The non-linear Schr\"odinger equation and the conformal properties of non-relativistic space-time

The cubic non-linear Schr\"odinger equation where the coefficient of the nonlinear term is a function $F(t,x)$ only passes the Painlev\'e test of Weiss, Tabor, and Carnevale only for $F=(a+bt)^{-1}$, where $a$ and $b$ are constants. This is explained by transforming the time-dependent system into the constant-coefficient NLS by means of a time-dependent non-linear transformation, related to the conformal properties of non-relativistic space-time. A similar argument explains the integrability of the NLS in a uniform force field or in an oscillator background.Comment: Thoroughly revised version, in the light of new interest in non-relativistic conformal tranformation, with a new reference list. 8 pages, LaTex, no figures. To be published in Int. J. Theor. Phy

Prioritising research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team, organisation and policy levels, evidence from the behavioural sciences is underutilised in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimising effective implementation of ASPs in hospital settings, using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four high-income countries with publicly-funded health care systems (that is Canada, Germany, Norway and the UK), met face-to-face to agree on broad research priority areas using a structured consensus method. QUESTION ADDRESSED AND RECOMMENDATIONS: The consensus process on the 10 identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimise effective implementation of antibiotic stewardship programmes for hospital inpatients in HICs with publicly-funded health care systems. We suggest and detail, behavioural science evidence-guided research efforts in the following areas: 1) Comprehensively identifying barriers and facilitators to implementing antibiotic stewardship programmes and clinical recommendations intended to optimise antibiotic prescribing; 2) Identifying actors ('who') and actions ('what needs to be done') of antibiotic stewardship programmes and clinical teams; 3) Synthesising available evidence to support future research and planning for antibiotic stewardship programmes; 4) Specifying the activities in current antibiotic stewardship programmes with the purpose of defining a 'control group' for comparison with new initiatives; 5) Defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; 6) Conducting robust evaluations of antibiotic stewardship programmes with built-in process evaluations and fidelity assessments; 7) Defining and designing antibiotic stewardship programmes; 8) Establishing the evidence base for impact of antibiotic stewardship programmes on resistance; 9) Investigating the role and impact of government and policy contexts on antibiotic stewardship programmes; and 10) Understanding what matters to patients in antibiotic stewardship programmes in hospitals. Assessment, revisions and updates of our priority-setting exercise should be considered, at intervals of 2 years. To propose research priority areas in low- and medium income countries (LIMCs), the methodology reported here could be applied

Dentists’ perspectives on selective caries removal for the management of deep carious lesions in permanent teeth

Background To explore the views of dentists participating in the Selective Caries Removal in Permanent Teeth (SCRiPT) randomised controlled clinical trial on selective caries removal versus complete or near complete caries removal for the management of deep carious lesions. Methods Nineteen semi-structured one-to-one telephone or online video interviews were conducted with dentists involved in SCRiPT, using an interview guide informed by the Theoretical Domains Framework (TDF). Data were initially analysed deductively using a framework informed by the TDF, and subsequently using reflexive thematic analysis. Results Three themes and 25 sub-themes were generated. Themes were ‘comfort using selective caries removal’, ‘potential value of SCRiPT’ and ‘challenges of subjectivity’. Sub-themes included six enablers and five barriers to the use of selective caries removal, as well as five contextual factors potentially impacting dentists’ decision-making. The SCRiPT trial was found to have potential value in terms of ‘overcoming uncertainty’, although perceived limitations were noted. The potential value of SCRiPT may depend on other factors, including the willingness of dentists to follow evidence from the trial (reflecting personal attributes and comfort with selective caries removal). The interviews also highlighted how caries removal is perceived as subjective and involves the application of clinical judgement to individual cases. General dental practitioners who are less comfortable with selective caries removal may not start to use this approach as defined within SCRiPT, particularly if there is a lack of strong evidence from the trial. Conclusions Dentists’ level of comfort with selective caries removal is multi-faceted and informed by contextual factors. SCRiPT has the potential to increase acceptance of selective caries removal, but the findings may not be interpreted in this way. Future work should further explore the concept of comfort with selective caries removal, using the thematic framework outlined here to inform the design of interview topic guides. Trial registration Trial registry: ISRCTN. Trial registration number: ISRCTN76503940. Date of Registration: 30.10.2019

Selective Caries Removal in Permanent Teeth (SCRiPT) for the treatment of deep carious lesions : a randomised controlled clinical trial in primary care

Background Dental caries is one of the most prevalent non-communicable disease globally and can have serious health sequelae impacting negatively on quality of life. In the UK most adults experience dental caries during their lifetime and the 2009 Adult Dental Health Survey reported that 85% of adults have at least one dental restoration. Conservative removal of tooth tissue for both primary and secondary caries reduces the risk of failure due to tooth-restoration, complex fracture as well as remaining tooth surfaces being less vulnerable to further caries. However, despite its prevalence there is no consensus on how much caries to remove prior to placing a restoration to achieve optimal outcomes. Evidence for selective compared to complete or near-complete caries removal suggests there may be benefits for selective removal in sustaining tooth vitality, therefore avoiding abscess formation and pain, so eliminating the need for more complex and costly treatment or eventual tooth loss. However, the evidence is of low scientific quality and mainly gleaned from studies in primary teeth. Method This is a pragmatic, multi-centre, two-arm patient randomised controlled clinical trial including an internal pilot set in primary dental care in Scotland and England. Dental health professionals will recruit 623 participants over 12-years of age with deep carious lesions in their permanent posterior teeth. Participants will have a single tooth randomised to either the selective caries removal or complete caries removal treatment arm. Baseline measures and outcome data (during the 3-year follow-up period) will be assessed through clinical examination, patient questionnaires and NHS databases. A mixed-method process evaluation will complement the clinical and economic outcome evaluation and examine implementation, mechanisms of impact and context. The primary outcome at three years is sustained tooth vitality. The primary economic outcome is net benefit modelled over a lifetime horizon. Clinical secondary outcomes include pulp exposure, progession of caries, restoration failure; as well as patient-centred and economic outcomes. Discussion SCRiPT will provide evidence for the most clinically effective and cost-beneficial approach to managing deep carious lesions in permanent posterior teeth in primary care. This will support general dental practitioners, patients and policy makers in decision making. Trial Registration Trial registry: ISRCTN. Trial registration number: ISRCTN76503940. Date of Registration: 30.10.2019

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