Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease:the STOP-ACEi trial

Background: Blood pressure (BP) control and reduction of urinary protein excretion using agents that block the renin–angiotensin aldosterone system are the mainstay of therapy for chronic kidney disease (CKD). Research has confirmed the benefits in mild CKD, but data on angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use in advanced CKD are lacking. In the STOP-ACEi trial, we aim to confirm preliminary findings which suggest that withdrawal of ACEi/ARB treatment can stabilize or even improve renal function in patients with advanced progressive CKD. Methods: The STOP-ACEi trial (trial registration: current controlled trials, ISRCTN62869767) is an investigator-led multicentre open-label, randomized controlled clinical trial of 410 participants with advanced (Stage 4 or 5) progressive CKD receiving ACEi, ARBs or both. Patients will be randomized in a 1:1 ratio to either discontinue ACEi, ARB or combination of both (experimental arm) or continue ACEi, ARB or combination of both (control arm). Patients will be followed up at 3 monthly intervals for 3 years. The primary outcome measure is eGFR at 3 years. Secondary outcome measures include the number of renal events, participant quality of life and physical functioning, hospitalization rates, BP and laboratory measures, including serum cystatin-C. Safety will be assessed to ensure that withdrawal of these treatments does not cause excess harm or increase mortality or cardiovascular events such as heart failure, myocardial infarction or stroke. Results: The rationale and trial design are presented here. The results of this trial will show whether discontinuation of ACEi/ARBs can improve or stabilize renal function in patients with advanced progressive CKD. It will show whether this simple intervention can improve laboratory and clinical outcomes, including progression to end-stage renal disease, without causing an increase in cardiovascular events

Conditional Ablation of Macrophages Halts Progression of Crescentic Glomerulonephritis

The presence of macrophages in inflamed glomeruli of rat kidney correlates with proliferation and apoptosis of resident glomerular mesangial cells. We assessed the contribution of inflammatory macrophages to progressive renal injury in murine crescentic glomerulonephritis (GN). Using a novel transgenic mouse (CD11b-DTR) in which tissue macrophages can be specifically and selectively ablated by minute injections of diphtheria toxin, we depleted renal inflammatory macrophages through days 15 and 20 of progressive crescentic GN. Macrophage depletion reduced the number of glomerular crescents, improved renal function, and reduced proteinuria. Morphometric analysis of renal tubules and interstitium revealed a marked attenuation of tubular injury that was associated with reduced proliferation and apoptosis of tubular cells. The population of interstitial myofibroblasts decreased after macrophage depletion and interstitial fibrosis also decreased. In the presence of macrophages, interstitial myofibroblasts exhibited increased levels of both proliferation and apoptosis, suggesting that macrophages act to support a population of renal myofibroblasts in a high turnover state and in matrix deposition. Finally, deletion of macrophages reduced CD4 T cells in the diseased kidney. This study demonstrates that macrophages are key effectors of disease progression in crescentic GN, acting to regulate parenchymal cell populations by modulating both cell proliferation and apoptosis

A brief guide to polymer characterization: structure (IUPAC technical report)

To bolster the series of Brief Guides released by International Union of Pure and Applied Chemistry (IUPAC), here we introduce the first Brief Guide to Polymer Characterization. This article provides a concise overview of characterization methods for teachers, students, non-specialists, and newcomers to polymer science as well as being a useful manual for researchers and technicians. Unlike pure low molar mass chemical substances, polymers are not composed of identical molecules. The macromolecules which comprise a single polymer sample vary from one another, primarily in terms of size and shape, but often also in the arrangement or positioning of atoms within macromolecules (e.g., chain branching, isomerism, etc.). Polymer properties are often drastically different from those of other substances and their characterization relies on specialist equipment and/or common equipment used in a specialized way (e.g., particular sample preparation or data analysis). This Brief Guide focuses uniquely on the structural characterization (i.e., analyzing the molecular and multi-molecular aspects) of polymers. The complex nature of the structural variables possible in macromolecular materials often presents a challenge with regard to the detailed structural characterization of polymers. This Brief Guide provides a useful starting point to direct the reader to the most commonly used and useful techniques to characterize these structural variables

Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ

The recently characterised 299-residue human XLF/Cernunnos protein plays a crucial role in DNA repair by non-homologous end joining (NHEJ) and interacts with the XRCC4–DNA Ligase IV complex. Here, we report the crystal structure of the XLF (1–233) homodimer at 2.3 Å resolution, confirming the predicted structural similarity to XRCC4. The XLF coiled-coil, however, is shorter than that of XRCC4 and undergoes an unexpected reverse in direction giving rise to a short distorted four helical bundle and a C-terminal helical structure wedged between the coiled-coil and head domain. The existence of a dimer as the major species is confirmed by size-exclusion chromatography, analytical ultracentrifugation, small-angle X-ray scattering and other biophysical methods. We show that the XLF structure is not easily compatible with a proposed XRCC4:XLF heterodimer. However, we demonstrate interactions between dimers of XLF and XRCC4 by surface plasmon resonance and analyse these in terms of surface properties, amino-acid conservation and mutations in immunodeficient patients. Our data are most consistent with head-to-head interactions in a 2:2:1 XRCC4:XLF:Ligase IV complex

MYC is a major determinant of mitotic cell fate

Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Surgical site infections after emergency hernia repair: substudy from the Management of Acutely Symptomatic Hernia (MASH) study

Introduction Acutely symptomatic abdominal wall and groin hernias (ASH) are a common acute surgical presentation. There are limited data to guide decisions related to surgical repair technique and use of antibiotics, which can be driven by increased risk of surgical site infection (SSI) in this group. This study aims to report rates of SSI following ASH repair and explore the use of patient-reported outcome measure reporting in this setting. Methods An 18-week, UK-based, multicentre prospective cohort study (NCT04197271) recruited adults with ASH. This study reports operatively managed patients. Data on patient characteristics, inpatient management, quality of life, complications, and wound healing (Bluebelle score) were collected. Descriptive analyses were performed to estimate event rates of SSI and regression analysis explored the relationship between Bluebelle scores and SSI. The 30 and 90-day follow-up visits assessed complications and quality of life. Results The MASH study recruited 273 patients, of whom 218 were eligible for this study, 87.2 per cent who underwent open repair. Mesh was used in 123 patients (50.8 per cent). Pre- and postoperative antibiotics were given in 163 (67.4 per cent) and 28 (11.5 per cent) patients respectively. There were 26 reported SSIs (11.9 per cent). Increased BMI, incisional, femoral, and umbilical hernia were associated with higher rates of SSI (P = 0.006). In 238 patients, there was a difference in healthy utility values at 90 days between patients with and without SSI (P = 0.025). Also, when analysing 191 patients with Bluebelle scores, those who developed an SSI had higher Bluebelle values (P < 0.001). Conclusion SSI is frequent in repair of acutely symptomatic hernia and correlates with BMI and site of hernia

Variation in postoperative outcomes of patients with intracranial tumors: insights from a prospective international cohort study during the COVID-19 pandemic

Background: This study assessed the international variation in surgical neuro-oncology practice and 30-day outcomes of patients who had surgery for an intracranial tumor during the COVID-19 pandemic. Methods: We prospectively included adults aged ≥18 years who underwent surgery for a malignant or benign intracranial tumor across 55 international hospitals from 26 countries. Each participating hospital recorded cases for 3 consecutive months from the start of the pandemic. We categorized patients’ location by World Bank income groups (high [HIC], upper-middle [UMIC], and low- and lower-middle [LLMIC]). Main outcomes were a change from routine management, SARS-CoV-2 infection, and 30-day mortality. We used a Bayesian multilevel logistic regression stratified by hospitals and adjusted for key confounders to estimate the association between income groups and mortality. Results: Among 1016 patients, the number of patients in each income group was 765 (75.3%) in HIC, 142 (14.0%) in UMIC, and 109 (10.7%) in LLMIC. The management of 200 (19.8%) patients changed from usual care, most commonly delayed surgery. Within 30 days after surgery, 14 (1.4%) patients had a COVID-19 diagnosis and 39 (3.8%) patients died. In the multivariable model, LLMIC was associated with increased mortality (odds ratio 2.83, 95% credible interval 1.37–5.74) compared to HIC. Conclusions: The first wave of the pandemic had a significant impact on surgical decision-making. While the incidence of SARS-CoV-2 infection within 30 days after surgery was low, there was a disparity in mortality between countries and this warrants further examination to identify any modifiable factors

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome