Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Comparison of Malated Ringer’s with Two Other Balanced Crystalloid Solutions in Resuscitation of Both Severe and Moderate Hemorrhagic Shock in Rats

In preclinical treatment of polytraumatized patients crystalloids are preferentially used. To avoid metabolic acidosis, metabolizable anions like lactate or acetate are used to replace chloride in these solutions. We here studied the effects of malated Ringer’s in resuscitation of both shock severities in comparison to lactated and acetated Ringer’s. Male Wistar rats underwent severe (mean arterial blood pressure (MAP) of 25–30 mmHg) or moderate (MAP 40–45 mmHg) hemorrhagic shock. Adjacent to the shock period animals were resuscitated with acetated (AR), lactated (LR), or malated Ringer’s (MR) and observed for 150 min. MR improved survival compared with LR and AR in severe hemorrhagic shock whereas it was equally effective to LR and superior to AR in moderate hemorrhagic shock. In all other parameters tested, MR was also effective similar to the other solutions under these conditions. We conclude that MR is preferable to AR and LR in resuscitation of hemorrhagic shock independent of shock depth. The positive effects of MR may stem from the absence of any adverse impact on energy metabolism under both conditions

Gender-specific differences in severely injured patients between 2002 and 2011: data analysis with matched-pair analysis

INTRODUCTION: Previous studies reported divergent results concerning the effect of gender on patient outcome after severe injury. Results suggest that women have better outcomes because they have lower rates of sepsis and multi-organ failure. The objective of this analysis was to study gender differences in a Level 1 trauma center in Germany. METHODS: Patients who were admitted to hospital between 2002 and 2011 with an Injury Severity Score (ISS) ≥16 were included. Data were collected from the Trauma Registry of the German Society for Trauma Surgery and from hospital records. The effects of gender on a variety of parameters were investigated. To eliminate the influence of differences in ISS, an analysis of groups with similar ISS was performed. Also, a matched-pair analysis of 422 patients was performed. RESULTS: A total of 962 patients met the inclusion criteria. The mortality rate was lower in male patients (25.4% versus 36.59%). Female patients had more severe head injuries, received less fluid volume and had a lower rate of sepsis. Men were more frequently involved in motorcycle accidents and sustained more penetrating trauma. Women were more frequently involved in pedestrian accidents and sustained more falls from under 3 m. The effects of gender were reduced when the data were analyzed by matching ISS. The mortality rate was significantly different in the ISS 26 to 35 group but in mostly all groups, the mortality rate was higher in women. In the matched-pair analysis, the rate of sepsis and the length of the ICU stay were significantly lower in women and the mortality rate showed no significant difference (28.1% for male patients versus 33.01% for female patients). Women died after an average of 5.22 days, and men died after an average of 9.02 days. CONCLUSIONS: Gender-based differences in patient outcome after severe trauma were observed in this study. Women are more likely to die in the first days after trauma. Upon extended hospital stay, women had a better survival rate because they had a lower rate of sepsis. No significant differences in mortality rate could be found, but there was a trend towards a higher rate in female patients

Prehospital Volume Therapy as an Independent Risk Factor after Trauma

Background. Prehospital volume therapy remains widely used after trauma, while evidence regarding its disadvantages is growing. The primary objective of this study was to investigate the volume administered in a prehospital setting as an independent risk factor for mortality. Material and Methods. Patients who met the following criteria were analyzed retrospectively: Injury Severity Score = 16, primary admission (between 2002 and 2010), and age = 16 years. The following data had to be available: volume administered (including packed red cells), blood pressure, Glasgow Coma Scale, therapeutic measures, and laboratory results. Following a univariate analysis, independent risk factors for mortality after trauma were investigated using a multivariate regression analysis. Results. A collective of 7,641 patients met the inclusion criteria, showing that increasing volumes administered in a prehospital setting were an independent risk factor for mortality (odds ratio: 1.34). This tendency was even more pronounced in patients without severe traumatic brain injury (TBI) (odds ratio: 2.71), while the opposite tendency was observed in patients with TBI. Conclusions. Prehospital volume therapy in patients without severe TBI represents an independent risk factor for mortality. In such cases, respiratory and circulatory conditions should be stabilized during permissive hypotension, and patient transfer should not be delayed

Evaluation of Storage Tubes for Combined Analysis of Circulating Nucleic Acids in Liquid Biopsies

In the last decade, circulating nucleic acids such as microRNAs (miRNAs) and cell-free DNA (cfDNA) have become increasingly important in serving as potential novel biomarkers for a variety of human diseases. If cell-free nucleic acids are to become routinely used in diagnostics, the difference in plasma miRNA and cfDNA levels between healthy and diseased subjects must exceed pre-analytical and analytical variability. Until now, few studies have addressed the time limitations of pre-processing or explored the potential use of long-term blood storage tubes, which might need to be implemented in real-life diagnostics. In this study, we analyzed the stability of four breast cancer-associated miRNAs and two cancer-associated genes under various storage conditions, to test their limitations for potential application in clinical diagnostics. In two consecutive experiments, we tested the limits of conventional EDTA tubes, as well as long-term storage blood collection tubes (BCTs) from four different manufacturers. We found that circulating miRNAs are relatively stable when stored in EDTA monovettes for up to 12 h before processing. When stored in BCTs, circulating miRNAs and cfDNA are stable for up to 7 days, depending on the manufacturer. Norgen tubes were superior for cfDNA yield, while Streck tubes performed the worst in our study with hemolysis induction. In conclusion, plasma prepared from whole blood is suitable for the quantification of both cf-miRNAs and cfDNA simultaneously

Acute cardiac side effects after COVID-19 mRNA vaccination:a case series

BACKGROUND: Vaccination against SARS-CoV-2 has been the main tool to contain the pandemic. The rush development of the 3 vaccines and their expedited approval have led to inoculation of millions of patients around the world, leading to a containment of the disease. Despite continuous viral mutations and the identification of weaker variants, the severity of the infections has been mild, with many patients being either asymptomatic or recovering at home. Currently the focus has shifted from the host of organ damage related to the infection to potential side effects of the vaccine. Myocarditis has been reported as one of the potential side effects from the mRNA vaccine, affecting young healthy individuals. Up to September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty© were registered in young adults by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty© or mRNA-1237 Moderna, Spikevax©). PATIENTS AND METHODS: Eight patients between 13 and 56 years of age, vaccinated with either BNT162b2 or mRNA-1273 mRNA vaccine between January and August 2021 developed cardiac side effects shortly after either their first or second dose of the vaccine. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after the onset of symptoms, with further investigations in severe cases. Symptoms were defined as dyspnea, chest pain and cardiac arrhythmia as determined by electrocardiography. RESULTS: Eight patients (5 males and 3 females) developed cardiac symptoms compatible with myocarditis, according to the CDC criteria, shortly after SARS-CoV-2 mRNA vaccination. Three patients (2 males, 1 female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within 7 days from the symptom onset. CONCLUSIONS: Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health