Transient expression analysis of promoters of okra enation leaf curl virus in Nicotiana benthamiana, cotton and okra plants.

Viral promoters can be used to drive heterologous gene expression in transgenic plants. As part of our quest to look for new promoters, we have explored, for the first time, the promoters of okra enation leaf curl virus (OELCuV), a begomovirus infecting okra (Abelmoschus esculentus). The Rep and CP promoters of OELCuV fused with the gfp reporter gene, were expressed transiently in the natural host okra and the laboratory host cotton and Nicotiana benthamiana. The expression levels of the promoters were quantified through confocal laser scanning microscopy and GFP assay in N. benthamiana and okra. The results indicated that the Rep promoter was more active than the CP promoter, whose activity was similar to that of CaMV 35S promoter. Additionally, the Rep and CP promoters showed increase of expression, probably due to transactivation, when assayed following inoculation of OELCuV and betasatellite DNAs in cotton plants. A moderate increase in promoter activity in N. benthamiana was also seen, when assayed following the inoculation of the heterologous begomovirus Sri Lankan cassava mosaic virus.

Comparison of outcomes on hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in anaemia associated with chronic kidney disease: network meta-analyses in dialysis and non-dialysis dependent populations.

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to current standard-of-care treatments for anaemia in chronic kidney disease (CKD). We conducted network meta-analyses to indirectly compare clinical outcomes for three HIF-PHIs in dialysis and non-dialysis populations with anaemia in CKD. Methods: The evidence base comprised phase III, randomised, controlled trials evaluating daprodustat, roxadustat, or vadadustat. Three outcomes were evaluated: efficacy [change from baseline in haemoglobin (Hgb)], cardiovascular safety [time to first major adverse cardiovascular event (MACE)] and quality of life [change from baseline in 36-Item Short Form Health Survey (SF-36) Vitality score]. Analyses were performed separately for all patients and for erythropoiesis-stimulating agent (ESA) non-users at baseline (non-dialysis population) or prevalent dialysis patients (dialysis population). Bayesian Markov Chain Monte Carlo methods with non-informative priors were used to estimate the posterior probability distribution and generate pairwise treatment comparisons. Point estimates (medians of posterior distributions) and 95% credible intervals (CrI) were calculated. Results: Seventeen trials were included. In non-dialysis patients, there were no clinically meaningful differences between the three HIF-PHIs with respect to Hgb change from baseline [all patients analysis (total n = 7907): daprodustat vs. roxadustat, 0.09 g/dL (95% CrI -0.14, 0.31); daprodustat vs. vadadustat, 0.09 g/dL (-0.04, 0.21); roxadustat vs. vadadustat, 0.00 g/dL (-0.22, 0.22)] or risk of MACE [all patients analysis (total n = 7959): daprodustat vs. roxadustat, hazard ratio (HR) 1.16 (95% CrI 0.76, 1.77); daprodustat vs. vadadustat, 0.88 (0.71, 1.09); roxadustat vs. vadadustat, 0.76 (0.50, 1.16)]. Daprodustat showed a greater increase in SF-36 Vitality compared with roxadustat [total n = 4880; treatment difference 4.70 points (95% CrI 0.08, 9.31)]. In dialysis patients, Hgb change from baseline was higher with daprodustat and roxadustat compared with vadadustat [all patients analysis (total n = 11 124): daprodustat, 0.34 g/dL (0.22, 0.45); roxadustat, 0.38 g/dL (0.27, 0.49)], while there were no clinically meaningful differences in the risk of MACE between the HIF-PHIs [all patients analysis (total n = 12 320): daprodustat vs. roxadustat, HR 0.89 (0.73, 1.08); daprodustat vs. vadadustat, HR 0.99 (0.82, 1.21); roxadustat vs. vadadustat, HR 1.12 (0.92, 1.37)]. Results were similar in analyses of ESA non-users and prevalent dialysis patients. Conclusions: In the setting of anaemia in CKD, indirect treatment comparisons suggest that daprodustat, roxadustat, and vadadustat are broadly clinically comparable in terms of efficacy and cardiovascular safety (precision was low for the latter), while daprodustat may be associated with reduction in fatigue to a greater extent than roxadustat.

P4 protein of an Indian isolate of rice tungro bacilliform virus modulates gene silencing.

Plant hosts and their viral pathogens are engaged in a constant cycle of defense and counter-defense as part of a molecular arms race, principal among them being the plant RNAi defense and the viral RNAi suppressor counter-defense. Rice tungro bacilliform virus (RTBV), member of the family Caulimoviridae, genus Tungrovirus, species Tungrovirus oryzae, infects rice in South- and Southeast Asia and causes severe symptoms of stunting, yellow-orange discoloration and twisting of leaf tips. To better understand the possible counter-defensive roles of RTBV against the host RNAi defense system, we explored the ability of the P4 protein of an Indian isolate of RTBV to act as a possible modulator of RNAi. Using a transient silencing and silencing suppression assay in Nicotiana benthamiana, we show that P4 not only displays an RNAi suppressor function, but also potentially enhances RNAi. The results also suggests that the N-terminal 168 amino acid residues of P4 are sufficient to maintain RNAi suppressor activity. Taken together with the earlier reports this work strengthens the view that the P4 protein carries out RNAi suppressor and a potential RNAi enhancer function.

Inequalities in the management of diabetic kidney disease in UK primary care: A cross-sectional analysis of a large primary care database.

AIMS: To determine differences in the management of diabetic kidney disease (DKD) relevant to patient sex, ethnicity and socio-economic group in UK primary care. METHODS: A cross-sectional analysis as of January 1, 2019 was undertaken using the IQVIA Medical Research Data dataset, to determine the proportion of people with DKD managed in accordance with national guidelines, stratified by demographics. Robust Poisson regression models were used to calculate adjusted risk ratios (aRR) adjusting for age, sex, ethnicity and social deprivation. RESULTS: Of the 2.3 million participants, 161,278 had type 1 or 2 diabetes, of which 32,905 had DKD. Of people with DKD, 60% had albumin creatinine ratio (ACR) measured, 64% achieved blood pressure (BP, <140/90 mmHg) target, 58% achieved glycosylated haemoglobin (HbA1c, <58 mmol/mol) target, 68% prescribed renin-angiotensin-aldosterone system (RAAS) inhibitor in the previous year. Compared to men, women were less likely to have creatinine: aRR 0.99 (95% CI 0.98-0.99), ACR: aRR 0.94 (0.92-0.96), BP: aRR 0.98 (0.97-0.99), HbA1c : aRR 0.99 (0.98-0.99) and serum cholesterol: aRR 0.97 (0.96-0.98) measured; achieve BP: aRR 0.95 (0.94-0.98) or total cholesterol (<5 mmol/L) targets: aRR 0.86 (0.84-0.87); or be prescribed RAAS inhibitors: aRR 0.92 (0.90-0.94) or statins: aRR 0.94 (0.92-0.95). Compared to the least deprived areas, people from the most deprived areas were less likely to have BP measurements: aRR 0.98 (0.96-0.99); achieve BP: aRR 0.91 (0.8-0.95) or HbA1c : aRR 0.88 (0.85-0.92) targets, or be prescribed RAAS inhibitors: aRR 0.91 (0.87-0.95). Compared to people of white ethnicity; those of black ethnicity were less likely to be prescribed statins aRR 0.91 (0.85-0.97). CONCLUSIONS: There are unmet needs and inequalities in the management of DKD in the UK. Addressing these could reduce the increasing human and societal cost of managing DKD.

Active Vitamin D Use and Fractures in Hemodialysis Patients: Results from the International DOPPS.

Active vitamin D is commonly used to control secondary hyperparathyroidism in dialysis patients, but it is unknown whether active vitamin D directly improves bone strength, independently of its ability to suppress parathyroid hormone (PTH). We analyzed the association between the prescription of active vitamin D and incidence of any fracture and hip fracture in 41,677 in-center hemodialysis patients from 21 countries in phases 3 to 6 (2005 to 2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS). We used Cox regression, adjusted for PTH and other potential confounders, and used a per-protocol approach to censor patients at treatment switch during follow-up. We also used a facility preference approach to minimize confounding by indication. Overall, 55% of patients were prescribed active vitamin D at study enrollment. Event rates (per patient-year) were 0.024 for any fracture and 0.010 for hip fracture. The adjusted hazard ratio (95% confidence interval) comparing patients prescribed versus not prescribed active vitamin D was 1.02 (0.90 to 1.17) for any fracture and 1.00 (0.81 to 1.23) for hip fracture. In the facility preference approach, there was no difference in fracture rate between facilities with higher versus lower active vitamin D prescriptions. Thus, our results do not suggest a PTH-independent benefit of active vitamin D in fracture prevention and support the current KDIGO guideline suggesting the use of active vitamin D only in subjects with elevated or rising PTH. Further research is needed to determine the role of active vitamin D beyond PTH control. © 2023 American Society for Bone and Mineral Research (ASBMR).

Do we practice what we preach? Dialysis modality choice among healthcare workers in the United Kingdom.

BACKGROUND: In the United Kingdom, over 80% of end-stage kidney disease patients receive in-center hemodialysis. We conducted a survey of UK renal healthcare workers on their preferred dialysis modality if they needed dialysis themselves. METHODS: An anonymized online survey was disseminated to all renal healthcare workers in the United Kingdom. We asked "Assume you are an otherwise well 40-year-old (and, separately, 75-year-old) person approaching end stage kidney disease, you have no living kidney donor options at present. There are no contraindications to any dialysis options. Which dialysis therapy would you choose?" We also asked about factors influencing their choice. RESULTS: 858 individuals with a median age of 44.3 years responded. 70.2% were female, 37.4% doctors, and 31.1% were senior nurses. There was a preference for peritoneal dialysis over in-center hemodialysis (50.47% v. 6.18%; p < 0.001 for 40-year-old and 49.18% v. 17.83%; p < 0.001 for 75-year-old assumption) and home hemodialysis (50.47% v. 39.28%; p < 0.001 for 40-year-old and 49.18% v. 18.41% for 75-year-old assumption). There was a preference for home hemodialysis over in-center hemodialysis for 40-year-old (39.28% v. 6.18%; p < 0.001) but not for 75-year-old. On logistic regression, senior doctors were more likely to opt for PD when compared to nurses. Nurses, allied healthcare professionals, and those of Asian/British Asian ethnicity were more likely to choose in-center hemodialysis. CONCLUSIONS: Most healthcare workers in renal medicine would choose home-based treatment for themselves although the majority of end-stage kidney disease patients receive in-center hemodialysis in the United Kingdom; the reasons for the discrepancy need to be explored.

Bio-impedance spectroscopy added to a fluid management protocol does not improve preservation of residual kidney function in incident hemodialysis patients in a randomized controlled trial.

Avoiding excessive dialysis-associated volume depletion may help preserve residual kidney function (RKF). To establish whether knowledge of the estimated normally hydrated weight from bioimpedance measurements (BI-NHW) when setting the post-hemodialysis target weight (TW) might mitigate rate of loss of RKF, we undertook an open label, randomized controlled trial in incident patients receiving HD, with clinicians and patients blinded to bioimpedance readings in controls. A total of 439 patients with over 500 ml urine/day or residual GFR exceeding 3 ml/min/1.73m2 were recruited from 34 United Kingdom centers and randomized 1:1, stratified by center. Fluid assessments were made for up to 24 months using a standardized proforma in both groups, supplemented by availability of BI-NHW in the intervention group. Primary outcome was time to anuria, analyzed using competing-risk survival models adjusted for baseline characteristics, by intention to treat. Secondary outcomes included rate of RKF decline (mean urea and creatinine clearance), blood pressure and patient-reported outcomes. There were no group differences in cause-specific hazard rates of anuria (0.751; 95% confidence interval (0.459, 1.229)) or sub-distribution hazard rates (0.742 (0.453, 1.215)). RKF decline was markedly slower than anticipated, pooled linear rates in year 1: -0.178 (-0.196, -0.159)), year 2: -0.061 (-0.086, -0.036)) ml/min/1.73m2/month. Blood pressure and patient-reported outcomes did not differ by group. The mean difference agreement between TW and BI-NHW was similar for both groups, Bioimpedance: -0.04 kg; Control: -0.25 kg. Thus, use of a standardized clinical protocol for fluid assessment when setting TW is associated with excellent preservation of RKF. Hence, bioimpedance measurements are not necessary to achieve this.

Narrative Review of Glycemic Management in People With Diabetes on Peritoneal Dialysis.

There is an increasing number of people with diabetes on peritoneal dialysis (PD) worldwide. However, there is a lack of guidelines and clinical recommendations for managing glucose control in people with diabetes on PD. The aim of this review is to provide a summary of the relevant literature and highlight key clinical considerations with practical aspects in the management of diabetes in people undergoing PD. A formal systematic review was not conducted because of the lack of sufficient and suitable clinical studies. A literature search was performed using PubMed, MEDLINE, Central, Google Scholar and ClinicalTrials.gov., from 1980 through February 2022. The search was limited to publications in English. This narrative review and related guidance have been developed jointly by diabetologists and nephrologists, who reviewed all available current global evidence regarding the management of diabetes in people on PD.We focus on the importance of individualized care for people with diabetes on PD, the burden of hypoglycemia, glycemic variability in the context of PD and treatment choices for optimizing glucose control. In this review, we have summarized the clinical considerations to guide and inform clinicians providing care for people with diabetes on PD.

Silencing suppressor protein PRT of rice tungro bacilliform virus interacts with the plant RNA silencing-related protein SGS3.

BACKGROUND: Rice tungro bacilliform virus (RTBV) is a double stranded DNA containing virus which causes the devastating tungro disease of rice in association with an RNA virus, rice tungro spherical virus. RNA silencing is an evolutionarily conserved antiviral defence pathway in plants as well as in several classes of higher organisms. Many viruses, in turn, encode proteins which are termed Viral Suppressor of RNA Silencing (VSR) because they downregulate or suppress RNA silencing. RESULTS: Using an RNA silencing suppressor assay we show that RTBV protease (PRT) acts as a mild VSR. A truncated version of PRT gene abolished the silencing suppression activity. We also show in planta interaction of PRT with the SGS3 protein of Solanum tuberosum and Arabidopsis thaliana using bimolecular fluorescence complementation assay (BIFC). Transient expression of PRT in Nicotiana benthamiana caused an increased accumulation of the begomovirus Sri Lankan cassava mosaic virus (SLCMV) DNA-A, which indicated a virulence function imparted on an unrelated virus. CONCLUSION: The finding supports the idea that PRT acts as suppressor of RNA silencing and this action may be mediated by its interaction with SGS3.

Geminiviral C4/AC4 proteins: An emerging component of the viral arsenal against plant defence.

Virus infection triggers a plethora of defence reactions in plants to incapacitate the intruder. Viruses, in turn, have added additional functions to their genes so that they acquire capabilities to neutralize the above defence reactions. In plant-infecting viruses, the family Geminiviridae comprises members, majority of whom encode 6-8 genes in their small single-stranded DNA genomes. Of the above genes, one which shows the most variability in its amino acid sequence is the C4/AC4. Recent studies have uncovered evidence, which point towards a wide repertoire of functions performed by C4/AC4 revealing its role as a major player in suppressing plant defence. This review summarizes the various plant defence mechanisms against viruses and highlights how C4/AC4 has evolved to counter most of them.

Serum Phosphorus Level Rises in US Hemodialysis Patients Over the Past Decade: A DOPPS Special Report.

Mineral bone disorder (MBD) is a frequent consequence of chronic kidney disease, more so in patients with kidney failure treated by kidney replacement therapy. Despite the wide availability of interventions to control serum phosphate and parathyroid hormone levels, unmet gaps remain on optimal targets and best practices, leading to international practice pattern variations over time. In this Special Report, we describe international trends from the Dialysis Outcomes and Practice Patterns Study (DOPPS) for MBD biomarkers and treatments from 2002-2021, including data from a group of 7 European countries (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom), Japan, and the United States. From 2002-2012, mean phosphate levels declined in Japan (5.6 to 5.2 mg/dL), Europe (5.5 to 4.9 mg/dL), and the United States (5.7 to 5.0 mg/dL). Since then, levels rose in the United States (to mean 5.6 mg/dL, 2021), were stable in Japan (5.3 mg/dL), and declined in Europe (4.8 mg/dL). In 2021, 52% (United States), 27% (Europe), and 39% (Japan) had phosphate >5.5 mg/dL. In the United States, overall phosphate binder use was stable (80%-84% over 2015-2021), and parathyroid hormone levels rose only modestly. Although these results potentially stem from pervasive knowledge gaps in clinical practice, the noteworthy steady increase in serum phosphate in the United States over the past decades may be consequential to patient outcomes, an uncertainty that hopefully will soon be addressed by ongoing clinical trials. The DOPPS will continue to monitor international trends as new interventions and strategies ensue for MBD management in chronic kidney disease.

