADP ribose polymerase (PARP) activation, lower intra-epidermal nerve fiber density (IENFD), and diabetic foot ulceration (DFU). METHODS: A cross-sectional study of adults with type 2 diabetes recruited from a secondary care hospital in the UK. OSA was assessed by multi-channel home-based cardio-respiratory device (Alice PDX, Philips Respironics). DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). IENFD and % PAR stained nuclei were assessed using immunohistochemistry staining on skin biopsies. DFU was assessed based on MNSI. RESULTS: Skin biopsies and DFU data were available from 52 and 234 patients respectively. OSA was associated with lower IENFD (12.75±1.93 vs. 10.55±1.62 vs. 9.42±1.16 fibers/mm of epidermis for no OSA, mild OSA and moderate to severe OSA respectively, p<0.001). Following adjustment, mild (B=-2.19, p=0.002) and moderate to severe OSA (B=-3.45, p<0.001) were independently associated with IENFD. The apnea hypopnea index (AHI) was associated with IENFD following adjustment (B=-2.45, p<0.001). AHI was associated with percentage of PAR stained nuclei following adjustment (B=13.67, p=0.025). DFU prevalence was greater in patients with OSA (7.1% vs. 28.1% vs. 26.2% for patients with no OSA, mild OSA and moderate to severe OSA respectively, p=0.001). Following adjustment, OSA was associated with DFU (OR 3.34, 95% CI 1.19-9.38, p=0.022). CONCLUSIONS: OSA is associated with lower IENFD, PARP activation and DFU in patients with type 2 diabetes. Our findings suggest that OSA is associated with small fiber neuropathy. PARP activation is a potential mechanisms linking OSA to DPN and endothelial dysfunction in patients with type 2 diabetes. Whether OSA treatment will have a favorable impact on these parameters and DFU requires interventional studies.

Ethnic differences in health related quality of life for patients with type 2 diabetes.

BACKGROUND: The objective of this study was to investigate the association between ethnicity and health related quality of life (HRQoL) in patients with type 2 diabetes. METHODS: The EuroQol EQ-5D measure was administered to 1,978 patients with type 2 diabetes in the UK Asian Diabetes Study (UKADS): 1,486 of south Asian origin (Indian, Pakistani, Bangladeshi or other south Asian) and 492 of white European origin. Multivariate regression using ordinary least square (OLS), Tobit, fractional logit and Censored Least Absolutes Deviations estimators was used to estimate the impact of ethnicity on both visual analogue scale (VAS) and utility scores for the EuroQol EQ-5D. RESULTS: Mean EQ-5D VAS and utility scores were lower among south Asians with diabetes compared to the white European population; the unadjusted effect on the mean EQ-5D VAS score was -7.82 (Standard error [SE] = 1.06, p < 0.01) and on the EQ-5D utility score was -0.06 (SE = 0.02, p < 0.01) (OLS estimator). After controlling for socio-demographic and clinical confounders, the adjusted effect on the EQ-5D VAS score was -9.35 (SE = 2.46, p < 0.01) and on the EQ-5D utility score was 0.06 (SE = 0.04), although the latter was not statistically significant. CONCLUSIONS: There was a large and statistically significant association between south Asian ethnicity and lower EQ-5D VAS scores. In contrast, there was no significant difference in EQ-5D utility scores between the south Asian and white European sub-groups. Further research is needed to explain the differences in effects on subjective EQ-5D VAS scores and population-weighted EQ-5D utility scores in this context.

Cluster randomised controlled trial evaluation of a Link Worker-delivered intervention to improve uptake of diabetic retinopathy screening in a South Asian population.

Attendance at diabetic retinopathy screening in minority ethnic groups, including the South Asian population, is known to be poor. We describe a cluster randomised controlled trial conducted in 10 general practitioner (GP) surgeries in Coventry, UK, during 2007 which aimed to evaluate the use of a Link Worker-delivered intervention to improve attendance. The intervention consisted of a simple telephone reminder with the main outcome measure being attendance at diabetic retinopathy screening. We found a statistically significant difference between mean attendance proportions for intervention (0.89) and control (0.74) practices: difference (95% confidence interval (CI)) 0.15 (0.04-0.27), t = 3.03, p = 0.0162; this difference remained significant when adjusted for previous year's proportions. In this proof-of-concept study, in inner city Coventry, we demonstrated increased attendance at diabetic retinopathy screening by use of a simple Link Worker-implemented telephone call intervention. The use of Link Worker phone calls may be a useful tool to increase attendance for diabetic retinopathy screening in a group with high did-not-attend (DNA) rates and a high prevalence of diabetic retinopathy and visual impairment.

Evaluation of the clinical and cost effectiveness of intermediate care clinics for diabetes (ICCD): a multicentre cluster randomised controlled trial.

BACKGROUND: Configuring high quality care for the rapidly increasing number of people with type 2 diabetes (T2D) is a major challenge worldwide for both providers and commissioners. In the UK, about two thirds of people with T2D are managed entirely in primary care, with wide variation in management strategies and achievement of targets. Pay for performance, introduced in 2004, initially resulted in improvements but disparities exist in ethnic minorities and the improvements are levelling off. Community based, intermediate care clinics for diabetes (ICCDs) were considered one solution and are functioning across the UK. However, there is no randomised trial evidence for the effectiveness of such clinics. TRIAL DESIGN, METHODS AND FINDINGS: This is a cluster-randomised trial, involving 3 primary care trusts, with 49 general practices randomised to usual care (n=25) or intervention (ICCDs; n=24). All eligible adult patients with T2D were invited; 1997 were recruited and 1280 followed-up after 18-months intervention. PRIMARY OUTCOME: achievement of all three of the NICE targets [(HbA1c ≤ 7.0%/53 mmol/mol; Blood Pressure <140/80 mmHg; cholesterol <154 mg/dl (4 mmol/l)]. PRIMARY OUTCOME was achieved in 14.3% in the intervention arm vs. 9.3% in the control arm (p=0.059 after adjustment for covariates). The odds ratio (95% CI) for achieving primary outcome in the intervention group was 1.56 (0.98, 2.49). Primary care and community clinic costs were significantly higher in the intervention group, but there were no significant differences in hospital costs or overall healthcare costs. An incremental cost-effectiveness ratio (ICER) of +£7,778 per QALY gained, indicated ICCD was marginally more expensive at producing health gain. CONCLUSIONS: Intermediate care clinics can contribute to improving target achievement in patients with diabetes. Further work is needed to investigate the optimal scale and organisational structure of ICCD services and whether, over time, their role may change as skill levels in primary care increase. TRIAL REGISTRATION: ClinicalTrials.gov NCT00945204; National Research Register (NRR) M0014178167.

Elevated serum free light chains predict cardiovascular events in type 2 diabetes.

OBJECTIVE: Elevated polyclonal serum immunoglobulin free light chains (FLCs; combined FLCκ+FLCλ [cFLC]) are associated with adverse clinical outcomes and increased mortality; we investigated cFLC and cardiovascular disease (CVD) events in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort study of 352 south Asian patients with type 2 diabetes, serum cFLC, high-sensitivity C-reactive protein (hsCRP), and standard biochemistry were measured. CVD events over 2 years were recorded and assessed using multiple logistic regression. RESULTS: cFLC levels were elevated significantly in 29 of 352 (8%) patients with CVD events during 2 years of follow-up (50.7 vs. 42.8 mg/L; P = 0.004). In multivariate analysis, elevated cFLC (>57.2 mg/L) was associated with CVD outcomes (odds ratio 3.3 [95% CI 1.3-8.2]; P = 0.012) and remained significant after adjusting for age, albumin-to-creatinine ratio, diabetes duration, or treatment. CONCLUSIONS: cFLC elevation is a novel marker for CVD outcomes in type 2 diabetes that warrants further investigation.

Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study.

AIMS/HYPOTHESIS: The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. METHODS: We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR > 3.4 mg/mmol) or an estimated (eGFR) < 60 ml min(-1) 1.73 m(-2). CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability. RESULTS: Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (-9.0 ± 17.8% vs -3.3 ± 10.3%, p = 0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (ß = -3.5, p = 0.03). Spectral analysis variables were also independent predictors of eGFR decline. CONCLUSIONS/INTERPRETATION: CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.

Obstructive sleep apnea and diabetic nephropathy: a cohort study.

OBJECTIVE: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN. RESEARCH DESIGN AND METHODS: This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. DN progression was based on eGFR measurements. OSA was defined as apnea hypopnea index (AHI) ≥5 events/h. Serum nitrotyrosine abundance (a marker of nitrosative stress) was measured by ELISA. RESULTS: A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA-) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13-6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA- patients (median -6.8% [interquartile range -16.1 to 2.2] vs. -1.6% [-7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = -3.8, P = 0.044) and AHI (B = -4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = -0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment. CONCLUSIONS: OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed.

Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation.

BACKGROUND: HLA directed antibodies play an important role in acute and chronic allograft rejection. During viral infection of a patient with HLA antibodies, the HLA antibody levels may rise even though there is no new immunization with antigen. However it is not known whether the converse occurs, and whether changes on non-donor specific antibodies are associated with any outcomes following HLA antibody incompatible renal transplantation. METHODS: 55 patients, 31 women and 24 men, who underwent HLAi renal transplant in our center from September 2005 to September 2010 were included in the studies. We analysed the data using two different approaches, based on; i) DSA levels and ii) rejection episode post transplant. HLA antibody levels were measured during the early post transplant period and corresponding CMV, VZV and Anti-HBs IgG antibody levels and blood group IgG, IgM and IgA antibodies were quantified. RESULTS: Despite a significant DSA antibody rise no significant non-donor specific HLA antibody, viral or blood group antibody rise was found. In rejection episode analyses, multiple logistic regression modelling showed that change in the DSA was significantly associated with rejection (p = 0.002), even when adjusted for other antibody levels. No other antibody levels were predictive of rejection. Increase in DSA from pre treatment to a post transplant peak of 1000 was equivalent to an increased chance of rejection with an odds ratio of 1.47 (1.08, 2.00). CONCLUSION: In spite of increases or decreases in the DSA levels, there were no changes in the viral or the blood group antibodies in these patients. Thus the DSA rise is specific in contrast to the viral, blood group or third party antibodies post transplantation. Increases in the DSA post transplant in comparison to pre-treatment are strongly associated with occurrence of rejection.

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of intermediate care clinics for diabetes (ICCD): study protocol for a randomized controlled trial.

BACKGROUND: World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. METHODS/DESIGN: This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or CONTROL GROUP: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients. DISCUSSION: Forty-nine practices have been randomized, 1,997 patients have been recruited to the trial, and 20 patients have been recruited to the qualitative study. Results will be available late 2012. TRIAL REGISTRATION: [ClinicalTrials.gov: Identifier NCT00945204].