Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021.

People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.

Gapless Quantum Spin Liquid in the Triangular System Sr_{3}CuSb_{2}O_{9}.

We report gapless quantum spin liquid behavior in the layered triangular Sr_{3}CuSb_{2}O_{9} system. X-ray diffraction shows superlattice reflections associated with atomic site ordering into triangular Cu planes well separated by Sb planes. Muon spin relaxation measurements show that the S=1/2 moments at the magnetically active Cu sites remain dynamic down to 65 mK in spite of a large antiferromagnetic exchange scale evidenced by a large Curie-Weiss temperature θ_{CW}≃-143 K as extracted from the bulk susceptibility. Specific heat measurements also show no sign of long-range order down to 0.35 K. The magnetic specific heat (C_{m}) below 5 K reveals a C_{m}=γT+αT^{2} behavior. The significant T^{2} contribution to the magnetic specific heat invites a phenomenology in terms of the so-called Dirac spinon excitations with a linear dispersion. From the low-T specific heat data, we estimate the dominant exchange scale to be ∼36 K using a Dirac spin liquid ansatz which is not far from the values inferred from microscopic density functional theory calculations (∼45 K) as well as high-temperature susceptibility analysis (∼70 K). The linear specific heat coefficient is about 18 mJ/mol K^{2} which is somewhat larger than for typical Fermi liquids.

Hopping-Induced Ground-State Magnetism in 6H Perovskite Iridates.

Investigation of elementary excitations has advanced our understanding of many-body physics governing most physical properties of matter. Recently spin-orbit excitons have drawn much attention, whose condensates near phase transitions exhibit Higgs mode oscillations, a long-sought-after physical phenomenon [A. Jain, et al., Nat. Phys. 13, 633 (2017)NPAHAX1745-247310.1038/nphys4077]. These critical transition points, resulting from competing spin-orbit coupling (SOC), local crystalline symmetry, and exchange interactions, are not obvious in iridium-based materials, where SOC prevails in general. Here, we present results of resonant inelastic x-ray scattering on a spin-orbital liquid Ba_{3}ZnIr_{2}O_{9} and three other 6H-hexagonal perovskite iridates that show magnetism, contrary to the nonmagnetic singlet ground state expected due to strong SOC. Our results show that substantial hopping between closely placed Ir^{5+} ions within Ir_{2}O_{9} dimers in these 6H iridates modifies spin-orbit coupled states and reduces spin-orbit excitation energies. Here, we are forced to use at least a two-site model to match the excitation spectrum going in-line with the strong intradimer hopping. Apart from SOC, low-energy physics of iridates is thus critically dependent on hopping and may not be ignored even for systems having moderate hopping, where the excitation spectra can be explained using an atomic model. SOC, which is generally found to be 0.4-0.5 eV in iridates, is scaled in effect down to ∼0.26 eV for the 6H systems, sustaining the hope of achieving quantum criticality by tuning Ir-Ir separation.

Assessment of resistance to rice tungro disease in popular rice varieties in India by introgression of a transgene against Rice tungro bacilliform virus.

Rice crops in South and Southeast Asian countries suffer critical yield losses due to rice tungro disease caused by joint infection with rice tungro bacilliform virus (RTBV) and rice tungro spherical virus (RTSV). Previously, for generating RNA interference-based transgenic resistance against tungro viruses, RTBV ORF IV was used as a transgene to develop RTBV resistance in a popular high-yielding scented rice variety. The transgene from this line was then introgressed into five popular high-yielding but tungro-susceptible rice varieties by marker-assisted backcross breeding with a view to combine the resistant trait with the agronomic traits. The present work includes a resistance assay of the BC3F5 lines of these varieties under glasshouse conditions. Out of a total of 28 lines tested, each consisting of 12 individual plants, eight lines showed significant amelioration in height reduction and 100- to 1000-fold reduction in RTBV titers. The RNAi-mediated resistance was clearly manifested by the presence of virus-derived small RNA (vsRNA) specific for RTBV ORF IV in the transgenic backcrossed lines.

Natural History of Common Autologous Arteriovenous Fistulae: Consequences for Planning of Dialysis.