Principles and practice of virus induced gene silencing for functional genomics in plants.

Virus induced gene silencing (VIGS) has, of late, emerged as an important tool for transient silencing of genes in plants. This is now being increasingly used to determine functions of novel genes in a wide variety of plants, many of which are important crops yielding food and fiber or are sources of products having pharmaceutical uses. The technology for VIGS comprises the development of vectors derived from viruses, choosing the optimal orientation and size of the gene to be targeted and adopting the most suitable method of inoculation. This review gives a brief overview of the main aspects of VIGS technology as is being practiced. It also discusses the challenges the technology faces and the possible way ahead to improve its robustness, so that the technology finds wider applications.

Acute kidney injury in critically ill COVID-19 infected patients requiring dialysis: experience from India and Pakistan.

BACKGROUND: Acute kidney injury (AKI) was common in the first two waves of the SARS-COV-2 pandemic in critically ill patients. A high percentage of these patients required renal replacement therapy and died in the hospital. METHODS: The present study examines the clinical presentation, laboratory parameters and therapeutic interventions in critically ill patients with AKI admitted to the ICU in two centres, one each in India and Pakistan. Patient and outcome details of all critically ill COVID 19 patients admitted to the ICU requiring renal replacement therapy were collected. Data was analysed to detect patient variables associated with mortality. RESULTS: A total of 1,714 critically ill patients were admitted to the ICUs of the two centres. Of these 393 (22.9%) had severe acute kidney injury (AKIN stage 3) requiring dialysis. Of them, 60.5% were men and the mean (± SD) age was 58.78 (± 14.4) years. At the time of initiation of dialysis, 346 patients (88%) were oligo-anuric. The most frequent dialysis modality in these patients was intermittent hemodialysis (48.1%) followed by slow low efficiency dialysis (44.5%). Two hundred and six (52.4%) patients died. The mortality was higher among the Indian cohort (68.1%) than the Pakistani cohort (43.4%). Older age (age > 50 years), low serum albumin altered sensorium, need for slower forms of renal replacement therapy and ventilatory support were independently associated with mortality. CONCLUSION: There was a very high mortality in patients with COVID-19 associated AKI undergoing RRT in the ICUs in this cohort from the Indian sub-continent.

Clinical characteristics do not reliably identify non-adherence in patients with uncontrolled hypertension.

PURPOSE: Chemical adherence testing is a reliable method to assess adherence to antihypertensive drugs. However, it is expensive and has limited availability in clinical practice. To reduce the number and costs of chemical adherence tests, we aimed to develop and validate a clinical screening tool to identify patients with a low probability of non-adherence in patients with uncontrolled hypertension. MATERIALS AND METHODS: In 495 patients with uncontrolled hypertension referred to the University Medical Centre Utrecht (UMCU), the Netherlands, a penalised logistic regression model including seven pre-specified easy-to-measure clinical variables was derived to estimate the probability of non-adherence. Non-adherence was defined as not detecting at least one of the prescribed antihypertensive drugs in plasma or urine. Model performance and test characteristics were evaluated in 240 patients with uncontrolled hypertension referred to the Heartlands Hospital, United Kingdom. RESULTS: Prevalence of non-adherence to antihypertensive drugs was 19% in the UMCU and 44% in the Heartlands Hospital population. After recalibration of the model's intercept, predicted probabilities agreed well with observed frequencies. The c-statistic of the model was 0.63 (95%CI 0.53-0.72). Predicted probability cut-off values of 15%-22.5% prevented testing in 5%-15% of the patients, carrying sensitivities between 97% (64-100) and 90% (80-95), and negative predictive values between 74% (10-99) and 70% (50-85). CONCLUSION: The combination of seven clinical variables is not sufficient to reliably discriminate adherent from non-adherent individuals to safely reduce the number of chemical adherence tests. This emphasises the complex nature of non-adherence behaviour and thus the need for objective chemical adherence tests in patients with uncontrolled hypertension.

Challenges of Conducting Clinical Trials during the SARS-CoV-2 Pandemic: The ASCEND Global Program Experience.

The coronavirus disease 2019 pandemic has had an unprecedented effect on health and health care and posed challenges to the conduct of clinical trials.Targeted mitigating strategies, on the basis of early and continued data collection from site surveys, limited disruption to the ASCEND trials.Flexibly allowing hemoglobin assessment at local laboratories to inform randomized treatment dosing was key to limiting the discontinuation of treatment.

Management of Hypertension in Patients With Diabetic Kidney Disease: Summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021.

Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here.

Characterization of the functional domains of nuclear shuttle protein (NSP) of Indian cassava mosaic virus using green fluorescent protein as reporter.

Indian cassava mosaic virus (ICMV), responsible for the cassava mosaic disease in India, harbours two circular genomic components, DNA-A and DNA-B; the former being responsible for the encapsidation and replication and the latter for intra- and inter-cellular movement of the viral DNA. Two proteins, encoded by DNA-B, the movement protein (MP) and the nuclear shuttle protein (NSP), act in concert on the newly replicated viral DNA to move it from the nucleus to the cell periphery. To map the functional domains of NSP, the intra-cellular localization of its full-length protein and deletion derivatives was studied in the epidermal cells of detached leaves of the laboratory host plant, Nicotiana benthamiana, where the target proteins were transiently expressed as GFP fusions. This analysis revealed domains for nuclear localization at the N-terminus, as well as for localization towards the cell periphery both at the C-terminus and center of the NSP.

RTBV-Based VIGS Vector for Functional Genomics in Rice: Methodology, Advances, Challenges, and Future Implications.

The availability of protocols for virus-induced gene silencing (VIGS) in rice has opened up an important channel for the elucidation of gene functions in this important crop plant. Here, we present an updated protocol of a VIGS system based on Rice tungro bacilliform virus (RTBV) for gene silencing in rice. We present complete updated protocols for VIGS in rice, compare the system with other existing ones for monocots, identify some of the challenges faced by this system and discuss ways in which the vector could be improved for better silencing efficiency.

CRISPR/Cas-Mediated Resistance against Viruses in Plants.

CRISPR/Cas9 provides a robust and widely adaptable system with enormous potential for genome editing directed towards generating useful products. It has been used extensively to generate resistance against viruses infecting plants with more effective and prolonged efficiency as compared with previous antiviral approaches, thus holding promise to alleviate crop losses. In this review, we have discussed the reports of CRISPR/Cas-based virus resistance strategies against plant viruses. These strategies include approaches targeting single or multiple genes (or non-coding region) in the viral genome and targeting host factors essential for virus propagation. In addition, the utilization of base editing has been discussed to generate transgene-free plants resistant to viruses. This review also compares the efficiencies of these approaches. Finally, we discuss combinatorial approaches, including multiplexing, to increase editing efficiency and bypass the generation of escape mutants.

Clinical practice guidelines for management of hyperglycaemia in adults with diabetic kidney disease.

A significant percentage of people with diabetes develop chronic kidney disease and diabetes is also a leading cause of end-stage kidney disease (ESKD). The term diabetic kidney disease (DKD) includes both diabetic nephropathy (DN) and diabetes mellitus and chronic kidney disease (DM CKD). DKD is associated with high morbidity and mortality, which are predominantly related to cardiovascular disease. Hyperglycaemia is a modifiable risk factor for cardiovascular complications and progression of DKD. Recent clinical trials of people with DKD have demonstrated improvement in clinical outcomes with sodium glucose co-transporter-2 (SGLT-2) inhibitors. SGLT-2 inhibitors have significantly reduced progression of DKD and onset of ESKD and these reno-protective effects are independent of glucose lowering. At the time of this update Canagliflozin and Dapagliflozin have been approved for delaying the progression of DKD. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have undertaken a literature review and critical appraisal of the available evidence to inform clinical practice guidelines for management of hyperglycaemia in adults with DKD. This 2021 guidance is for the variety of clinicians who treat people with DKD, including GPs and specialists in diabetes, cardiology and nephrology.