Assessment of the comparative agreement between chest radiographs and CT scans in intensive care units.

PURPOSE: Chest radiographs in critically ill patients can be difficult to interpret due to technical and clinical factors. We sought to determine the agreement of chest radiographs and CT scans, and the inter-observer variation of chest radiograph interpretation, in intensive care units (ICUs). METHODS: Chest radiographs and corresponding thoracic computerised tomography (CT) scans (as reference standard) were collected from 45 ICU patients. All radiographs were analysed by 20 doctors (radiology consultants, radiology trainees, ICU consultants, ICU trainees) from 4 different centres, blinded to CT results. Specificity/sensitivity were determined for pleural effusion, lobar collapse and consolidation/atelectasis. Separately, Fleiss' kappa for multiple raters was used to determine inter-observer variation for chest radiographs. RESULTS: The median sensitivity and specificity of chest radiographs for detecting abnormalities seen on CTs scans were 43.2% and 85.9% respectively. Diagnostic sensitivity for pleural effusion was significantly higher among radiology consultants but no specialty/experience distinctions were observed for specificity. Median inter-observer kappa coefficient among assessors was 0.295 ("fair"). CONCLUSIONS: Chest radiographs commonly miss important radiological features in critically ill patients. Inter-observer agreement in chest radiograph interpretation is only "fair". Consultant radiologists are least likely to miss thoracic radiological abnormalities. The consequences of misdiagnosis by chest radiographs remain to be determined.

"Knowing that I had HPV, I literally just shut down": A qualitative exploration of the psychosocial impact of human papillomavirus (HPV) in women living with mental health conditions.

OBJECTIVE: Psychological distress after testing positive for human papillomavirus (HPV) at cervical cancer screening is well documented in the general population. However, little is known about the impact of an HPV-positive result on those with pre-existing mental health conditions, who may be at higher risk of experiencing clinically significant distress. This study explored the psychosocial impact of HPV in women with co-morbid mental health conditions, as well as their experience of cervical screening during the COVID-19 pandemic. METHODS: Semi-structured telephone interviews were conducted with 22 women aged 27-54 who had tested positive for HPV at routine cervical screening in England, and who reported having at least one mental health condition. Data were analysed using thematic analysis. RESULTS: Being informed of an HPV-positive result increased distress and heightened pre-existing psychological challenges. Psychosocial response and duration of HPV-related distress appeared to be influenced by the ability to regulate emotions, number of consecutive HPV-positive results, interactions with health care professionals, and other life stressors. The experience added further complexity to many women's perceptions of self and self-esteem. Women who had received psychological treatment for their mental health condition were best able to self-manage HPV-related distress by applying learned coping skills. CONCLUSIONS: Receiving an HPV-positive result at cervical screening appears to be a distressing experience for women with co-morbid mental health conditions. Future hypothesis-driven research is needed to confirm findings and develop effective interventions to reduce psychosocial burden.

Type 1 diabetes incidence in Scotland between 2006 and 2019.

AIMS: To describe type 1 diabetes incidence in Scotland between 2006 and 2019. METHODS: Repeated annual cross-sectional studies of type 1 diabetes incidence were conducted. Incident cases were identified from the Scottish Care Information-Diabetes Collaboration (SCI-DC), a population-based register of people with diagnosed diabetes derived from primary and secondary care data. Mid-year population estimates for Scotland were used as the denominator to calculate annual incidence with stratification by age and sex. Joinpoint regression was used to investigate whether incidence changed during the study period. Age and sex-specific type 1 diabetes incidence over the whole time period was estimated by quintile of the Scottish Index of Multiple Deprivation (SIMD), an area-based measure, in which Q1 and Q5 denote the most and least deprived fifths of the population, respectively, with quasi-Poisson regression used to compare incidence for Q5 compared to Q1. RESULTS: The median (IQR) age of the study population of 14,564 individuals with incident type 1 diabetes was 24.1 (12.3-42.4) years, 56% were men, 23% were in Q1 and 16% were in Q5. Incidence of T1DM was higher in men than women overall (at around 22 and 17 per 100,000, respectively) and in under 15 year olds (approximately 40 per 100,000 in both sexes) than other age groups and was similar across the study period in all strata. There was an inverse association between socio-economic status and type 1 diabetes incidence for 15-29, 30-49 and 50+ year olds [incidence rate ratio (IRR) for Q5 compared to Q1; IRR (95% CI) 0.52 (0.47-0.58), 0.68 (0.61-0.76) and 0.53(0.46-0.61), respectively] but not for under 15 year olds [1.02 (0.92-1.12)]. CONCLUSION: Incidence of type 1 diabetes varies by age, sex and socio-economic status and has remained approximately stable from 2006 to 2019 in Scotland.

Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432.

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

Total Synthesis of (±)-Aspidospermidine, (±)-Aspidofractinine, (±)-Limaspermidine, and (±)-Vincadifformine via a Cascade and Common Intermediate Strategy.

A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki-Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels-Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.

Acceptability and facilitators of and barriers to point-of-care HIV testing in a homeless-focused service in Gloucestershire: a qualitative evaluation.

OBJECTIVES: Late HIV diagnosis increases the risks of onward transmission, morbidity and mortality. Rapid point-of-care testing (POCT) reaches people who have never been tested and people living with HIV who are undiagnosed. This study explored the acceptability and feasibility of HIV POCT from the perspectives of service providers and users. METHODS: A pilot study introduced HIV POCT to one service in Gloucestershire, England. Eleven semi-structured interviews with service users and a focus group with three service providers were conducted. The Theoretical Framework of Acceptability and the Theoretical Domains Framework were used to design the topic guide and analysis. RESULTS: Acceptability of HIV POCT was high. Seven facilitators were identified (e.g. understanding the test purpose and process), alongside two potential barriers, one relevant to service providers and users (anxiety) and the other to service users (stigma). CONCLUSIONS: To maximize the benefits of implementation of HIV POCT, health care providers require appropriate training and supervision to offer and administer POCT.

Acceptability of, and barriers and facilitators to, a pilot physical health service for people who inject drugs: A qualitative study with service users and providers.

BACKGROUND: People who inject drugs may experience difficulty accessing or maintaining involvement with traditional healthcare services. This is associated with increased health inequalities and bio-psychosocial difficulties. Embedding physical healthcare services within community-based drug services may provide a practical and feasible approach to increase access and delivery of healthcare. This study explored the acceptability of, and barriers and facilitators to, embedding a pilot physical healthcare service within a community-based drug service in the United Kingdom (Bristol, England). METHODS: Semi-structured interviews were conducted with service users (people who inject drugs) (n = 13), and a focus group was conducted with service providers (n = 11: nine harm reduction workers, two nurses, one service manager). Topic guides included questions to explore barriers and facilitators to using and delivering the service (based on the COM-B Model), and acceptability of the service (using the Theoretical Framework of Acceptability). Transcripts were analysed using a combined deductive framework and inductive thematic analysis approach. RESULTS: The service was viewed as highly acceptable. Service users and providers were confident they could access and provide the service respectively, and perceived it to be effective. Barriers included competing priorities of service users (e.g. drug use) and the wider service (e.g. equipment), and the potential impact of the service being removed in future was viewed as a barrier to overall healthcare access. Both service users and providers viewed embedding the physical health service within an existing community-based drug service as facilitating accessible and holistic care which reduced stigma and discrimination. CONCLUSIONS: The current study demonstrated embedding a physical health service within an existing community-drug based and alcohol service was acceptable and beneficial. Future studies are required to demonstrate cost-effectiveness and ensure long-term sustainability, and to determine transferability of findings to other settings, organisations and countries.

Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode.

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

Feasibility study of hospital antimicrobial stewardship analytics using electronic health records.

BACKGROUND: Hospital antimicrobial stewardship (AMS) programmes are multidisciplinary initiatives to optimize antimicrobial use. Most hospitals depend on time-consuming manual audits to monitor clinicians' prescribing. But much of the information needed could be sourced from electronic health records (EHRs). OBJECTIVES: To develop an informatics methodology to analyse characteristics of hospital AMS practice using routine electronic prescribing and laboratory records. METHODS: Feasibility study using electronic prescribing, laboratory and clinical coding records from adult patients admitted to six specialities at Queen Elizabeth Hospital, Birmingham, UK (September 2017-August 2018). The study involved: (i) a review of AMS standards of care; (ii) their translation into concepts measurable from commonly available EHRs; and (iii) a pilot application in an EHR cohort study (n = 61679 admissions). RESULTS: We developed data modelling methods to characterize antimicrobial use (antimicrobial therapy episode linkage methods, therapy table, therapy changes). Prescriptions were linked into antimicrobial therapy episodes (mean 2.4 prescriptions/episode; mean length of therapy 5.8 days), enabling several actionable findings. For example, 22% of therapy episodes for low-severity community-acquired pneumonia were congruent with prescribing guidelines, with a tendency to use broader-spectrum antibiotics. Analysis of therapy changes revealed IV to oral therapy switching was delayed by an average 3.6 days (95% CI: 3.4-3.7). Microbial cultures were performed prior to treatment initiation in just 22% of antibacterial prescriptions. The proposed methods enabled fine-grained monitoring of AMS practice down to specialities, wards and individual clinical teams by case mix, enabling more meaningful peer comparison. CONCLUSIONS: It is feasible to use hospital EHRs to construct rapid, meaningful measures of prescribing quality with potential to support quality improvement interventions (audit/feedback to prescribers), engagement with front-line clinicians on optimizing prescribing, and AMS impact evaluation studies.

How are emotional distress and reassurance expressed in medical consultations for people with long-term conditions who were unable to receive curative treatment? A pilot observational study with huntington's disease and prostate cancer.

OBJECTIVE: It is unclear whether how people with long-term conditions express distress, and how clinicians respond, influences perceptions of consultation outcomes. The pilot study examined emotional distress and reassurance in consultations with people whose long-term conditions (at the time of consultations) were treated using active surveillance or symptom management (as no curative treatment was suitable). METHODS: An observational pilot study was conducted involving consultations between people with long-term conditions and their respective clinician. Consultations between three clinicians (two Huntington's Disease; one Prostate Cancer) and 22 people with long-term conditions (11 Huntington's Disease; 11 Prostate Cancer) were audio-recorded. Participants also completed an expanded Consultation and Relational Empathy (CARE) Measure. Two researchers coded sessions using Verona Coding Definitions of Emotional Sequences (VR-CoDES/VR-CoDES-P). Code frequencies were calculated, t tests performed between conditions, and Pearson's correlations performed for associations between CARE responses and clinician utterances. RESULTS: People with long-term conditions expressed emotional distress on average 4.45 times per session, averaging 1.09 Concern and 3.36 Cue utterances. Clinicians responded with more explicit (2.59) and space-providing (3.36), than non-explicit (1.86) and space-reducing (1.09), responses per session. Clinicians expressed spontaneous reassurance on average 5.18 times per session, averaging 3.77 Cognitive and 1.5 Affective reassurance utterances. Huntington's Disease consultations featured significantly more 'Cues', 'Concerns' and 'Overall' 'Emotional Distress', and 'Cognitive' and 'Overall' 'Reassurance'. CONCLUSION: Emotional distress was expressed more using hints than explicit concern utterances. Clinicians predominantly explicitly explored distress rather than providing information/advice and provided advice using spontaneous cognitive reassurance. People with Huntington's Disease expressed more concerns and received more reassurance, indicating different needs between conditions. Future research is required to explore emotional distress and reassurance in a larger sample of participants and long-term condition types, and how the practical implications of these findings may be used to enhance outcomes of consultations. TRIAL REGISTRATION: N/A.

Variations of risk factors for ischemic stroke and its subtypes in Chinese patients in Taiwan.

Chinese have a higher stroke incidence and a different distribution of ischemic stroke (IS) subtypes as compared with Caucasians. Herein we aimed to investigate the prevalence and associations of major risk factors in IS and its subtypes in Chinese patients. From 2006 to 2011, we included 4953 acute IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry (mean age 68 years; male 59%). For each risk factor, we accessed the proportion in all IS patients, and calculated odds ratios for each main IS subtype versus other subtypes. Multiple logistic regression models were used to adjust for confounders, and to examine the associations of risk factors with IS subtypes. Compared with other ischemic subtypes, large artery atherosclerotic and lacunar strokes were associated with hypertension, diabetes, and hyperlipidaemia, while cardioembolic strokes were associated with ischemic heart disease. Furthermore, the associations with hypertension and diabetes became stronger in lacunar strokes after adjusting for confounders, but not in other ischemic subtypes. Here we report the variable effects of risk factors on different IS subtypes in Chinese patients in Taiwan. Our findings could help shed light on different mechanisms of IS subtypes and provide targets to make more effective strategies for IS prevention.

Which factors influence the extent of indoor transmission of SARS-CoV-2? A rapid evidence review.

BACKGROUND: This rapid evidence review identifies and integrates evidence from epidemiology, microbiology and fluid dynamics on the transmission of SARS-CoV-2 in indoor environments. METHODS: Searches were conducted in May 2020 in PubMed, medRxiv, arXiv, Scopus, WHO COVID-19 database, Compendex & Inspec. We included studies reporting data on any indoor setting except schools, any indoor activities and any potential means of transmission. Articles were screened by a single reviewer, with rejections assessed by a second reviewer. We used Joanna Briggs Institute and Critical Appraisal Skills Programme tools for evaluating epidemiological studies and developed bespoke tools for the evaluation of study types not covered by these instruments. Data extraction and quality assessment were conducted by a single reviewer. We conducted a meta-analysis of secondary attack rates in household transmission. Otherwise, data were synthesised narratively. RESULTS: We identified 1573 unique articles. After screening and quality assessment, fifty-eight articles were retained for analysis. Experimental evidence from fluid mechanics and microbiological studies demonstrates that aerosolised transmission is theoretically possible; however, we found no conclusive epidemiological evidence of this occurring. The evidence suggests that ventilation systems have the potential to decrease virus transmission near the source through dilution but to increase transmission further away from the source through dispersal. We found no evidence for faecal-oral transmission. Laboratory studies suggest that the virus survives for longer on smooth surfaces and at lower temperatures. Environmental sampling studies have recovered small amounts of viral RNA from a wide range of frequently touched objects and surfaces; however, epidemiological studies are inconclusive on the extent of fomite transmission. We found many examples of transmission in settings characterised by close and prolonged indoor contact. We estimate a pooled secondary attack rate within households of 11% (95% confidence interval (CI) = 9, 13). There were insufficient data to evaluate the transmission risks associated with specific activities. Workplace challenges related to poverty warrant further investigation as potential risk factors for workplace transmission. Fluid mechanics evidence on the physical properties of droplets generated by coughing, speaking and breathing reinforce the importance of maintaining 2 m social distance to reduce droplet transmission. CONCLUSIONS: This review provides a snap-shot of evidence on the transmission of SARS-CoV-2 in indoor environments from the early months of the pandemic. The overall quality of the evidence was low. As the quality and quantity of available evidence grows, it will be possible to reach firmer conclusions on the risk factors for and mechanisms of indoor transmission.

An ontology-based modelling system (OBMS) for representing behaviour change theories applied to 76 theories.

Background: To efficiently search, compare, test and integrate behaviour change theories, they need to be specified in a way that is clear, consistent and computable. An ontology-based modelling system (OBMS) has previously been shown to be able to represent five commonly used theories in this way. We aimed to assess whether the OBMS could be applied more widely and to create a database of behaviour change theories, their constructs and propositions. Methods: We labelled the constructs within 71 theories and used the OBMS to represent the relationships between the constructs. Diagrams of each theory were sent to authors or experts for feedback and amendment. The 71 finalised diagrams plus the five previously generated diagrams were used to create a searchable database of 76 theories in the form of construct-relationship-construct triples. We conducted a set of illustrative analyses to characterise theories in the database. Results: All 71 theories could be satisfactorily represented using this system. In total, 35 (49%) were finalised with no or very minor amendment. The remaining 36 (51%) were finalised after changes to the constructs (seven theories), relationships between constructs (15 theories) or both (14 theories) following author/expert feedback. The mean number of constructs per theory was 20 (min. = 6, max. = 72), with the mean number of triples per theory 31 (min. = 7, max. = 89). Fourteen distinct relationship types were used, of which the most commonly used was 'influences', followed by 'part of'. Conclusions: The OBMS can represent a wide array of behavioural theories in a precise, computable format. This system should provide a basis for better integration and synthesis of theories than has hitherto been possible.

Interventions to improve appropriate antibiotic prescribing in long-term care facilities: a systematic review.

