A community jury study exploring the public acceptability of using risk stratification to determine eligibility for cancer screening

IntroductionUsing risk stratification to determine eligibility for cancer screening is likely to improve the efficiency of screening programmes by targeting resources towards those most likely to benefit. We aimed to explore the implications of this approach from a societal perspective by understanding public views on the most acceptable stratification strategies.MethodsWe conducted three online community juries with 9 or 10 participants in each. Participants were purposefully sampled by age (40–79 years), sex, ethnicity, social grade and English region. On the first day, participants were informed of the potential benefits and harms of cancer screening and the implications of different ways of introducing stratification using scenarios based on phenotypic and genetic risk scores. On the second day, participants deliberated to reach a verdict on the research question, ‘Which approach(es) to inviting people to screening are acceptable, and under what circumstances?’ Deliberations and feedback were recorded and analysed using thematic analysis.ResultsAcross the juries, the principle of risk stratification was generally considered to be an acceptable approach for determining eligibility for screening. Disregarding increasing capacity, the participants considered it to enable efficient resource allocation to high‐risk individuals and could see how it might help to save lives. However, there were concerns regarding fair implementation, particularly how the risk assessment would be performed at scale and how people at low risk would be managed. Some favoured using the most accurate risk prediction model whereas others thought that certain risk factors should be prioritized (particularly factors considered as non‐modifiable and relatively stable, such as genetics and family history). Transparently justifying the programme and public education about cancer risk emerged as important contributors to acceptability.ConclusionUsing risk stratification to determine eligibility for cancer screening was acceptable to informed members of the public, particularly if it included risk factors they considered fair and when communicated transparently.Patient or Public ContributionTwo patient and public involvement representatives were involved throughout this study. They were not involved in synthesizing the results but contributed to producing study materials, co‐facilitated the community juries and commented on the interpretation of the findings and final report.     

Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

The emergence and growing incidence of antimicrobial resistance (AMR) in common pathogens has created a global public health crisis, with 4.95 million deaths worldwide associated with AMR in 2019 (1). Some reports estimate that the number of deaths could reach 10 million per year by 2050 without the advancement of new therapies and public health interventions (2). For more than 30 years, the majority of approved antibiotics have been derived from existing chemical structures (3). Only a few new classes of clinically approved antibiotics have been discovered since the mid-1980s including: i) oxazolidinones (e.g., linezolid); ii) lipopeptides (e.g., daptomycin), both of which were discovered in 1987; and iii) the antimycobacterial diarylquinolines (e.g., bedaquiline) in 2004 (4). However, resistance to each of these three classes of antibiotics has already been reported (5–7). Overall, antibiotic resistance is reaching a tipping point, creating an urgent need to develop new therapeutics with novel mechanisms of action that work either alone or in combination with existing therapeutics as a way to successfully treat troubling AMR infections.The Centers for Disease Control and Prevention’s 2019 AR Threats Report categorizes 18 AMR bacterial and fungal pathogens as urgent, serious, or concerning threats. Among these are vancomycin-resistant enterococci (VRE), which have been recognized as serious threats (8). The most well studied VRE primarily belong to the species Enterococcus faecalis and Enterococcus faecium and are important causes of healthcare-associated infections (HAIs), which cost up to $28.4 billion in additional healthcare expenses in the United States and are responsible for 100,000 deaths per year (9). Among the HAIs caused by enterococcal species are catheter-associated urinary tract infections (CAUTI), as well as noncatheter-associated urinary tract infections (UTI), infective endocarditis (IE), and septicemia (10, 11). The prevention and treatment of enterococcal infections in the clinical setting has been increasingly difficult due to: i) the ability of enterococci to withstand heat (12, 13), UV radiation (14), and aseptic solutions, such as chloride and alcohol preparations (15, 16); ii) their inherent resistance to antimicrobial agents, such as cephalosporins, monobactams, penicillins and aminoglycosides (17, 18); iii) their ability to form antibiotic resistant biofilms (19–21); and iv) their capacity to acquire antibiotic resistance genes, such as those that encode proteins giving resistance to vancomycin (22–24). Thus, new and innovative therapeutics to combat this serious threat are needed.Here, we developed compounds based on a peptidomimetic bicyclic central scaffold (a dihydrothiazolo ring-fused 2-pyridone with the peptidomimetic backbone highlighted in red, Fig. 1A). Structural diversity of the 2-pyridone core is possible using synthetic methodologies (25) and the nature of the substitution pattern of the scaffold is crucial to the function of the compound. For example, compared to the early lead 2-pyridone compound, EC305, the refined compound, PS757, has an aliphatic alkyl chain connected to position 2 via a phenoxy linker with a hexyl chain, which significantly improves potency (Fig. 1). We demonstrate that PS757 has potent bacteriostatic effects against growing enterococcal cells. In addition, unlike many existing classes of antibiotics that only target actively dividing cells, PS757 is also bactericidal against stationary phase enterococcal cells. The mechanism of PS757-mediated stationary phase killing involves the enterococcal Atn autolysin and the protease GelE, which is expressed during the stationary growth phase. Further, we show that sublethal concentrations of PS757 synergize with sublethal concentrations of gentamicin and vancomycin to kill multidrug resistant enterococci, including VRE strains. PS757 also shows broad spectrum bactericidal activity against multidrug-resistant (MDR) Gram-positive pathogens, including staphylococci, methicillin-resistant Staphylococcus aureus (MRSA), and streptococcal species, suggesting that this new family of antibiotics has the potential to be broadly efficacious for treatment of Gram-positive infections, including those caused by highly antibiotic resistant pathogens.Open in a separate windowFig. 1.First generation 2-pyridone compounds have bactericidal activity against E. faecalis OG1RF and clinical isolates. (A) Structure of the 2-pyridone scaffold. (B) First-generation compounds EC240 and EC305, and second-generation compound PS757. MICs (see Materials and Methods) of EC240, EC305, and PS757 for E. faecalis OGR1RF are shown. (C) Net fold change (see Materials and Methods) in CFU/mL of clinical enterococcal isolates treated with DMSO (green), 100 µM EC240 (orange), and 100 µM EC305 relative to the CFU/mL of the untreated initial inoculum. Black bars represent SDs of replicates. Statistical analysis by two-way ANOVA (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).     

An Atlas of Optical Coherence Tomography (OCT): Elucidating In Vivo Differences of Scar Types Using OCT in Order to Guide Laser Treatment Parameters

ObjectiveWhen using laser therapy to effectively treat scars, the choice of treatment parameters depends on the knowledge accuracy of the underlying scar pathology, which is often difficult to judge by gross physical exam. As such, more quantitative measures are needed. In recent years, optical coherencetomography (OCT) has shown promise as a real-time imaging technolgoy of skin microstructure. A key step in developing a methodology for utilizing OCT to develop a comprehensive ‘atlas’ of OCT characteristics of a wide variety of scar types. This atlas may then be used as a tool for selecting the optimal treatment modality and parameters for each scar type.MethodsOne hundred and fifty scars of a wide range of anatomical locations were imaged using OCT, capturing both vascular and structural data. A variety of scar etiologies (e.g. burn, surgical, traumatic) and types (e.g. hypertrophic, keloidal, atrophic) were included. Comparator scans were also taken from normal, unscarred skin.ResultsOCT revealed morphological differences in the epidermis and dermis between scars and normal tissue, and between scar subtypes. Features affected by scar pathology included epidermal thickness, skin surface texture, dermal epidermal junction rugosity, blood vessel density, vessel shape and diameter, vessel direction and vascular network, dermis scattering intensity and non-uniformity. Each scar subtype showed consistent characteristics distinct from other scar subtypes.LimitationsThis was a single-site study of a patient population in South Florida.ConclusionOCT is a powerful new objective tool for the clinician to utilize in the pursuit of effective laser treatment parameters by enabling personalized treatment based on individual scar characteristics in order to maximize treatment capabilities.     

Cross-sectional and longitudinal associations between cardiometabolic measures and clinical stage in young people accessing early intervention mental health services

Aim

This retrospective cohort study aimed to identify the cardiometabolic characteristics, cross-sectionally and longitudinally, associated with clinical stage in youth accessing early intervention mental health services.

Methods

Cardiometabolic data we collected in 511 young people (aged 12–25 years at entry) receiving mental health care at the early intervention services in Sydney, Australia.

