Changes in public health-seeking behaviours for self-limiting respiratory tract infections across England during the COVID-19 pandemic.

BACKGROUND: National Health Service (NHS) guidance for acute respiratory tract infections (RTIs) advocates self-care, encourages utilization of local pharmacies and recommends consulting general practitioners (GPs) primarily for the vulnerable or those with persistent symptoms. Coronavirus disease 2019 exerted substantial strain on the English NHS, affecting public access to primary care services. METHODS: For 3 years, public surveys assessed RTI incidences in the previous 12 months and associated health-seeking behaviours. Telephone surveys of 1676 respondents across England were conducted in March 2021 and 1663 respondents in March 2022. Findings were compared with a face-to-face baseline survey of 2022 respondents from March 2020. Key demographics were representative of the population. RESULTS: In 2021, the proportion of respondents who reported an RTI (51%) significantly declined from 2020 (70%, P < 0.05), then returned to pre-pandemic rates in 2022 (67%). Respondents reported more proactive symptom management in both 2021 and 2022 from 2020: there were greater reports of seeking over-the-counter treatments (55%, 55% vs. 35%, P < 0.05) and use of alternative remedies (38%, 38% vs. 21%, P < 0.05). 2022 observed a reduction in those who reported consulting their GP for their most recent RTI (15%) compared to 2021 (25%, P < 0.05) and 2020 (23%), which was not accounted for through greater consultation rates with other healthcare services. CONCLUSIONS: Public health bodies should consider how pandemic-related changes may have facilitated increased self-care for self-limiting infections such as RTIs. Resources and support must include safety-netting advice to safeguard against unintentional consequences of increased self-care.

Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site.

Nanobodies can achieve remarkable neutralization of genetically diverse pathogens, including HIV-1. To gain insight into their recognition, we determined crystal structures of four llama nanobodies (J3, A12, C8, and D7), all of which targeted the CD4-binding site, in complex with the HIV-1 envelope (Env) gp120 core, and determined a cryoelectron microscopy (cryo-EM) structure of J3 with the Env trimer. Crystal and cryo-EM structures of J3 complexes revealed this nanobody to mimic binding to the prefusion-closed trimer for the primary site of CD4 recognition as well as a secondary quaternary site. In contrast, crystal structures of A12, C8, and D7 with gp120 revealed epitopes that included portions of the gp120 inner domain, inaccessible on the prefusion-closed trimer. Overall, these structures explain the broad and potent neutralization of J3 and limited neutralization of A12, C8, and D7, which utilized binding modes incompatible with the neutralization-targeted prefusion-closed conformation of Env.

What the public in England know about antibiotic use and resistance in 2020: a face-to-face questionnaire survey.

OBJECTIVES: To describe public attitudes and knowledge around antibiotic activity, resistance and use. DESIGN: Face-to-face household 18 question survey using computer-assisted data collection undertaken by Ipsos Market and Opinion Research International. SETTING: Randomly selected households across England, January-February 2020. PARTICIPANTS: 2022 adults (aged 15+,) including 521 black, Asian and minority ethnic (BAME) participants, and 406 aged 15-25 years olds. MAIN OUTCOME MEASURES: Responses to questions about antibiotic activity, resistance and expectations for antibiotics and trust in healthcare professionals. Analyses were weighted to obtain estimates representative of the population with multivariable analysis undertaken for questions with five or more significant univariate variables. RESULTS: 84% stated they would be pleased if their general practitioner (GP) said they did not need antibiotics. Trust in GPs to make antibiotic decisions remains high (89%) and has increased for nurses (76%) and pharmacists (71%). Only 21% would challenge an antibiotic decision; this was significantly greater in BAME participants (OR 2.5; 95% CI 1.89 to 3.35). 70% reported receiving advice when prescribed antibiotics. Belief in benefits of antibiotics for ear infections was very high (68%). Similar to 2017, 81% agreed that antibiotics work for bacterial, 28% cold and influenza viruses. 84% agreed antibiotic resistant bacteria (ARB) are increasing, only 50% agreed healthy people can carry ARB and 39% agreed there was nothing they personally could do about ARB. Social grade DE and BAME participants, and those with less education had significantly less understanding about antibiotics and resistance. CONCLUSIONS: As trust in healthcare practitioners is high, we need to continue antibiotic education and other interventions at GP surgeries and community pharmacies but highlight that most ear infections are not benefitted by antibiotics. Targeted interventions are needed for socioeconomic DE, BAME groups and previous antibiotic users. We need to explore if increasing perceived personal responsibility for preventing ARB reduces antibiotic use.

Private Video Consultation Services and the Future of Primary Care.

In many countries, private companies provide primary care services based predominantly on offering video consultations via smartphones. One example is Babylon GP at Hand (BGPaH), which offers video consultations to National Health Service patients, 24 hours a day, and has grown rapidly in London over the last 3 years. The development of this type of service has been controversial, particularly in the United Kingdom, but there has been little formal published evaluation of these services in any country. This paper outlines the main controversies about the use of privately provided video consultation services for primary care and shows how they are informed by the limited evaluations that have been conducted, particularly the evaluation of BGPaH. This paper describes the advantages of these services in terms of convenience, speed of access, the ability to consult without traveling or face-to-face patient-doctor contact, and the possibility of recruiting doctors who cannot work in conventional settings or do not live near the patients. It also highlights the concerns and uncertainties about quality and safety, demand, fragmentation of care, impact on other health services, efficiency, and equity. There are questions about whether private primary care services based on video consultations have a sustainable business model and whether they will undermine other health care providers. During the recent COVID-19 pandemic, the use of video consulting has become more widespread within conventional primary care services, and this is likely to have lasting consequences for the future delivery of primary care. It is important to understand the extent to which lessons from the evaluation of BGPaH and other private services based on a video-first model are relevant to the use of video consulting within conventional general practices, and to consider the advantages and disadvantages of these developments, before video consultation-based services in primary care become more widely established.

How much information about antibiotics do people recall after consulting in primary care?

BACKGROUND: Sharing information with patients within a consultation about their infection and value of antibiotics can help reduce antibiotic prescriptions for respiratory tract infections. However, we do not know how often information is given about antibiotics or infections, and if this is related to knowledge and attitudes. OBJECTIVES: To determine the public's reported use of antibiotics, receipt of information from health professionals about antibiotics and resistance, trust in health professionals and knowledge levels about antibiotics and resistance. METHODS: Face-to-face computer-assisted survey with 1625 adults over 15 years in randomly selected households using multistage sampling. Rim weighting was used to correct for any selection biases. RESULTS: About 88% trusted their GP to determine the need for antibiotics. Of those who took antibiotics in the past year, 62% were for a throat infection, 60% for sinus infection and 42% for a cough. Although 67% who had been prescribed an antibiotic recalled being given advice about their infection or antibiotics, only 8% recalled information about antibiotic resistance. Those in lower social grades were less likely to recall advice. About 44% correctly indicated that antibiotics effectively treat bacterial rather than viral infections. Only 45% agreed that 'healthy people can carry antibiotic resistant bacteria'. CONCLUSION: GPs and health carers are trusted decision-makers, but could share more information with patients about the need or not for antibiotics, self-care and antibiotic resistance, especially with younger patients and those of lower social grade. Better ways are needed for effective sharing of information about antibiotic resistance.

Delayed/back up antibiotic prescriptions: what do the public think?

OBJECTIVE: To describe the general public's understanding, acceptance and use of delayed antibiotics. DESIGN: Face to face computer-assisted survey using an Ipsos MORI Capibus survey. SETTING: Randomly selected households in England using multistage sampling. RESPONDENTS: A representative sample of 1625 adults aged over 15 years and recruited from household visits in England, using age and gender quotas for each area. DATA COLLECTION AND ANALYSIS: The survey was undertaken in January 2014. Weights based on gender, age, ethnicity, working status, social grade, housing tenure and Government Office Region corrected for selection biases, so that results are broadly representative of the population. MAIN OUTCOMES MEASURES: Proportion of respondents; understanding the meaning of the term delayed antibiotic prescription and how the strategy is used in general practice; in favour of, or opposed to clinicians offering them a delayed antibiotic; reporting receipt, use and acceptability of delayed antibiotic prescriptions in the past year. RESULTS: 17% reported fully understanding the meaning of delayed antibiotic prescription and strategy use in general practice;72% were unaware of the term or strategy; 36-39% were in favour of, and 28-30% opposed to clinicians offering them a delayed antibiotic for throat, urine, ear or chest infections. Half of those who were fully aware of the term and practice were in favour of delayed antibiotics. Women, and older respondents, were more strongly opposed to delayed prescribing. Only 4% of all respondents, and 15% of those prescribed an antibiotic, reported being offered a delayed antibiotic in the last year. CONCLUSIONS: Wider understanding and acceptance of delayed prescribing may facilitate increased uptake. Further research is needed to determine why groups are so strongly in favour or opposed to delayed prescribing.

Incidence, severity, help seeking, and management of uncomplicated urinary tract infection: a population-based survey.

BACKGROUND: Limited knowledge of the population incidence and management of uncomplicated urinary tract infection (UTI) limits information provision and interventions to enhance care in the community. AIM: To describe incidence and severity, help seeking, and management of UTI from a population perspective. DESIGN AND SETTING: Household survey in England in 2014. METHOD: In total, a random sample of 2424 females aged ≥16 years were interviewed in their own homes using computer-assisted interviewing about their UTI symptoms, help seeking, and management. Data were weighted by sex, age, ethnicity, working status, social grade, and housing tenure, and Government Office Region to be broadly representative of the general population. RESULTS: Of the females interviewed, 892 (37%) reported having had at least one UTI in their lifetime (29% had more than one episode). In the past year, 11% of all females reported a UTI and 3% recurrent UTI (≥3 or more). Of those who had ever had a UTI, 48% rated their last UTI as fairly or very severe. In total, 95% consulted a health professional; 65% at their local GP practice during routine consulting hours. Out-of-hours consulting was uncommon but more prevalent in younger females. Of those contacting a health professional, 76% had a urine test, 74% were prescribed an antibiotic, but only 63% of these reported taking the antibiotic. Delayed antibiotic prescribing was rare. CONCLUSION: UTI symptoms are common; most females consult in general practice, and are prescribed antibiotics, but one-third report not taking the antibiotics as prescribed. Benefit and harms in those taking, and not taking, antibiotics need to be better understood in order to improve help seeking, management, and adherence. Urine tests and antibiotics could be reduced by basing empirical antibiotics on symptoms, and increasing use of back-up prescriptions.

A gp41 MPER-specific llama VHH requires a hydrophobic CDR3 for neutralization but not for antigen recognition.

The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.

Identification of proteins susceptible to thiol oxidation in endothelial cells exposed to hypochlorous acid and N-chloramines.

Hypochlorous acid (HOCl) is a potent oxidant produced by the enzyme myeloperoxidase, which is released by neutrophils under inflammatory conditions. Although important in the immune system, HOCl can also damage host tissue, which contributes to the development of disease. HOCl reacts readily with free amino groups to form N-chloramines, which also cause damage in vivo, owing to the extracellular release of myeloperoxidase and production of HOCl. HOCl and N-chloramines react readily with cellular thiols, which causes dysfunction via enzyme inactivation and modulation of redox signaling processes. In this study, the ability of HOCl and model N-chloramines produced on histamine and ammonia at inflammatory sites, to oxidize specific thiol-containing proteins in human coronary artery endothelial cells was investigated. Using a proteomics approach with the thiol-specific probe, 5-iodoacetamidofluorescein, we show that several proteins including peptidylprolyl isomerase A (cyclophilin A), protein disulfide isomerase, glyceraldehyde-3-phosphate dehydrogenase and galectin-1 are particularly sensitive to oxidation by HOCl and N-chloramines formed at inflammatory sites. This will contribute to cellular dysfunction and may play a role in inflammatory disease pathogenesis.

Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization.

Llamas (Lama glama) naturally produce heavy chain-only antibodies (Abs) in addition to conventional Abs. The variable regions (VHH) in these heavy chain-only Abs demonstrate comparable affinity and specificity for antigens to conventional immunoglobulins despite their much smaller size. To date, immunizations in humans and animal models have yielded only Abs with limited ability to neutralize HIV-1. In this study, a VHH phagemid library generated from a llama that was multiply immunized with recombinant trimeric HIV-1 envelope proteins (Envs) was screened directly for HIV-1 neutralization. One VHH, L8CJ3 (J3), neutralized 96 of 100 tested HIV-1 strains, encompassing subtypes A, B, C, D, BC, AE, AG, AC, ACD, CD, and G. J3 also potently neutralized chimeric simian-HIV strains with HIV subtypes B and C Env. The sequence of J3 is highly divergent from previous anti-HIV-1 VHH and its own germline sequence. J3 achieves broad and potent neutralization of HIV-1 via interaction with the CD4-binding site of HIV-1 Env. This study may represent a new benchmark for immunogens to be included in B cell-based vaccines and supports the development of VHH as anti-HIV-1 microbicides.

Llama antibody fragments recognizing various epitopes of the CD4bs neutralize a broad range of HIV-1 subtypes A, B and C.

Many of the neutralising antibodies, isolated to date, display limited activities against the globally most prevalent HIV-1 subtypes A and C. Therefore, those subtypes are considered to be an important target for antibody-based therapy. Variable domains of llama heavy chain antibodies (VHH) have some superior properties compared with classical antibodies. Therefore we describe the application of trimeric forms of envelope proteins (Env), derived from HIV-1 of subtype A and B/C, for a prolonged immunization of two llamas. A panel of VHH, which interfere with CD4 binding to HIV-1 Env were selected with use of panning. The results of binding and competition assays to various Env, including a variant with a stabilized CD4-binding state (gp120(Ds2)), cross-competition experiments, maturation analysis and neutralisation assays, enabled us to classify the selected VHH into three groups. The VHH of group I were efficient mainly against viruses of subtype A, C and B'/C. The VHH of group II resemble the broadly neutralising antibody (bnmAb) b12, neutralizing mainly subtype B and C viruses, however some had a broader neutralisation profile. A representative of the third group, 2E7, had an even higher neutralization breadth, neutralizing 21 out of the 26 tested strains belonging to the A, A/G, B, B/C and C subtypes. To evaluate the contribution of certain amino acids to the potency of the VHH a small set of the mutants were constructed. Surprisingly this yielded one mutant with slightly improved neutralisation potency against 92UG37.A9 (subtype A) and 96ZM651.02 (subtype C). These findings and the well-known stability of VHH indicate the potential application of these VHH as anti-HIV-1 microbicides.

Llama antibody fragments have good potential for application as HIV type 1 topical microbicides.

There is an urgent global need for preventive strategies against HIV-1 infections. Llama heavy-chain antibody fragments (VHH) are a class of molecules recently described as potent cross-clade HIV-1 entry inhibitors. We studied the potential of a VHH-based microbicide in an application-oriented fashion. We show that VHH can be inexpensively produced in high amounts in the GRAS organism Saccharomyces cerevisiae, resulting in a very pure and endotoxin free product. VHH are very stable under conditions they might encounter during transport, storage, or use by women. We developed active formulations of VHH in aqueous gel and compressed and lyophilized tablets for controlled release from an intravaginal device. The release profile of the VHH from, e.g., a vaginal ring suggests sufficient bioavailability and protective concentration of the molecule at the mucosal site at the moment of the infection. The ex vivo penetration kinetics through human tissues show that the VHH diffuse into the mucosal layer and open the possibility to create a second defense layer either by blocking the HIV receptor binding sites or by blocking the receptors of immune cells in the mucosa. In conclusion, our data show that VHH have a high potential for HIV-1 microbicide application because of their low production costs, their high stability, and their favorable release and tissue penetration properties.

NHS survey: impact of conflict resolution training on working lives of healthcare staffs.

The Consumer Fraud and Security Management Service (CFSMS) is responsible for security and safety for the 1600 hospitals and other health services of England's National Health Service (NHS). Between June 2004 and May 2005, in order to counter violence directed at nurses, other caregivers and employees, SMS provided conflict resolution training (CRT) for some 250,000 NHS healthcare workers. The survey, conducted a year after the training was completed, sought to quantify the extent to which receiving CRT improved staffers' ability to deal with verbal and physical abuse. It is reprinted with NHS permission.