BACKGROUND: Overuse of antibiotics has contributed to antimicrobial resistance; a growing public health threat. In long-term care facilities, levels of inappropriate prescribing are as high as 75%. Numerous interventions targeting long-term care facilities' antimicrobial stewardship have been reported with varying, and largely unexplained, effects. Therefore, this review aimed to apply behavioural science frameworks to specify the component behaviour change techniques of stewardship interventions in long-term care facilities and identify those components associated with improved outcomes. METHOD: A systematic review (CRD42018103803) was conducted through electronic database searches. Two behavioural science frameworks, the Behaviour Change Wheel and Behaviour Change Technique Taxonomy were used to classify intervention descriptions into intervention types and component behaviour change techniques used. Study design and outcome heterogeneity prevented meta-analysis and meta-regression. Interventions were categorised as 'very promising' (all outcomes statistically significant), 'quite promising' (some outcomes statistically significant), or 'not promising' (no outcomes statistically significant). 'Promise ratios' (PR) were calculated for identified intervention types and behaviour change techniques by dividing the number of (very or quite) promising interventions featuring the intervention type or behaviour change technique by the number of interventions featuring the intervention type or behaviour change technique that were not promising. Promising intervention types and behaviour change techniques were defined as those with a PR ≥ 2. RESULTS: Twenty studies (of19 interventions) were included. Seven interventions (37%) were 'very promising', eight 'quite promising' (42%) and four 'not promising' (21%). Most promising intervention types were 'persuasion' (n = 12; promise ratio (PR) = 5.0), 'enablement' (n = 16; PR = 4.33) and 'education' (n = 19; PR = 3.75). Most promising behaviour change techniques were 'feedback on behaviour' (n = 9; PR = 8.0) and 'restructuring the social environment' (e.g. staff role changes; n = 8; PR = 7.0). CONCLUSION: Systematic identification of the active ingredients of antimicrobial stewardship in long-term care facilities was facilitated through the application of behavioural science frameworks. Incorporating environmental restructuring and performance feedback may be promising intervention strategies for antimicrobial stewardship interventions within long-term care facilities.

Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation.

BACKGROUND: Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1ß and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1ß and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia. METHODS: VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1ß and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 104 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425. FINDINGS: Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes. INTERPRETATION: Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect. FUNDING: UK Department of Health and the Wellcome Trust.

Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis.

The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).

Identifying inequalities in childhood immunisation uptake and timeliness in southeast Scotland, 2008-2018: A retrospective cohort study.

BACKGROUND: In 2018, there was a record incidence of measles and other vaccine-preventable diseases across developed countries. Declining childhood immunisation uptake in southeast Scotland-an area with a large, highly mobile, and socioeconomically diverse population-threatens regional herd immunity and warrants investigation of suboptimal coverage. As deprivation of social and material resources increases risk of non-vaccination, we examined here the relationship between deprivation, uptake, and timeliness for four routine childhood vaccines and identified trends over the past decade. METHODS: This retrospective cohort study analysed immunisation data from the Scottish Immunisation Recall System (SIRS) for four routine childhood vaccines in the UK: the third dose of the primary vaccine (TPV), both doses of measles, mumps, rubella (MMR 1 and MMR 2), and the preschool booster (PSB). Immunisations (N = 329,897) were administered between 2008 and 2018. Deprivation was measured via the Scottish Index of Multiple Deprivation (SIMD), ranking postcodes by deprivation decile. Chi-squared tests and cox proportional hazards models assessed the relationship between uptake, timeliness, and deprivation. RESULTS: There is strong evidence for an association between deprivation, uptake, and timeliness. Uptake for all childhood immunisations are very high, especially for TPV and MMR 1 (>98.0%), though certain deprivation deciles exhibit increased risks of non-vaccination for all vaccines. Delay was pronounced for the 40% most deprived population and for immunisations scheduled at later ages. Absolute PSB and MMR 2 uptake has improved since 2008; however, disparities in uptake have increased for all vaccines since the 2006 birth cohort. CONCLUSION: Both timeliness and uptake are strongly associated with deprivation. While absolute uptake was high for all vaccines, relative uptake and timeliness has been worsening for most groups; the reason for this decline is unclear. Here we identified subgroups that may require targeted interventions to facilitate uptake and timeliness for essential childhood vaccines.

Targeting IRAK4 for Degradation with PROTACs.

Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein's kinase activity with the most advanced reaching Phase II clinical trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound 9 leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1ß stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation. Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncological diseases.