Optimizing design of research to evaluate antibiotic stewardship interventions: consensus recommendations of a multinational working group.

BACKGROUND: Antimicrobial stewardship interventions and programmes aim to ensure effective treatment while minimizing antimicrobial-associated harms including resistance. Practice in this vital area is undermined by the poor quality of research addressing both what specific antimicrobial use interventions are effective and how antimicrobial use improvement strategies can be implemented into practice. In 2016 we established a working party to identify the key design features that limit translation of existing research into practice and then to make recommendations for how future studies in this field should be optimally designed. The first part of this work has been published as a systematic review. Here we present the working group's final recommendations. METHODS: An international working group for design of antimicrobial stewardship intervention evaluations was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). The group comprised clinical and academic specialists in antimicrobial stewardship and clinical trial design from six European countries. Group members completed a structured questionnaire to establish the scope of work and key issues to develop ahead of a first face-to-face meeting that (a) identified the need for a comprehensive systematic review of study designs in the literature and (b) prioritized key areas where research design considerations restrict translation of findings into practice. The working group's initial outputs were reviewed by independent advisors and additional expertise was sought in specific clinical areas. At a second face-to-face meeting the working group developed a theoretical framework and specific recommendations to support optimal study design. These were finalized by the working group co-ordinators and agreed by all working group members. RESULTS: We propose a theoretical framework in which consideration of the intervention rationale the intervention setting, intervention features and the intervention aims inform selection and prioritization of outcome measures, whether the research sets out to determine superiority or non-inferiority of the intervention measured by its primary outcome(s), the most appropriate study design (e.g. experimental or quasi- experimental) and the detailed design features. We make 18 specific recommendation in three domains: outcomes, objectives and study design. CONCLUSIONS: Researchers, funders and practitioners will be able to draw on our recommendations to most efficiently evaluate antimicrobial stewardship interventions

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Sedimentary records of sewage pollution using faecal markers in contrasting peri-urban shallow lakes

Sewage contamination in shallow lake sediments is of concern because the pathogens, organic matter and nutrients contribute to the deterioration of the water-bodies' health and ecology. Sediment cores from three shallow lakes (Coneries, Church and Clifton Ponds) within Attenborough nature reserve located downstream of sewage treatment works were analysed for TOC, C/N, δ13C, δ15N, bacterial coliforms and faecal sterols. 210Pb and 137Cs activities were used to date the sediments. Elemental analysis suggests that the source of organic matter was algal and down profile changes in δ13C indicate a possible decrease in productivity with time which could be due to improvements in sewage treatment. δ15N for Coneries Pond are slightly higher than those observed in Church or Clifton and are consistent with a sewage-derived nitrate source which has been diluted by non-sewage sources of N. The similarity in δ15N values (+ 12‰ to + 10‰) indicates that the three ponds were not entirely hydrologically isolated. Analysis by gas chromatography/mass spectrometry (GC/MS) reveals that Coneries Pond had sterol concentrations in the range 20 to 30 μg/g (dry wt.), whereas, those from Clifton and Church Ponds were lower. The highest concentrations of the human-sourced sewage marker 5β-coprostanol were observed in the top 40 cm of Coneries Pond with values up to 2.2 μg/g. In contrast, Church and Clifton Pond sediments contain only trace amounts throughout. Down-profile comparison of 5β-coprostanol/cholesterol, 5β-coprostanol/(5β-coprostanol + 5α-cholestanol) and 5β-epicoprostanol/coprostanol as well as 5α-cholestanol/cholesterol suggests that Coneries Pond has received appreciable amounts of faecal contamination. Examination of 5β-stigmastanol (marker for herbivorous/ruminant animals) down core concentrations suggests a recent decrease in manure slurry input to Coneries Pond. The greater concentration of β-sitosterol in sediments from Church and Clifton Ponds as compared to Coneries is attributed in part to their greater diversity and extent of aquatic plants and avian faeces

A Novel Form of Ataxia Oculomotor Apraxia Characterized by Oxidative Stress and Aapoptosis Resistance

Several different autosomal recessive genetic disorders characterized by ataxia with oculomotor apraxia (AOA) have been identified with the unifying feature of defective DNA damage recognition and/or repair. We describe here the characterization of a novel form of AOA showing increased sensitivity to agents that cause single-strand breaks (SSBs) in DNA but having no gross defect in the repair of these breaks. Evidence for the presence of residual SSBs in DNA was provided by dramatically increased levels of poly (ADP-ribose)polymerase (PARP-1) auto-poly (ADP-ribosyl)ation, the detection of increased levels of reactive oxygen/nitrogen species (ROS/RNS) and oxidative damage to DNA in the patient cells. There was also evidence for oxidative damage to proteins and lipids. Although these cells were hypersensitive to DNA damaging agents, the mode of death was not by apoptosis. These cells were also resistant to TRAIL-induced death. Consistent with these observations, failure to observe a decrease in mitochondrial membrane potential, reduced cytochrome c release and defective apoptosis-inducing factor translocation to the nucleus was observed. Apoptosis resistance and PARP-1 hyperactivation were overcome by incubating the patient\u27s cells with antioxidants. These results provide evidence for a novel form of AOA characterized by sensitivity to DNA damaging agents, oxidative stress, PARP-1 hyperactivation but resistance to apoptosis