Neurovirulent Vaccine-Derived Polioviruses in Sewage from Highly Immune Populations

BACKGROUND: Vaccine-derived polioviruses (VDPVs) have caused poliomyelitis outbreaks in communities with sub-optimal vaccination. Israeli environmental surveillance of sewage from populations with high (>95%) documented vaccine coverage of confirmed efficacy identified two separate evolutionary clusters of VDPVs: Group 1 (1998–2005, one system, population 1.6×10(6)) and Group 2 (2006, 2 systems, populations 0.7×10(6) and 5×10(4)). PRINCIPAL FINDINGS: Molecular analyses support evolution of nine Group 1 VDPVs along five different lineages, starting from a common ancestral type 2 vaccine-derived Sabin-2/Sabin-1 recombinant strain, and independent evolution of three Group 2 VDPVs along one lineage starting from a different recombinant strain. The primary evidence for two independent origins was based on comparison of unique recombination fingerprints, the number and distribution of identical substitutions, and evolutionary rates. Geometric mean titers of neutralizing antibodies against Group 1 VDPVs were significantly lower than against vaccine strains in all age-group cohorts tested. All individuals had neutralizing titers >1∶8 against these VDPVs except 7% of the 20–50 year cohort. Group 1 VDPVs were highly neurovirulent in a transgenic mouse model. Intermediate levels of protective immunity against Group 2 VDPVs correlated with fewer (5.0+1.0) amino acid substitutions in neutralizing antigenic sites than in Group 1 VDPV's (12.1±1.5). SIGNIFICANCE: VDPVs that revert from live oral attenuated vaccines and reacquire characteristics of wild-type polioviruses not only threaten populations with poor immune coverage, but are also a potential source for re-introduction of poliomyelitis into highly immune populations through older individuals with waning immunity. The presence of two independently evolved groups of VDPVs in Israel and the growing number of reports of environmental VDPV elsewhere make it imperative to determine the global frequency of environmental VDPV. Our study underscores the importance of the environmental surveillance and the need to reconsider the global strategies for polio eradication and the proposed cessation of vaccination

Antiviral Activity of 3(2H)- and 6-Chloro-3(2H)-Isoflavenes against Highly Diverged, Neurovirulent Vaccine-Derived, Type2 Poliovirus Sewage Isolates

BACKGROUND: Substituted flavanoids interfere with uncoating of Enteroviruses including Sabin-2 polio vaccine strains. However flavanoid resistant and dependent, type-2 polio vaccine strains (minimally-diverged), emerged during in vitro infections. Between 1998-2009, highly-diverged (8 to >15%) type-2, aVDPV(2)s, from two unrelated persistent infections were periodically isolated from Israeli sewage. AIM: To determine whether highly evolved aVDPV(2)s derived from persistent infections retained sensitivity to isoflavenes. METHODS: Sabin-2 and ten aVDPV(2) isolates from two independent Israeli sources were titered on HEp2C cells in the presence and absence of 3(2H)- Isoflavene and 6-chloro-3(2H)-Isoflavene. Neurovirulence of nine aVDPV(2)s was measured in PVR-Tg-21 transgenic mice. Differences were related to unique amino acid substitutions within capsid proteins. PRINCIPAL FINDINGS: The presence of either flavanoid inhibited viral titers of Sabin-2 and nine of ten aVDPV(2)s by one to two log(10). The tenth aVDPV(2), which had unique amino acid substitution distant from the isoflavene-binding pocket but clustered at the three- and five-fold axies of symmetry between capsomeres, was unaffected by both flavanoids. Genotypic neurovirulence attenuation sites in the 5'UTR and VP1 reverted in all aVDPV(2)s and all reacquired a full neurovirulent phenotype except one with amino acid substitutions flanking the VP1 site. CONCLUSION: Both isoflavenes worked equally well against Sabin 2 and most of the highly-diverged, Israeli, aVDPV(2)s isolates. Thus, functionality of the hydrophobic pocket may be unaffected by selective pressures exerted during persistent poliovirus infections. Amino acid substitutions at sites remote from the drug-binding pocket and adjacent to a neurovirulence attenuation site may influence flavanoid antiviral activity, and neurovirulence, respectively

Coming Full Circle: Reflections and Inspirations from a Cystic Fibrosis Patient Scientist Panel

Care for many progressive chronic diseases continues to improve, allowing patients to survive and thrive for longer periods of time1. People living with such conditions may now find themselves able to achieve long-term goals in education and career development2. Many people now occupy the dual roles of scientist and patient3. This commentary article synthesizes experiences of scientists and advocates with the progressive genetic disease cystic fibrosis (CF) who collaborated on a career development session for the Cystic Fibrosis Foundation’s inaugural ResearchCon event in 2019. It explores how such collaborations affirm and transform individual perspectives on patient science and its importance in broader scientific research agenda setting. We first share our own individual insights about the experience and impact of the ResearchCon panel session before progressing to discussion and future directions centering the shared insights from one another’s reflections

The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth

Chromobox 2 (CBX2) is a chromatin-binding component of polycomb repressive complex 1, which causes gene silencing. CBX2 expression is elevated in triple-negative breast cancer (TNBC), for which there are few therapeutic options. Here, we aimed to investigate the functional role of CBX2 in TNBC. CBX2 knockdown in TNBC models reduced cell numbers, which was rescued by ectopic expression of wild-type CBX2 but not a chromatin binding-deficient mutant. Blocking CBX2 chromatin interactions using the inhibitor SW2_152F also reduced cell growth, suggesting CBX2 chromatin binding is crucial for TNBC progression. RNA sequencing and gene set enrichment analysis of CBX2-depleted cells identified downregulation of oncogenic signalling pathways, including mTORC1 and E2F signalling. Subsequent analysis identified that CBX2 represses the expression of mTORC1 inhibitors and the tumour suppressor RBL2. RBL2 repression, in turn, inhibits DREAM complex activity. The DREAM complex inhibits E2F signalling, causing cell senescence; therefore, inhibition of the DREAM complex via CBX2 may be a key oncogenic driver. We observed similar effects in oestrogen receptor-positive breast cancer, and analysis of patient datasets suggested CBX2 inhibits RBL2 activity in other cancer types. Therapeutic inhibition of CBX2 could therefore repress mTORC1 activation and promote DREAM complex-mediated senescence in TNBC and could have similar effects in other cancer types

Understanding consumers’ perceptions of smoke-affected wines

Smoke taint in grapes and wine is complicated. If a vineyard is exposed to smoke, there are a whole range of factors that determine whether or not the wine eventually made from those grapes will be smoke-affected and to what degree. While many of those factors are now quite well understood (Coulter, 2022; Parker et al., 2023), questions still remain about what consumers think. Do they notice smoke characters in wine? Do they like or dislike them? How strong do smoke characters need to be to cause a reaction in consumers? And are all consumers the same when it comes to smoky wines? Three recent consumer sensory studies at the AWRI aimed to learn more about the answers to these questions. This article presents a summary of the results and conclusions of this work. Full details were recently published by Bilogrevic et al. (2023) as an open access article in the peer-reviewed journal, OENO One (https://doi.org/10.20870/oeno-one.2023.57.2.7261)

Interventions to increase attendance for diabetic retinopathy screening

BACKGROUND: Despite evidence supporting the effectiveness of diabetic retinopathy screening (DRS) in reducing the risk of sight loss, attendance for screening is consistently below recommended levels.OBJECTIVES: The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.Secondary objectives were:To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness.SEARCH METHODS: We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, Web of Science, ProQuest Family Health, OpenGrey, the ISRCTN, ClinicalTrials.gov, and the WHO ICTRP to identify randomised controlled trials (RCTs) that were designed to improve attendance for DRS or were evaluating general quality improvement (QI) strategies for diabetes care and reported the effect of the intervention on DRS attendance. We searched the resources on 13 February 2017. We did not use any date or language restrictions in the searches.SELECTION CRITERIA: We included RCTs that compared any QI intervention to usual care or a more intensive (stepped) intervention versus a less intensive intervention.DATA COLLECTION AND ANALYSIS: We coded the QI strategy using a modification of the taxonomy developed by Cochrane Effective Practice and Organisation of Care (EPOC) and BCTs using the BCT Taxonomy version 1 (BCTTv1). We used Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status, and Social capital (PROGRESS) elements to describe the characteristics of participants in the included studies that could have an impact on equity of access to health services.Two review authors independently extracted data. One review author entered the data into Review Manager 5 and a second review author checked them. Two review authors independently assessed risks of bias in the included studies and extracted data. We rated certainty of evidence using GRADE.MAIN RESULTS: We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs 'goal setting (outcome)' (RD 0.26, 95% CI 0.16 to 0.36) and 'feedback on outcomes of behaviour' (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and 'restructuring the social environment' (RD 0.19, 95% CI 0.12 to 0.26) and 'credible source' (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).Fourteen studies reporting any QI intervention compared to usual care included economic outcomes. However, only five of these were full economic evaluations. Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.With the exception of gender and ethnicity, the characteristics of participants were poorly described in terms of PROGRESS elements. Seventeen studies (25.8%) were conducted in disadvantaged populations. No studies were carried out in low- or middle-income countries.AUTHORS' CONCLUSIONS: The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care. This is a significant finding, due to the additional benefits of general QI interventions in terms of improving glycaemic control, vascular risk management and screening for other microvascular complications. It is likely that further (but smaller) improvements in DRS attendance can also be achieved by increasing the intensity of a particular QI component or adding further components.</p

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Polymer hydrogel-based microneedles for metformin release

Drug delivery devices ensure the effective delivery of a broad range of therapeutics to millions of patients worldwide on a daily basis.1 Microneedles are a class of drug delivery device that provide pain free transdermal delivery with improved patient compliance.2-4 The release of metformin, a drug used in the treatment of cancer and diabetes, from polymer hydrogel-based microneedle patches was demonstrated in vitro. Tuning the composition of the polymer hydrogels enabled preparation of robust microneedle patches with mechanical properties such that they would penetrate skin (insertion force of a single microneedle to be ca. 40 N). Swelling experiments conducted at 20°C, 35°C and 60°C show temperature dependent degrees of swelling and kinetics (Fickian diffusion). Drug release from the hydrogel-based microneedles was fitted to various models (e.g., zero order, first order, second order, Korsmeyer-Peppas, Peppas-Sahlins), observing the best fit for the zero-order model. Such microneedles have potential application for transdermal delivery of metformin for the treatment of cancer and diabetes