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Complementary and alternative medicine: Do physicians believe they can meet the requirements of the Collège des médecins du Québec?
OBJECTIVE: To determine whether medical training prepares FPs to meet the requirements of the Collège des médecins du Québec for their role in advising patients on the use of complementary and alternative medicine (CAM). DESIGN: Secondary analysis of survey results. SETTING: Quebec. PARTICIPANTS: Family physicians and GPs in active practice. MAIN OUTCOME MEASURES: Perceptions of the role of the physician as an advisor on CAM; level of comfort responding to questions and advising patients on CAM; frequency with which patients ask their physicians about CAM; personal position on CAM; and desire for training on CAM. RESULTS: The response rate was 19.5% (195 respondents of 1000) and the sample appears to be representative of the target population. Most respondents (85.8%) reported being asked about CAM several times a month. A similar proportion (86.7%) believed it was their role to advise patients on CAM. However, of this group, only 33.1% reported being able to do so. There is an association between an urban practice and knowledge of the advisory role of physicians. More than three-quarters of respondents expressed interest in receiving additional training on CAM. CONCLUSION: There is a gap between the training that Quebec physicians receive on CAM and their need to meet legal and ethical obligations designed to protect the public where CAM products and therapies are concerned. One solution might be more thorough training on CAM to help physicians meet the Collège des médecins du Québec requirements.
Autovaccination revisited: potential to boost antiviral immunity and facilitate HIV-1 cure/remission in children.
PURPOSE OF REVIEW: To review the concept of autovaccination as a strategy to boost anti-HIV-1 immunity and improve immune control, especially as a means to facilitate cure/remission in paediatric HIV-1 infection, where effective interventions in clinical testing remain limited compared to adults. RECENT FINDINGS: Early autovaccination studies, conducted 15-25 years ago, suggested potential immunological benefits from exposure to autologous virus in both children and adults, specifically when antiretroviral therapy (ART) was initiated during acute infection. More recent work in nonhuman primates (NHPs) has shown that early ART initiation can significantly reduce the viral setpoint following treatment interruption, primarily through CD8+ T-cell responses, and prevent early immune escape - a phenomenon commonly observed in ART-naive acute infections. Additionally, NHP studies indicate that multiple, short analytical treatment interruptions (ATIs) can delay viral rebound and further lower the viral setpoint via enhanced CD8+ T-cell responses. SUMMARY: Recent studies in NHP support the potential for autovaccination via short ATIs to enhance antiviral immunity and improve immune control of HIV-1. With well tolerated, well monitored ATI protocols, autovaccination could be a valuable approach to facilitating cure/remission in children living with HIV (LWH), in whom very early-ART initiation and early-life immunity are associated with low viral reservoirs and high cure/remission potential.
Mass testing for discovery and control of COVID-19 outbreaks in adult social care: an observational study and cost-effectiveness analysis of 14 805 care homes in England.
INTRODUCTION: We retrospectively evaluated the impact of COVID-19 testing among residents and staff in social care homes in England. METHODS: We obtained 80 million reported PCR and lateral flow device (LFD) test results, from 14 805 care homes (residents and staff) in England, conducted between October 2020 and March 2022. These testing data were then linked to care home characteristics, test costs and 24 500 COVID-19-related deaths of residents. We decomposed the mechanism of outbreak mitigation into outbreak discovery and outbreak control and used Poisson regressions to investigate how reported testing intensity was associated with the size of outbreak discovered and to uncover its association with outbreak control. We used negative binomial regressions to determine the factors influencing COVID-19-related deaths subsequent to outbreaks. We performed a cost-effectiveness analysis of the impact of testing on preventing COVID-19-related deaths of residents. RESULTS: Reported testing intensity generally reflected changes in testing policy over time, although there was considerable heterogeneity among care homes. Client type was the strongest determinant of whether COVID-19-related deaths in residents occurred subsequent to testing positive. Higher staff-to-resident ratios were associated with larger outbreak sizes but rapid outbreak control and a decreased risk of COVID-19-related deaths. Assuming our regression estimates represent causal effects, care home testing in England was cost-effective at preventing COVID-19-related deaths among residents during the pandemic and approximately 3.5 times more cost-effective prior to the vaccine rollout. CONCLUSIONS: PCR and LFD testing was likely an impactful intervention for detecting and controlling COVID-19 outbreaks in care homes in England and cost-effective for preventing COVID-19-related deaths among residents. In future pandemics, testing must be prioritised for care homes, especially if severe illness and death particularly affect older people or individuals with characteristics similar to care home residents, and an efficacious vaccine is unavailable.
First-trimester nutrition insights from the United Arab Emirate Birth Cohort Study (UAE-BCS): assessment of dietary intake, micronutrient profiles, and folic acid supplementation in Emirati Women.
Maternal health and nutrition in early pregnancy play a vital role in the growth and development of the foetus. During this time, macro and micronutrients contribute to nutritional programming, which helps form the foundations of the foetus's life course health outcomes. This study aimed to investigate dietary habits, macro and micronutrient intake, micronutrient status, and folic acid supplement adherence among Emirati pregnant women in their first trimester. Data were collected according to the UAE-BCS study protocol, which was set up to investigate maternal nutrition, health, child growth, and developmental outcomes within the first 1000 days. Pregnant Emirati women with singleton pregnancies within their first trimester of pregnancy (between 8 and 12 weeks of gestation) were enrolled. The 24-hour food recall method was administered to collect dietary intake. The maternal mean average age was 29 years. Participants had high adherence to supplementation during pregnancy compared to preconception. The mean energy intake was 1345kcal, and 56% of participants consumed saturated fats above the acceptable macronutrient distribution ranges (AMDR), while 94% consumed below AMDR for total fibre. The consumption of micronutrients was below the recommended dietary allowance (RDA). Biochemical results show a high prevalence of low haemoglobin (74%) and deficiencies in vitamin D (39%) and vitamin E (96%). There is a need for research into dietary patterns and influences in pregnant women in the UAE. Furthermore, investigations of knowledge practices and attitudes towards supplementation and the factors contributing to folic acid supplement use are needed to inform government strategies and interventions.
Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments.
Of the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants are suitable candidates for this type of genetic therapy. The patient identification working group of the N=1 Collaborative (N1C), alongside an international group of volunteer assessors, has developed and piloted consensus guidelines for assessing the eligibility of pathogenic DNA variants for ASO treatments. We herein present the N1C VARIANT (variant assessments toward eligibility for antisense oligonucleotide treatment) guidelines, including the guiding scientific principles and our approach to consensus building. Pathogenic, disease-causing variants can be assessed for the three currently best-established ASO treatment approaches: splice correction, exon skipping, and downregulation of RNA transcripts. A genetic variant is classified as "eligible," "likely eligible," "unlikely eligible," or "not eligible" in relation to the different approaches or as "unable to assess." We also review key considerations related to assessing the upregulation of transcripts from the wild-type allele, an emerging ASO therapeutic strategy. We provide additional tools and training materials to enable clinicians and researchers to use these guidelines for their eligibility assessments. With this initial edition of our N1C VARIANT guidelines, we provide the rare genetic disease community with guidance on how to identify suitable candidates for variant-specific ASO-based therapies and the possibility of integrating such assessments into routine clinical practice.
Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals.
With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments.
Influential drivers of the cost-effectiveness of respiratory syncytial virus vaccination in European older adults: a multi-country analysis
Background: We aimed to identify influential drivers of the cost-effectiveness of older adult respiratory syncytial virus (RSV) vaccination in Denmark, Finland, the Netherlands and Valencia-Spain. Methods: A static multi-cohort model was parameterised using country- and age-specific hospitalisations using three approaches: (A) the International Classification of Diseases (ICD)-coded hospitalisations, (B) laboratory RSV-confirmed hospitalisations and (C) time-series modelling (TSM). Plausible hypothetical RSV vaccine characteristics were derived from two protein subunit vaccines for adults aged ≥60 years. A full incremental analysis was conducted by comparing three RSV vaccination strategies: (1) in adults aged ≥60 years (“60y+”); (2) in adults aged ≥65 years (“65y+”); (3) in adults aged ≥75 years (“75y+”) to “no intervention” and to each other. Both costs and quality-adjusted life-years (QALYs) were discounted at country-specific discount rates and the analysis was conducted from both the healthcare payers’ and societal perspectives. Value of information, probabilistic sensitivity and scenario analyses identified influential drivers. Results: Besides vaccine price, the hospitalisation estimates were most influential: (A) Using adjusted RSV-ICD-coded hospitalisations at a vaccine price of €150 per dose, no intervention was cost-effective up to willingness-to-pay (WTP) values of €150,000 per QALY gained in Denmark and the Netherlands, and up to €124,000 per QALY gained in Finland. (B) Using the adjusted RSV-confirmed dataset, the findings were consistent in Denmark and comparable in Finland. In Spain-Valencia, the 75y+ strategy became cost-effective at WTP >€55,000. (C) Using TSM-based estimates, the 75y+ strategy was cost-effective at WTP >€45,000, >€101,000, >€41,000 and >€114,000 in Denmark, Finland, the Netherlands and Spain-Valencia, respectively. Sensitivity analyses showed that the (in-hospital) case fatality ratio and the specification of its age dependency were both influential. Duration of protection was found more influential than a variety of plausible waning patterns over the duration of protection. Conclusions: Data gaps and uncertainties on the RSV-related burden in older adults persist and influence the cost-effectiveness of RSV vaccination. More refined age- and country-specific data on the RSV attributable burden are crucial to aid decision making.
Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome.
The osteo-oto-hepato-enteric (O2HE) syndrome is a severe autosomal recessive disease ascribed to loss-of-function mutations in the Unc-45 myosin chaperone A (UNC45A) gene. The clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease-like enteropathy. Here, we present molecular and functional analysis of the UNC45A c.710T>C (p.Leu237Pro) missense variant, which revealed a unique pathogenicity compared with other genetic variants causing UNC45A deficiency. The UNC45A p.Leu237Pro mutant retained chaperone activity, prevented myosin aggregation, and supported proper nonmuscle myosin II (NMII) filament formation in patient fibroblasts and human osteosarcoma (U2OS) cells. However, the mutant formed atypically stable oligomers and prevented chaperone-myosin complex dissociation, thereby inhibiting NMII functions. Similar to biallelic UNC45A deficiency, this resulted in impaired intracellular trafficking, defective recycling, and abnormal retention of transferrin at various endocytic sites. In particular, coexpression of wild-type protein attenuated the pathogenic effects of the variant by inhibiting excessive oligomer formation. Our results elucidate the pathogenic mechanisms and recessive characteristics of this variant and may aid in the development of targeted therapies.
The respiratory syncytial virus vaccine and monoclonal antibody landscape: the road to global access.
Respiratory syncytial virus (RSV) is the second most common pathogen causing infant mortality. Additionally, RSV is a major cause of morbidity and mortality in older adults (age ≥60 years) similar to influenza. A protein-based maternal vaccine and monoclonal antibody (mAb) are now market-approved to protect infants, while an mRNA and two protein-based vaccines are approved for older adults. First-year experience protecting infants with nirsevimab in high-income countries shows a major public health benefit. It is expected that the RSV vaccine landscape will continue to develop in the coming years to protect all people globally. The vaccine and mAb landscape remain active with 30 candidates in clinical development using four approaches: protein-based, live-attenuated and chimeric vector, mRNA, and mAbs. Candidates in late-phase trials aim to protect young infants using mAbs, older infants and toddlers with live-attenuated vaccines, and children and adults using protein-based and mRNA vaccines. This Review provides an overview of RSV vaccines highlighting different target populations, antigens, and trial results. As RSV vaccines have not yet reached low-income and middle-income countries, we outline urgent next steps to minimise the vaccine delay.
Efficacy of a Novel BCL-xL Degrader, DT2216, in Preclinical Models of JAK2-mutated Post-MPN AML.
Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments don't significantly extend survival beyond 12 months. BCL-xL has been found to be overexpressed in leucocytes from MPN patients, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera (PROTAC), in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in post-MPN AML patients compared to those with de novo AML. Single-cell multi-omics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression, elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells (iPSC-HPCs), primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from post-MPN AML patients. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.
A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia.
Pneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A, BAG3, TDRD9, MXRA7, and KLF14) that effectively distinguishes bacterial from viral pneumonia (area under the curve (AUC): 0.95 [0.88-1.00]). Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77-0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83-1.00]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments and potentially transforming clinical practice.
A diagnostic host-specific transcriptome response for Mycoplasma pneumoniae pneumonia to guide pediatric patient treatment.
Mycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84-0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients.
Epidemiology of Group B Streptococcus: Maternal Colonization and Infant Disease in Kampala, Uganda
Abstract Background Child survival rates have improved globally, but neonatal mortality due to infections, such as group B Streptococcus (GBS), remains a significant concern. The global burden of GBS-related morbidity and mortality is substantial. However, data from low and middle-income countries is lacking. Vaccination during pregnancy could be a feasible strategy to address GBS-related disease burden. Methods We assessed maternal rectovaginal GBS colonization and neonatal disease rates in a prospective cohort of 6062 women-infant pairs. Surveillance for invasive infant disease occurred in parallel at two Kampala hospital sites. In a nested case-control study, we identified infants <90 days of age with invasive GBS disease (iGBS) (n=24) and healthy infants born to mothers colonized with GBS (n=72). We measured serotype-specific anti-capsular immunoglobulin G in cord blood/infant sera using a validated multiplex Luminex assay. Results We found a high incidence of iGBS (1.0 per 1,000 live births) within the first 90 days of life across the surveillance sites, associated with a high case fatality rate (18.2%). Maternal GBS colonization prevalence was consistent with other studies in the region (14.7%; 95% confidence interval 13.7-15.6%). IgG geometric mean concentrations were lower in cases than controls for serotypes Ia (0.005 vs 0.12 µg/mL; p=0.05), III (0.011 vs 0.036 µg/mL; p=0.07) and in an aggregate analysis of all serotypes, (0.014 vs 0.05 µg/mL; p=0.02). Conclusions We found that GBS is an important cause of neonatal and young infant disease in Uganda and confirmed that maternally derived antibodies were lower in early-onset GBS cases than in healthy exposed controls.
Biodistribution of therapeutic extracellular vesicles.
The field of extracellular vesicles (EVs) has seen a tremendous paradigm shift in the past two decades, from being regarded as cellular waste bags to being considered essential mediators in intercellular communication. Their unique ability to transfer macromolecules across cells and biological barriers has made them a rising star in drug delivery. Mounting evidence suggests that EVs can be explored as efficient drug delivery vehicles for a range of therapeutic macromolecules. In contrast to many synthetic delivery systems, these vesicles appear exceptionally well tolerated in vivo. This tremendous development in the therapeutic application of EVs has been made through technological advancement in labelling and understanding the in vivo biodistribution of EVs. Here in this review, we have summarised the recent findings in EV in vivo pharmacokinetics and discussed various biological barriers that need to be surpassed to achieve tissue-specific delivery.
Acceptability of the gonorrhoea human challenge model to accelerate vaccine development in UK men.
BACKGROUND: 281 million people worldwide were diagnosed with a bacterial sexually transmitted infection (STI) in 2020. Antimicrobial therapy for bacterial STIs is a key contributor to antimicrobial resistance (AMR) and multidrug resistant gonorrhoea is an urgent global health threat. Development of an efficacious gonorrhoea vaccine is a global health priority to address AMR. The controlled human infection model for gonorrhoea (GC-CHIM) could accelerate gonorrhoea vaccine development. This work sought to assess the acceptability of the urogenital model to UK men. METHODS: A mixed-methods study of UK men aged 18-35 years old was undertaken to assess acceptability of the urogenital GC-CHIM to UK men and attitudes to STI research, vaccines and AMR. Participants completed an online survey indicating their agreement with a series of statements using a Likert scale. Semi-structured interviews were performed on a subset of participants to gain insight into their survey responses. RESULTS: Survey responses from 72 participants and 13 interviewees highlighted stigma associated with STIs as a key barrier to, and perceived risk of, participation in STI research and GC-CHIM studies. Financial reimbursement was an important motivator, and some felt this should include compensation for intimate procedures, potential embarrassment and sexual abstinence. Individuals willing to participate in a GC-CHIM study were more likely to have personal experience of STIs, be educated to postgraduate level and describe their sexuality as gay or bisexual than those who were ambivalent or opposed to participation. CONCLUSIONS: Recruitment of participants to UK urogenital GC-CHIM studies is feasible. Sexual abstinence can be a significant inconvenience for individuals that could be recognised via reimbursement. Care should be taken generalising results from STI vaccine research where participants may not be representative of the general population. Investigators in STI research should recognise stigmatisation as a potential risk for participants and promote their STI research sensitively as a means to counter misinformation and stigma.