What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A systematic review and meta-analysis.

OBJECTIVES: To summarise evidence on temporary discontinuation of medications to prevent acute kidney injury (AKI). DESIGN: Systematic review and meta-analysis of randomised and non-randomised studies. PARTICIPANTS: Adults taking diuretics, ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), direct renin inhibitors, non-steroidal anti-inflammatories, metformin or sulfonylureas, experiencing intercurrent illnesses, radiological or surgical procedures. INTERVENTIONS: Temporary discontinuation of any of the medications of interest. PRIMARY AND SECONDARY OUTCOME MEASURES: Risk of AKI. Secondary outcome measures were estimated glomerular filtration rate and creatinine post-AKI, urea, systolic and diastolic blood pressure, death, clinical outcomes and biomarkers. RESULTS: 6 studies were included (1663 participants), 3 randomised controlled trials (RCTs) and 3 prospective cohort studies. The mean age ranged from 65 to 73 years, and the proportion of women ranged from 31% to 52%. All studies were in hospital settings; 5 evaluated discontinuation of medication prior to coronary angiography and 1 prior to cardiac surgery. 5 studies evaluated discontinuation of ACEI and ARBs and 1 small cohort study looked at discontinuation of non-steroidal anti-inflammatory drugs. No studies evaluated discontinuation of medication in the community following an acute intercurrent illness. There was an increased risk of AKI of around 15% in those in whom medication was continued compared with those in whom it was discontinued (relative risk (RR) 1.17, 95% CI 0.99 to 1.38; 5 studies). When only results from RCTs were pooled, the increase in risk was almost 50% (RR 1.48, 95% CI 0.84 to 2.60; 3 RCTs), but the CI was wider. There was no difference between groups for any secondary outcomes. CONCLUSIONS: There is low-quality evidence that withdrawal of ACEI/ARBs prior to coronary angiography and cardiac surgery may reduce the incidence of AKI. There is no evidence of the impact of drug cessation interventions on AKI incidence during intercurrent illness in primary or secondary care. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015023210

Screening for steroid sulfatase (STS) gene deletions by multiplex DNA amplification

Deletions are the most common molecular defect in steroid sulfatase (STS) deficiency. We describe the application of multiplex DNA amplification, by polymerase chain reaction, for deletion screening in patients with STS deficiency (STS-PCR). Genomic DNA from 38 unrelated patients was amplified using two sets of primers, corresponding to the 5′ and the 3′ ends of the STS gene. The analysis of the amplified products was always consistent with the results obtained by Southern analysis. This method represents a sensitive fast non-radioactive test for detecting STS gene deletions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47626/1/439_2004_Article_BF00210812.pd

Symptom clusters in chronic kidney disease and their association with people’s ability to perform usual activities

© 2022 Moore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/Background: People living with a long-term condition, such as chronic kidney disease (CKD), often suffer from multiple symptoms simultaneously, making symptom management challenging. This study aimed to identify symptom clusters in adults with CKD across treatment groups and investigate their association with people’s ability to perform their usual activities.  Methods: We conducted a secondary analysis of both cross-sectional and longitudinal data collected as part of a national service improvement programme in 14 kidney centres in England, UK. This data included symptom severity (17 items, POS-S Renal) and the extent to which people had problems performing their usual activities (single item, EQ-5D-5L). We categorised data by treatment group: haemodialysis (n = 1,462), transplantation (n = 866), peritoneal dialysis (n = 127), or CKD without kidney replacement therapy (CKD non-KRT; n = 684). We used principal component analysis to identify symptom clusters per treatment group, and proportional odds models to assess the association between clusters and usual activities.  Results: Overall, clusters related to: lack of energy and mobility; gastrointestinal; skin; and mental health. Across groups, the ‘lack of energy and mobility’ clusters were associated with having problems with usual activities, with odds ratios (OR) ranging between 1.24 (95% confidence interval [CI], 1.21–1.57) for haemodialysis and 1.56 for peritoneal dialysis (95% CI, 1.28–1.90). This association was confirmed longitudinally in haemodialysis (n = 399) and transplant (n = 249) subgroups. Implications: Our findings suggest that healthcare professionals should consider routinely assessing symptoms in the ‘lack of energy & mobility’ cluster in all people with CKD, regardless of whether they volunteer this information; not addressing these symptoms is likely to be related to them having problems with performing usual activities. Future studies should explore why symptoms within clusters commonly co-occur and how they interrelate. This will inform the development of cluster-level symptom management interventions with enhanced potential to improve outcomes for people with CKD.Peer reviewedFinal Published versio

Evolution of Nanoscale Pore Structure in Coordination Polymers During Thermal and Chemical Exposure Revealed by Positron Annihilation

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71372/1/1598_ftp.pd

Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy.

Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease\u27s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D. Nat Commun 2018 Mar 8; 9(1):1007

Improving risk prediction model quality in the critically ill:data linkage study

Background: A previous National Institute for Health and Care Research study [Harrison DA, Ferrando-Vivas P, Shahin J, Rowan KM. Ensuring comparisons of health-care providers are fair: development and validation of risk prediction models for critically ill patients. Health Serv Deliv Res 2015;3(41)] identified the need for more research to understand risk factors and consequences of critical care and subsequent outcomes. Objectives: First, to improve risk models for adult general critical care by developing models for mortality at fixed time points and time-to-event outcomes, end-stage renal disease, type 2 diabetes, health-care utilisation and costs. Second, to improve risk models for cardiothoracic critical care by enhancing risk factor data and developing models for longer-term mortality. Third, to improve risk models for in-hospital cardiac arrest by enhancing risk factor data and developing models for longer-term mortality and critical care utilisation. Design: Risk modelling study linking existing data. Setting: NHS adult critical care units and acute hospitals in England. Participants: Patients admitted to an adult critical care unit or experiencing an in-hospital cardiac arrest. Interventions: None. Main outcome measures: Mortality at hospital discharge, 30 days, 90 days and 1 year following critical care unit admission; mortality at 1 year following discharge from acute hospital; new diagnosis of end-stage renal disease or type 2 diabetes; hospital resource use and costs; return of spontaneous circulation sustained for > 20 minutes; survival to hospital discharge and 1 year; and length of stay in critical care following in-hospital cardiac arrest. Data sources: Case Mix Programme, National Cardiac Arrest Audit, UK Renal Registry, National Diabetes Audit, National Adult Cardiac Surgery Audit, Hospital Episode Statistics and Office for National Statistics. Results: Data were linked for 965,576 critical care admissions between 1 April 2009 and 31 March 2016, and 83,939 in-hospital cardiac arrests between 1 April 2011 and 31 March 2016. For admissions to adult critical care units, models for 30-day mortality had similar predictors and performance to those for hospital mortality and did not reduce heterogeneity. Models for longer-term outcomes reflected increasing importance of chronic over acute predictors. New models for end-stage renal disease and diabetes will allow benchmarking of critical care units against these important outcomes and identification of patients requiring enhanced follow-up. The strongest predictors of health-care costs were prior hospitalisation, prior dependency and chronic conditions. Adding pre- and intra-operative risk factors to models for cardiothoracic critical care gave little improvement in performance. Adding comorbidities to models for in-hospital cardiac arrest provided modest improvements but were of greater importance for longer-term outcomes. Limitations: Delays in obtaining linked data resulted in the data used being 5 years old at the point of publication: models will already require recalibration. Conclusions: Data linkage provided enhancements to the risk models underpinning national clinical audits in the form of additional predictors and novel outcomes measures. The new models developed in this report may assist in providing objective estimates of potential outcomes to patients and their families. Future work: (1) Develop and test care pathways for recovery following critical illness targeted at those with the greatest need; (2) explore other relevant data sources for longer-term outcomes; (3) widen data linkage for resource use and costs to primary care, outpatient and emergency department data

Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies

Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal IgGs and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1^A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4Å cryo-EM structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses and that characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies

1967: Abilene Christian College Bible Lectures - Full Text

LIFTING UP THE CHRIST” Being the Abilene Christian College Annual Bible Lectures 1967 $3.95 Published by ABILENE CHRISTIAN COLLEGE STUDENTS EXCHANGE ACC Station Abilene, Texa

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756