Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Acute pain in the prehospital setting: a register-based study of 41.241 patients

Abstract Background Acute pain is a frequent symptom, but little is known about the frequency and causes of acute pain in the prehospital population. The objectives of this study were to investigate the frequency of moderate to severe pain among prehospital patients and the underlying causes according to primary hospital diagnose codes. Methods This was a register-based study on 41.241 patients transported by ambulance. Information on moderate to severe pain [Numeric Rating Scale (NRS, 0–10) > 3 or moderate pain or higher on 4-point likert scale] was extracted from a national electronic prehospital patient record. Patient information was merged with primary hospital diagnose codes based on the 10th version of the International Classification of Diseases (ICD-10) to investigate underlying causes of pain. Results 11.430 patients (27.7%) reported moderate to severe pain during ambulance transport. As a measure of opioid demanding acute pain, 3.275 of 41.241 patients (7.9%) were treated with intravenous fentanyl. Underlying causes of pain were heterogenic according to ICD-10 chapters with injuries being the largest group of patients with moderate to severe pain (XIX: 42.8% of 8.041 patients), followed by non-specific diagnoses (XVIII: 28.5% of 7.101 patients and XXI: 31.6% of 5.148 patients), diseases of the circulatory system (IX: 22.1% of 4.812 patients) and other (20.3% of 16.139 miscellaneous patients). Discussion Due to the high frequency of moderate to severe pain affecting a wide range of patients, more attention on acute pain is necessary. Whether ambulance personnel have sufficient options for treating various pain conditions might be a subject of future evaluation. Non-specific diagnoses accounted for surprisingly many patients with moderate to severe pain, of which many were treated with intravenous fentanyl. This may be substance of further investigation. Conclusions Moderate to severe pain is a highly frequent and probably underestimated symptom among patients transported by ambulance. Underlying causes of pain are heterogenic as described by primary hospital diagnose codes. More focus on the treatment of acute pain is needed

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes