Favipiravir induces HuNoV viral mutagenesis and infectivity loss with clinical improvement in immunocompromised patients.

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.

Supporting families managing childhood eczema: developing and optimising eczema care online using qualitative research.

BACKGROUND: Childhood eczema is often poorly controlled owing to underuse of emollients and topical corticosteroids (TCS). Parents/carers report practical and psychosocial barriers to managing their child's eczema, including child resistance. Online interventions could potentially support parents/carers; however, rigorous research developing such interventions has been limited. AIM: To develop an online behavioural intervention to help parents/carers manage and co-manage their child's eczema. DESIGN AND SETTING: Intervention development using a theory-, evidence-, and person-based approach (PBA) with qualitative research. METHOD: A systematic review and qualitative synthesis of studies (n = 32) and interviews with parents/carers (n = 30) were used to identify barriers and facilitators to effective eczema management, and a prototype intervention was developed. Think-aloud interviews with parents/carers (n = 25) were then used to optimise the intervention to increase its acceptability and feasibility. RESULTS: Qualitative research identified that parents/carers had concerns about using emollients and TCS, incomplete knowledge and skills around managing eczema, and reluctance to transitioning to co-managing eczema with their child. Think-aloud interviews highlighted that, while experienced parents/carers felt they knew how to manage eczema, some information about how to use treatments was still new. Techniques for addressing barriers included providing a rationale explaining how emollients and TCS work, demonstrating how to use treatments, and highlighting that the intervention provided new, up-to-date information. CONCLUSION: Parents/carers need support in effectively managing and co-managing their child's eczema. The key output of this research is Eczema Care Online for Families, an online intervention for parents/carers of children with eczema, which is being evaluated in a randomised trial.

Eczema Care Online: development and qualitative optimisation of an online behavioural intervention to support self-management in young people with eczema.

OBJECTIVES: To describe the development of Eczema Care Online (ECO), an online behaviour change intervention for young people with eczema (phase I); and explore and optimise the acceptability of ECO among this target group using think-aloud interviews (phase II). METHODS: Theory-based, evidence-based and person-based approaches to intervention development were used. In phase I, a qualitative systematic review and qualitative interviews developed an in-depth understanding of the needs and challenges of young people with eczema. Guiding principles highlighted key intervention design objectives and features to address the needs of this target group to maximise user engagement. Behavioural analysis and logic modelling developed ECO's hypothesised programme theory. In phase II, qualitative think-aloud interviews were carried out with 28 young people with eczema and the intervention was optimised based on their feedback. RESULTS: The final intervention aimed to reduce eczema severity by supporting treatment use (emollients, topical corticosteroids/topical calcineurin inhibitors), management of irritants/triggers, emotional management and reducing scratching. Generally, young people expressed positive views of intervention content and design in think-aloud interviews. Quotes and stories from other young people with eczema and ECO's focus on living with eczema (not just topical treatments) were valuable for normalising eczema. Young people believed ECO addressed knowledge gaps they had from childhood and the safety information about topical corticosteroids was reassuring. Negative feedback was used to modify ECO. CONCLUSIONS: A prototype of the ECO intervention was developed using rigorous and complementary intervention development approaches. Subsequent think-aloud interviews helped optimise the intervention, demonstrated ECO is likely to be acceptable to this target group, and provided support for our guiding principles including key design objectives and features to consider when developing interventions for this population. A randomised controlled trial and process evaluation of the intervention is underway to assess effectiveness and explore user engagement with the intervention's behavioural goals.

From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin.

PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin's antiseizure action.

A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo.

Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound 4 inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC50 ~1 µM) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound 4 still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound 4 and rupintrivir. After testing new derivatives, compound 10d was the most potent (EC50 nanomolar range). Molecular docking indicated that the aldehyde group of compounds 4 and 10d bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound 10d inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile.

The content and conduct of GP consultations for dermatology problems: a cross-sectional study.

BACKGROUND: Skin complaints are common in primary care, and poor outcomes in long-term conditions are often due to low adherence to treatment. Shared decision making and self-management support may help, yet there is little understanding of patient involvement or the support provided by GPs. AIM: To describe the content of primary care consultations for skin problems, including shared decision making practice, delivery of self-management advice, and follow-up. DESIGN AND SETTING: Cross-sectional study of video-recorded UK adult GP consultations and linked data. METHOD: A coding tool was developed and applied to all consultations with skin problems. Shared decision making was assessed using the observer OPTION5 scale. RESULTS: A total of 45/318 consultations (14.2%) related to one or more skin problems, which were discussed alongside other problems in 71.1% (32/45) of consultations. Of the 100 different problems discussed in these consultations, 51 were dermatological. The mean amount of time spent on skin problems in the consultations was 4 minutes 16 seconds. Medication was recommended for 66.7% (34/51) of skin problems, with low shared decision making (mean OPTION5 score = 10.7). Self-management advice (verbal only) was given for 47.1% (24/51) of skin problems. Most skin problems (84.3%; 43/51) were not referred to secondary care; 32.6% (14/43) of the skin problems not referred were seen again in primary care within 12 weeks, of which 35.7% (5/14) follow-up appointments were not planned. CONCLUSION: In this study, skin problems were usually presented alongside other complaints and resulted in a medication recommendation. Shared decision making was uncommon and self-management advice not consistently given, with re-attendance for the same problem common. GPs' training should reflect how frequently skin problems are seen and seek to improve patient involvement in decision making and support self-management.

GP and parent dissonance about the assessment and treatment of childhood eczema in primary care: a qualitative study.

OBJECTIVES: To compare parents' and clinicians' perspectives on the assessment and treatment of children with eczema in primary care. DESIGN: Qualitative interview study with purposive and snowball sampling and thematic analysis. SETTING: 14 general practices in the UK. PARTICIPANTS: 11 parents of children with eczema and 15 general practitioners (GPs) took part in semistructured individual interviews. RESULTS: We identified several areas of dissonance between parents and GPs. First, parents sought a 'cause' of eczema, such as an underlying allergy, whereas GPs looked to manage the symptoms of an incurable condition. Second, parents often judged eczema severity in terms of psychosocial impact, while GPs tended to focus on the appearance of the child's skin. Third, parents sought 'more natural' over-the-counter treatments or complementary medicine, which GPs felt unable to endorse because of their unknown effectiveness and potential harm. Fourth, GPs linked poor outcomes to unrealistic expectations of treatment and low adherence to topical therapy, whereas parents reported persisting with treatment and despondency with its ineffectiveness. Consultations were commonly described by parents as being dominated by the GP, with a lack of involvement in treatment decisions. GPs' management of divergent views varied, but avoidance strategies were often employed. CONCLUSIONS: Divergent views between parents and clinicians regarding the cause and treatment of childhood eczema can probably only be bridged by clinicians actively seeking out opinions and sharing rationale for their approach to treatment. Together with assessing the psychosocial as well as the physical impact of eczema, asking about current or intended use of complementary therapy and involving parents in treatment decisions, the management of eczema and patient outcomes could be improved.

GPs' experiences of diagnosing and managing childhood eczema: a qualitative study in primary care.

BACKGROUND: Eczema is common among children, and in the UK the majority are managed by GPs. The most common cause of poor disease control is incorrect use of topical treatments. There is a lack of research into the challenges faced by GPs in diagnosing and managing this condition. AIM: To explore the experiences of GPs in assessing and managing children with eczema. DESIGN AND SETTING: Qualitative study in primary care in England. METHOD: Semi-structured interviews with 15 GPs were audiorecorded, transcribed verbatim, and analysed thematically using the framework method. RESULTS: GPs described a paucity of dermatology training. Although most GPs were confident diagnosing uncomplicated eczema, they reported using a trial-and-error approach to prescribing emollients, and were uncertain about quantities of topical treatments to issue. Mild and moderate potency topical corticosteroids (TCS) were commonly used, but most GPs lacked confidence in recommending potent TCS, and viewed parents or carers to be fearful of using all strengths of TCS. GPs perceived adherence to treatments to be low, but provision of information to support self-care was variable. Routine review of medication use or disease control was uncommon, which GPs attributed to service constraints. Participants' views on the causes and management of eczema were perceived to be at odds with parents and carers, who were said to be overly focused on an underlying cause, such as allergy. CONCLUSION: GP uncertainty in managing eczema, lack of routine information and review, and perceived dissonance with parents around causation and management may be contributing to low concordance with treatments.

Developing a written action plan for children with eczema: a qualitative study.

BACKGROUND: Eczema is common in children but adherence to treatments is poor. Written action plans (WAPs) have been shown to help in asthma but the potential value, format, and content of an eczema WAP is unknown. AIM: To explore the potential role of an eczema WAP, and to design an eczema-specific WAP. DESIGN AND SETTING: A qualitative study of parents of children with eczema, primary and secondary care health professionals, and other stakeholders. METHOD: A total of 41 semi-structured one-to-one interviews and two focus groups were audiorecorded, transcribed, and analysed thematically. RESULTS: Reported challenges of managing eczema included: parental confusion about treatment application; lack of verbal and written advice from GPs; differing beliefs about the cause and management of eczema; re-prescribing of failed treatments; and parents feeling unsupported by their GP. An eczema WAP was viewed as an educational tool that could help address these problems. Participants expressed a preference for a WAP that gives clear, individualised guidance on treatment use, presented in a step-up/step-down approach. Participants also wanted more general information about eczema, its potential triggers, and how to manage problem symptoms. CONCLUSION: An eczema WAP may help overcome some of the difficulties of managing eczema, and support families and clinicians in the management of the condition. Further evaluation is needed to determine if the eczema WAP the authors have developed is both acceptable and improves the outcomes for affected children and their families.

More Than Many: How to Manage the Most Frequent Cancer?

Leiter et al. report on the increasing incidence of keratinocyte cancers in Germany. The true population burden is even larger then reported, because many of these new patients will develop multiple keratinocyte cancers. Keratinocyte cancer puts a large burden on health care systems worldwide. Prevention and management strategies are needed to maintain high quality of care for all patients.