OBJECTIVES: The aim was to study primary failure, maturation times, and survival of common arteriovenous fistulae (AVF) to aid planning for vascular access, and to assess which strategy results in most dialysis days. METHODS: This was a longitudinal cohort study. Two databases of access operations and dialysis sessions over 9 years with 12-year follow-up were reviewed. Functional dialysis use is defined as achieving six consecutive dialysis sessions with two needles on AVF. Primary failure (PF) is failure to achieve functional dialysis use. Maturation time, calculated only for patients on dialysis with a central line at AVF operation, is defined from the operation date to the functional dialysis date. Cumulative patency, including PF, is calculated from the operation to date of AVF abandonment and is compared using Kaplan­Meier curves and adjusted hazard ratios (HRs). RESULTS: A total of 1206 AVF, 689 (57%) radiocephalic AVF (RCAVF), 383 (32%) brachiocephalic AVF (BCAVF), and 134 (11%) brachiobasilic AVF (BBAVF), were analysed. PF was 23%. PF was lower for BCAVF (17%) than RCAVF (26%) and BBAVF (26%) (p = .006). PF was higher for women (OR 1.59, 95% CI: 1.21­2.09) and patients with vascular kidney disease (OR 1.69, 95% CI: 1.19­2.59). Median maturation time was 10.3 weeks. Cumulative patency was worse for BCAVF (HR 1.36, 95% CI: 1.03­1.81) and BBAVF (HR 1.63 95% CI: 1.12­2.38), for patients on dialysis at AVF creation (HR 1.55, 95% CI: 1.13­2.12), and diabetics (HR 1.55, 95% CI: 1.12­1.85). RCAVFs resulted in 3% more dialysis-person-years (py) per 100 operations for all patients and in 15% more dialysis-py in the over 80s. CONCLUSION: RCAVFs have higher PF, but better survival than other AVF, and result in more dialysis time. AVF created pre-dialysis have better survival. An average maturation time of 10 weeks should be considered if planning to start dialysis on an AVF.

Evaluation of virus resistance and agronomic performance of rice cultivar ASD 16 after transfer of transgene against Rice tungro bacilliform virus by backcross breeding.

Severe losses of rice yield in south and southeast Asia are caused by Rice tungro disease (RTD) induced by mixed infection of Rice tungro bacilliform virus (RTBV) and Rice tungro spherical virus (RTSV). In order to develop transgene-based resistance against RTBV, one of its genes, ORF IV, was used to generate transgenic resistance based on RNA-interference in the easily transformed rice variety Pusa Basmati-1, and the transgene was subsequently introgressed to rice variety ASD 16, a variety popular in southern India, using transgene marker-assisted selection. Here, we report the evaluation of BC3F4 and BC3F5 generation rice plants for resistance to RTBV as well as for agronomic traits under glasshouse conditions. The BC3F4 and BC3F5 generation rice plants tested showed variable levels of resistance, which was manifested by an average of twofold amelioration in height reduction, 1.5-fold decrease in the reduction in chlorophyll content, and 100- to 10,000-fold reduction in the titers of RTBV, but no reduction of RTSV titers, in three backcrossed lines when compared with the ASD 16 parent. Agronomic traits of some of the backcrossed lines recorded substantial improvements when compared with the ASD 16 parental line after inoculation by RTBV and RTSV. This work represents an important step in transferring RTD resistance to a susceptible popular rice variety, hence enhancing its yield in areas threatened by the disease.

Phylogenetic analysis and biolistic infectivity of a cloned Sri Lankan cassava mosaic virus DNA-A from Tamil Nadu, India on Nicotiana benthamiana.

The complete nucleotide sequence of Sri Lankan cassava mosaic virus (SLCMV) DNA-A isolated from cassava in southern India was analyzed, a phylogenetic analysis with other begomoviral nucleotide sequences was performed and an efficient inoculation method of Nicotiana benthamiana with the cloned DNA was developed utilizing a biolistic device. The nucleotide sequence showed the conservation of all functional begomoviral protein domains and aligned most closely with begomoviruses reported from the Indian subcontinent, except for begomoviruses of cucurbits and legumes. Upon biolistic inoculation of N. benthamiana with the cloned DNA, most plants became symptomatic and showed the accumulation of viral DNA within 21-28 days post-inoculation.

Disordered magnetic ground state in a quasi-1-Dd4columnar iridate Sr3LiIrO6.

Spin-orbit coupling offers a large variety of novel and extraordinary magnetic and electronic properties in otherwise 'ordinary pool' of heavy ion oxides. Here we present a detailed study on an apparently isolated hexagonal 2Hspin-chaind4iridate Sr3LiIrO6with geometric frustration. Our structural studies reveal Li-Ir chemical order with desired stoichiometry in this compound, while x-ray absorption together with x-ray photoemission spectroscopic characterizations establish pure 5+ valence of Ir. We have established a magnetic ground state with finite Ir5+magnetic moments in this compound, contrary to the anticipated nonmagneticJeff= 0 state, through combined dc susceptibility,7Li nuclear magnetic resonance (NMR), muon spin relaxation (µSR) andab-initioelectronic structure studies. These investigations together with ac magnetic susceptibility and specific heat measurements reveal that despite having noticeable antiferromagnetic correlation among the Ir5+local moments, this system does not magnetically order down to at least 0.05 K, possibly due to geometrical exchange frustration, arising from the comparable nearest- and next-nearest-neighbor interchain Ir-O-O-Ir superexchange interaction strengths with opposite signs. However, the zero-fieldµSR analysis shows emergence of a considerable proportion of spin-freezing on top of a spin-fluctuating dynamic magnetic background down to the lowest measured temperature of 1.7 K, possibly due to some inhomogeneity and/or the much stronger intra-column Ir-Ir magnetic exchange interaction strength relative to the inter-column Ir-Ir ones. The linear temperature dependence of the magnetic specific heat (Cm) in both zero and applied magnetic fields, plus the power-law behavior of the NMR spin-lattice relaxation rate suggest a gapless spinon density of states in this charge gapped disordered magnetic ground state of Sr3LiIrO6.

Analysis of full-length sequences of two Citrus yellow mosaic badnavirus isolates infecting Citrus jambhiri (Rough Lemon) and Citrus sinensis L. Osbeck (Sweet Orange) from a nursery in India.

Citrus yellow mosaic badna virus (CMBV), a member of the Family Caulimoviridae, Genus Badnavirus is the causative agent of mosaic disease among Citrus species in southern India. Despite its reported prevalence in several citrus species, complete information on clear functional genomics or functional information of full-length genomes from all the CMBV isolates infecting citrus species are not available in publicly accessible databases. CMBV isolates from Rough Lemon and Sweet Orange collected from a nursery were cloned and sequenced. The analysis revealed high sequence homology of the two CMBV isolates with previously reported CMBV sequences implying that they represent new variants. Based on computational analysis of the predicted secondary structures, the possible functions of some CMBV proteins have been analyzed.

High glucose causes dysfunction of the human glomerular endothelial glycocalyx.

The endothelial glycocalyx is a gel-like layer which covers the luminal side of blood vessels. The glomerular endothelial cell (GEnC) glycocalyx is composed of proteoglycan core proteins, glycosaminoglycan (GAG) chains, and sialoglycoproteins and has been shown to contribute to the selective sieving action of the glomerular capillary wall. Damage to the systemic endothelial glycocalyx has recently been associated with the onset of albuminuria in diabetics. In this study, we analyze the effects of high glucose on the biochemical structure of the GEnC glycocalyx and quantify functional changes in its protein-restrictive action. We used conditionally immortalized human GEnC. Proteoglycans were analyzed by Western blotting and indirect immunofluorescence. Biosynthesis of GAG was analyzed by radiolabeling and quantified by anion exchange chromatography. FITC-albumin was used to analyze macromolecular passage across GEnC monolayers using an established in vitro model. We observed a marked reduction in the biosynthesis of GAG by the GEnC under high-glucose conditions. Further analysis confirmed specific reduction in heparan sulfate GAG. Expression of proteoglycan core proteins remained unchanged. There was also a significant increase in the passage of albumin across GEnC monolayers under high-glucose conditions without affecting interendothelial junctions. These results reproduce changes in GEnC barrier properties caused by enzymatic removal of heparan sulfate from the GEnC glycocalyx. They provide direct evidence of high glucose-induced alterations in the GEnC glycocalyx and demonstrate changes to its function as a protein-restrictive layer, thus implicating glycocalyx damage in the pathogenesis of proteinuria in diabetes.

Analysis of the complete DNA sequence of rice tungro bacilliform virus from southern India indicates it to be a product of recombination.

The complete nucleotide sequence of an isolate of rice tungro bacilliform virus (RTBV), collected from Kanyakumari, India, where RTBV was reported recently for the first time, has been analyzed. Sequence comparison revealed that the RTBV isolate from Kanyakumari (RTBV-KK) has a high degree of identity to the two previously reported RTBV sequences from India, RTBV-AP and RTBV-WB, which had been collected from field locations about 10 years ago and 1000-2000 km away from the collection site of RTBV-KK. Most of the sequence domains reported previously in other RTBV isolates were found to be conserved in RTBV-KK. Closer inspection revealed RTBV-KK to be a possible recombinant between RTBV-AP and RTBV-WB in the genomic region encompassing the coat protein gene.

Electronic structure of Na(2)CuP(2)O(7): a nearly 2D Heisenberg antiferromagnetic system.

We have employed first principles calculations to study the electronic structure and the implications for the magnetic properties of Na(2)CuP(2)O(7). Using the self-consistent tight-binding linearized muffin-tin orbital method and the Nth-order muffin-tin orbital downfolding method, we have calculated the various intrachain and interchain hopping parameters between the magnetic Cu(2+) ions. Our calculations for Na(2)CuP(2)O(7) reveal dominant intrachain hopping, but in contrast to the typical quantum spin chains the interchain hoppings are not negligible. The Wannier function plot of the Cu d(x(2)-y(2)) orbitals shows that the exchange interactions are primarily mediated by the oxygens and the distance between the oxygens in Na(2)CuP(2)O(7) is favorable for both intrachain and interchain interactions, suggesting the inapplicability of the one-dimensional Heisenberg model for this system, in agreement with recent experimental results.

"Benign" hypertensive nephrosclerosis.

BACKGROUND: Whether benign hypertensive nephrosclerosis (BHN) causes end-stage renal failure (ESRF) is controversial. One reason for this is the lack of biopsy evidence confirming the clinical diagnosis in most cases. AIM: To investigate whether biopsy-proven BHN leads to ESRF. DESIGN: Retrospective analysis. METHODS: We analysed all cases of biopsy-proven BHN from a single centre over a period of 20 years (n = 60), followed-up for a mean +/- SD 6.7 +/- 5.5 years. RESULTS: Patients were divided into those with stable renal function (n = 17) and those with declining function (n = 43). Mean eGFR at the time of biopsy was lower in the declining function group (29 +/- 3 vs. 44 +/- 4 ml/min/1.73 m(2), serum creatinine 280 +/- 165 vs. 161 +/- 89 mumol/l, p < 0.001), of whom 72% progressed to ESRF. Median renal survival for the whole group was 6.8 years, with 5- and 10-year survivals of 56% and 35%, respectively. Renal survival was significantly affected by initial serum creatinine, and mean systolic and diastolic blood pressures during follow-up period. Mean protein excretion was higher in the declining group, but not significantly so. On multivariate analysis, only diastolic blood pressure during follow-up predicted renal survival (p = 0.017). Median patient survival for the whole group was 9.95 years post renal biopsy, with 5- and 10-year survivals of 70% and 49% respectively. Survival was affected by initial serum creatinine, initial serum albumin and mean systolic blood pressure during follow-up. On multivariate analysis, only initial serum creatinine was significantly correlated with survival (p = 0.017). DISCUSSION: Biopsy-proven BHN led to ESRF in a high percentage of our patients, and was associated with significant mortality.

Insights into the control of geminiviral promoters.

Geminiviruses constitute one of the largest groups of plant viruses, having characteristic twinned geminate particles encapsidating small circular single-stranded DNA molecules. Geminiviral promoters are generally located within the intergenic region, although promoters have also been detected within the genes. Similarly, the geminivirus-associated betasatellite also harbours a promoter element for driving the expression of its only ORF. These regulatory elements of geminiviral and satellite origins have been subject of great interest to develop heterologous gene expression modules. Geminiviral promoter and regulatory elements show a complex regulation that is mediated by several host as well as viral proteins. Here, the structural and functional features of geminiviral and satellite promoters are discussed along with their regulation by plant and viral proteins. Although generalization in many cases is difficult and demands further studies, a pattern is seen to emerge on the regulation of the promoters.

First principles study of the electronic structure and magnetic properties of spin chain compounds: Ca3ZnMnO6 and Ca3ZnCoO6.

We have studied the electronic structure and magnetism of the spin chain compounds Ca3ZnMnO6 and Ca3ZnCoO6 using density functional theory with generalised gradient approximation (GGA). In agreement with experiment our calculations reveal that high spin (HS) state for Mn(4+) ion and low spin (LS) state for Co(4+) ion stabilize the magnetic structure of the respective compounds. The magnetic exchange paths, calculated using Nth order muffin-tin orbital downfolding method, shows dominant intra-chain exchange interaction between the magnetic ions (Mn, Co) is antiferromagnetic for Ca3ZnMnO6 and ferromagnetic for Ca3ZnCoO6. The magnetic order of both the compounds is in accordance with the Goodenough-Kanamori-Anderson rules and is consistent with the experimental results. Finally we have investigated the importance of spin-orbit coupling (SOC) in these compounds. While SOC practically has no effect for the Mn system, it is strong enough to favor the spin quantization along the chain direction for the Co system in the LS state.

Non-adherence to antihypertensive medication is very common among resistant hypertensives: results of a directly observed therapy clinic.

Resistant hypertension is common among the hypertensive population with reported prevalence of 12 to 15%. These patients have a higher cardiovascular risk and consequently a poorer cardiovascular prognosis. Suboptimal adherence with antihypertensive medication is a common contributing factor in apparent treatment-resistant hypertension. Patients were observed taking their medications under direct supervision at our directly observed therapy (DOT) clinic. At the DOT clinic visit, patients were fitted with a 24-h ambulatory blood pressure (ABP) monitor and each drug, at currently prescribed dose, was administered by a nurse; at an hourly interval and patient observed for 7 h. ABP readings between pre and post DOT clinic were compared. Fifty out of 56 patients had complete data on the ABP. Twenty four were female and the mean (s.d.) age was 62.0 (11.0) years. On the basis of the study methods that differentiated patients according to their BP response during the DOT clinic, twenty-five (50.0%) patients were deemed to be truly resistant (24-h ambulatory systolic blood pressure (SBP) fall <5 mm Hg) and the remaining 25 were deemed to have clinically significant non-adherence (24-h ambulatory SBP fall ⩾5 mm Hg) to prescribed therapy. In non-adherent patients, the mean 24-h ambulatory BP drop observed was 19.5/9.4 mm Hg (P<0.001 for both). Our results suggest that non-adherence is very common among patients considered to have apparent treatment-resistant hypertension. DOT clinic can be an effective method of identifying the truly resistant hypertensive patients.

Prevalence and determinants of white coat effect in a large UK hypertension clinic population.

White coat hypertension (WCH) is common and termed white coat effect (WCE) in those on treatment for hypertension. The UK guideline suggests that all patients in stage 1 and 2 hypertension, but not stage 3 hypertension, should have ambulatory blood pressure monitoring (ABPM) performed before commencing treatment. The relationship between office blood pressure (BP) and ABPM and the factors that influence the WCE were examined in a large British cohort (n=2056) from 2 hypertension clinics (1998-2011). Data were collected prospectively: the median age was 56 years: 53% were female, 76% Caucasian, 9% African Caribbean, 15% South Asian and 86% taking antihypertensives. Fifty-one percent had WCE and differences between clinic BP and ABPM measurements increased with the stage of hypertension varying from 2/4 (normotensive), 13/10 (stage 1 hypertension), 24/14 (stage 2) and 40/20 mm Hg (stage 3). The degree of difference is greater in this study than described in other populations. A positive correlation was found between clinic systolic and diastolic BP and the WCE (r=0.74 and r=0.56, respectively, P<0.0001). Significant (P<0.05) independent associations of systolic WCE were clinic systolic BP (ß=0.707), Caucasian ethnicity (South Asian ß=-0.06; African Caribbean ß=-0.043), female gender (male ß=-0.047), nonsmoking status (smoker ß=-0.100) and reduced renal function (estimated glomerular filtration rate ß=-0.036). Significant independent associations of diastolic WCH were clinic diastolic BP (ß=0.624), age (ß=0.207), female gender (male ß=-0.104), Caucasian ethnicity (South Asian ß=-0.052, African Caribbean ß=-0.079) and being a nonsmoker (ß=-0.082) or ex-smoker (ß=0.046). The results support current UK guidelines but suggest those with stage 3 hypertension would also benefit from ABPM.

Measurement of arterial stiffness in subjects with and without renal disease: Are changes in the vessel wall earlier and more sensitive markers of cardiovascular disease than intima media thickness and pulse pressure?

There is increased cardiovascular (CV) mortality in subjects with chronic kidney disease (CKD). Arterial stiffness in these subjects is increased when compared to a healthy population. Markers of arterial stiffness and intima media thickness (IMT) are predictors of CV mortality. The aim of this study was to investigate whether there is any difference in markers of arterial stiffness and IMT between subjects with normal renal function and those with mild renal disease. The arterial distension waveform, IMT, diameter, and brachial blood pressure were measured to calculate Young's modulus (E) and elastic modulus (Ep) in the common carotid arteries of subjects with normal kidney function (estimated glomerular filtration rate [eGFR] >90) and those mild CKD (stage 2, eGFR 89-60). Data were available for 15 patients with normal kidney function and 29 patients with mild CKD. The subjects with mild CKD were older, but other co-variables were not significantly different. Both arterial wall stiffness parameters (E and Ep), but not IMT were significantly higher in the mild CKD group. Logistic regression demonstrated that only the arterial wall stiffness parameters (Ep and E) were independently associated with mild renal disease compared with normal, in a model adjusting for sex, age and diabetes and history of cardiovascular disease (CVD). E and Ep may be early markers of CVD in subjects with mild CKD that may manifest change before other more recognized markers such as IMT and pulse pressure.