Results

The majority of young people (N = 448, 87.67%) were classified in stage 1a or 1b at entry. At entry to care, there was no cross-sectional relationship between clinical stage and age, gender, fasting insulin, fasting glucose, updated homeostatic model assessment for insulin resistance (HOMA2-IR) score, BMI or waist circumference. Of the 111 (21.7%) young people initially classified at stage 1a (‘non-specific symptoms’) and the 337 (65.9%) classified in stage 1b (‘attenuated syndromes’), 40 individuals transitioned to stage 2+ (7.8%) (“full-threshold disorders”) longitudinally. No cardiometabolic factors predicted clinical stage transitions. However, those with an increase in BMI over the course of care (n = 54) were 1.46 (OR; 95% CI: 1.02–2.17) times more likely to progress to stage 2+ at follow up.

Conclusions

Whilst no relationships were found between demographic or cardiometabolic variables and clinical stage at entry to care, an increased BMI over time was associated with clinical stage transition longitudinally. Further longitudinal research is needed to understand the demographic, clinical, illness progression or treatment factors associated with changes in cardiometabolic status.     

Using a Computerised Staircase and Incremental Optotype Sizes to Improve Visual Acuity Assessment Accuracy

Background:Given the impact of visual acuity results on diagnosis and management, it is essential that the test is accurate, determined by factors such as test-retest variability. Standardisation improves accuracy, which can be performed via a computerised staircase methodology. Standard clinical tests with scoring of 0.02 per optotype implies an incremental score per optotype despite optotype size remaining constant on each line. The aim of this study is to establish if near continuous incremental optotype display and scoring improves test-retest variability compared to current testing methods.Methods:A computerised three up, one down adaptive staircase was used to display Kay Picture optotypes on an LCD monitor. Three methods of visual acuity assessment were undertaken: ETDRS, Kay Pictures and computerised Kay Pictures. Tests were performed twice under standard clinical conditions.Results:One hundred nineteen adults were tested. Test-retest variability for computerised Kay pictures was 0.01 logMAR (±0.04, p = 0.001). Good levels of agreement were observed for computerised Kay pictures in terms of test-retest variability, where the test had the smallest mean bias (0.01 logMAR compared to 0.03 and 0.08 logMAR for Kay Pictures and ETDRS respectively) and narrowest limits of agreement. Participants performed better in computerised Kay pictures than Kay Pictures by 0.03 logMAR, and better in ETDRS than computerised Kay pictures by 0.1 logMAR.Conclusion:Computerised Kay pictures exhibited a low test-retest variability, demonstrating it is reliable and repeatable. This repeatability measure is lower than the test-retest variability of the ETDRS and Kay Pictures tests.     

Adolescence in lockdown: The protective role of mentalizing and epistemic trust

Objective

Mentalizing is the ability to interpret one's own and others' behavior as driven by intentional mental states. Epistemic trust (openness to interpersonally transmitted information) has been associated with mentalizing. Balanced mentalizing abilities allow people to cope with external and internal stressors. Studies show that social isolation imposed by the COVID-19 pandemic was highly stressful for most people, especially for adolescents. Here we examine whether mentalizing and epistemic trust were protective factors in relation to emotional distress during the lockdown.

Method

A total of 131 nonclinical adolescents, aged between 12 and 18 years, were evaluated during the lockdown using the Reflective Functioning Questionnaire for Youth, Inventory of Parent and Peer Attachment, Perceived Stress Scale, and Difficulties in Emotion Regulation Scale.

Results

Results from network analysis showed that epistemic trust and mentalizing were negatively associated with perceived stress and emotion dysregulation. Epistemic trust in fathers was associated with level of perceived stress, and epistemic trust in mothers with emotion dysregulation.

Conclusion

These findings suggest that epistemic trust and the capacity to mentalize were low in adolescents during lockdown, and this was associated with high levels of stress. However, robust levels of epistemic trust and mentalizing may have acted as protective factors that buffered individuals from the risk of emotional dysregulation during the lockdown.     

Clinical and radiological description of 120 pediatric stroke-like episodes

Background and purpose

Stroke-like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non-congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology.

Methods

We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20-year period. Inclusion criteria were compatible clinical symptoms and stroke-like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion-weighted imaging in a non-vascular territory.

Results

Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48-h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18).

Conclusion

Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE.