Recommendations for defining preventable HIV-related mortality for public health monitoring in the era of Getting to Zero: an expert consensus

Getting to Zero is a commonly cited strategic aim to reduce mortality due to both HIV and avoidable deaths among people with HIV. However, no clear definitions are attached to these aims with regard to what constitutes HIV-related or preventable mortality, and their ambition is limited. This Position Paper presents consensus recommendations to define preventable HIV-related mortality for a pragmatic approach to public health monitoring by use of national HIV surveillance data. These recommendations were informed by a comprehensive literature review and agreed by 42 international experts, including clinicians, public health professionals, researchers, commissioners, and community representatives. By applying the recommendations to 2019 national HIV surveillance data from the UK, we show that 30% of deaths among people with HIV were HIV-related or possibly HIV-related, and at least 63% of these deaths were preventable or potentially preventable. The application of these recommendations by health authorities will ensure consistent monitoring of HIV elimination targets and allow for the identification of inequalities and areas for intervention

Peanut Can Be Used as a Reference Allergen for Hazard Characterization in Food Allergen Risk Management: A Rapid Evidence Assessment and Meta-Analysis

Regional and national legislation mandates the disclosure of “priority” allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen (“may contain”) labels (PAL) that are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and nonuniformity in the use of PAL by food businesses. One potential solution would be to establish internationally agreed “reference doses,” below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to a low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at a low-level allergen exposure. Resumen: La legislación regional y nacional exige la divulgación de alérgenos "prioritarios" cuando están presentes como ingrediente en los alimentos, pero esto no se extiende a la presencia involuntaria de alérgenos debido a instalaciones de producción compartidas. Esto ha dado lugar a una proliferación de etiquetas de precaución para alérgenos ("pueden contener") (PAL) que los consumidores alérgicos a los alimentos suelen ignorar. Se han hecho intentos para mejorar la gestión del riesgo de alérgenos para informar mejor el uso de PAL, pero la falta de consenso ha llevado a una variedad de enfoques regulatorios y a la falta de uniformidad en el uso de PAL por parte de las empresas alimentarias. Una posible solución sería establecer “dosis de referencia” acordadas internacionalmente, por debajo de las cuales no se necesitaría PAL. Sin embargo, si se van a utilizar dosis de referencia para informar la necesidad de PAL, entonces es esencial caracterizar el peligro asociado con estas exposiciones de bajo nivel. Para el maní, ahora hay datos publicados relacionados con más de 3000 desafíos doble ciego controlados por placebo en individuos alérgicos, pero falta un nivel similar de evidencia para otros alérgenos prioritarios. Presentamos los resultados de una evaluación rápida de la evidencia y un metanálisis del riesgo deanafilaxia a una exposición a alérgenos de bajo nivel para alérgenos prioritarios. Sobre la base de este análisis, proponemos que el cacahuete puede y debe considerarse un alérgeno ejemplar para la caracterización del peligro en una exposición a un alérgeno de bajo nivel.Instituto de Investigación de Tecnología de AlimentosFil: Turner, Paul J. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Patel, Nandinee. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ballmer-Weber, Barbara K. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ballmer-Weber, Barbara K. Clínica de Dermatología y Alergología. Kantonsspital; Suiza.Fil: Baumert, Joe L. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Blom, W. Marty. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brooke-Taylor, Simon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brough, Helen. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brough, Helen. King's College London. Departamento de Alergia Pediátrica; Reino Unido.Fil: Campbell, Dianne E. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Campbell, Dianne E. Tecnologías DBV. Montrouge; Francia.Fil: Chen, Hongbing. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Chinthrajah, R. Sharon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Crevel, René W.R. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Dubois, Anthony E.J. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ebisawa, Motohiro. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Elizur, Arnon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Elizur, Arnon. Universidad de Tel Aviv. Facultad de Medicina Sackler. Departamento de Pediatría; Israel.Fil: Gerdts, Jennifer D. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Gowland, M. Hazel. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Houben, Geert F. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Hourihane, Jonathan O.B. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Knulst, André C. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: La Vieille, Sébastien. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: López, María Cristina. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Mills, E.N. Clare. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Polenta, Gustavo Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Polenta, Gustavo Alberto. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Purington, Natasha. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Said, María. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Sampson, Hugh A. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Sampson, Hugh A. Escuela de Medicina Icahn. División de Alergia e Inmunología Pediátricasen. Nueva York. Estados Unidos de América.Fil: Schnadt, Sabine. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Södergren, Eva. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Södergren, Eva. ThermoFisher Scientific; Suecia.Fil: Taylor, Stephen L. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Remington, Benjamin C. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Remington, Benjamin C. Grupo BV. Consultoría Remington; Holanda

Development and preliminary validation of the 'Caring for Country' questionnaire: measurement of an Indigenous Australian health determinant

<p>Abstract</p> <p>Background</p> <p>'Caring for Country' is defined as Indigenous participation in interrelated activities with the objective of promoting ecological and human health. Ecological services on Indigenous-owned lands are belatedly attracting some institutional investment. However, the health outcomes associated with Indigenous participation in 'caring for country' activities have never been investigated. The aims of this study were to pilot and validate a questionnaire measuring caring for country as an Indigenous health determinant and to relate it to an external reference, obesity.</p> <p>Methods</p> <p>Purposively sampled participants were 301 Indigenous adults aged 15 to 54 years, recruited during a cross-sectional program of preventive health checks in a remote Australian community. Questionnaire validation was undertaken with psychometric tests of internal consistency, reliability, exploratory factor analysis and confirmatory one-factor congeneric modelling. Accurate item weightings were derived from the model and used to create a single weighted composite score for caring for country. Multiple linear regression modelling was used to test associations between the caring for country score and body mass index adjusting for socio-demographic factors and health behaviours.</p> <p>Results</p> <p>The questionnaire demonstrated adequate internal consistency, test-retest validity and proxy-respondent validity. Exploratory factor analysis of the 'caring for country' items produced a single factor solution that was confirmed via one-factor congeneric modelling. A significant and substantial association between greater participation in caring for country activities and lower body mass index was demonstrated. Adjusting for socio-demographic factors and health behaviours, an inter-quartile range rise in caring for country scores was associated with 6.1 Kg and 5.3 Kg less body weight for non-pregnant women and men respectively.</p> <p>Conclusion</p> <p>This study indicates preliminary support for the validity of the caring for country concept and a questionnaire designed to measure it. This study also highlights the importance of investigating Indigenous-asserted health promotion activities. Further studies in similar populations are merited to test the generalisability of this questionnaire and to explore associations with other important Indigenous health outcomes.</p

Development and validation of combined symptom-medication scores for allergic rhinitis*

Background Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of allergic rhinitis treatments. This study aimed to use real-life data from the MASK-air(R) app to generate and validate hypothesis- and data-driven CSMSs. Methods We used MASK-air(R) data to assess the concurrent validity, test-retest reliability and responsiveness of one hypothesis-driven CSMS (modified CSMS: mCSMS), one mixed hypothesis- and data-driven score (mixed score), and several data-driven CSMSs. The latter were generated with MASK-air(R) data following cluster analysis and regression models or factor analysis. These CSMSs were compared with scales measuring (i) the impact of rhinitis on work productivity (visual analogue scale [VAS] of work of MASK-air(R), and Work Productivity and Activity Impairment: Allergy Specific [WPAI-AS]), (ii) quality-of-life (EQ-5D VAS) and (iii) control of allergic diseases (Control of Allergic Rhinitis and Asthma Test [CARAT]). Results We assessed 317,176 days of MASK-air(R) use from 17,780 users aged 16-90 years, in 25 countries. The mCSMS and the factor analyses-based CSMSs displayed poorer validity and responsiveness compared to the remaining CSMSs. The latter displayed moderate-to-strong correlations with the tested comparators, high test-retest reliability and moderate-to-large responsiveness. Among data-driven CSMSs, a better performance was observed for cluster analyses-based CSMSs. High accuracy (capacity of discriminating different levels of rhinitis control) was observed for the latter (AUC-ROC = 0.904) and for the mixed CSMS (AUC-ROC = 0.820). Conclusion The mixed CSMS and the cluster-based CSMSs presented medium-high validity, reliability and accuracy, rendering them as candidates for primary endpoints in future rhinitis trials.Peer reviewe

Development and validation of combined symptom‐medication scores for allergic rhinitis*

Background: Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of allergic rhinitis treatments. This study aimed to use real-life data from the MASK-air® app to generate and validate hypothesis- and data-driven CSMSs. Methods: We used MASK-air® data to assess the concurrent validity, test-retest reliability and responsiveness of one hypothesis-driven CSMS (modified CSMS: mCSMS), one mixed hypothesis- and data-driven score (mixed score), and several data-driven CSMSs. The latter were generated with MASK-air® data following cluster analysis and regression models or factor analysis. These CSMSs were compared with scales measuring (i) the impact of rhinitis on work productivity (visual analogue scale [VAS] of work of MASK-air® , and Work Productivity and Activity Impairment: Allergy Specific [WPAI-AS]), (ii) quality-of-life (EQ-5D VAS) and (iii) control of allergic diseases (Control of Allergic Rhinitis and Asthma Test [CARAT]). Results: We assessed 317,176 days of MASK-air® use from 17,780 users aged 16-90 years, in 25 countries. The mCSMS and the factor analyses-based CSMSs displayed poorer validity and responsiveness compared to the remaining CSMSs. The latter displayed moderate-to-strong correlations with the tested comparators, high test-retest reliability and moderate-to-large responsiveness. Among data-driven CSMSs, a better performance was observed for cluster analyses-based CSMSs. High accuracy (capacity of discriminating different levels of rhinitis control) was observed for the latter (AUC-ROC = 0.904) and for the mixed CSMS (AUC-ROC = 0.820). Conclusion: The mixed CSMS and the cluster-based CSMSs presented medium-high validity, reliability and accuracy, rendering them as candidates for primary endpoints in future rhinitis trials

Chemosensitivity profiling of osteosarcoma tumour cell lines identifies a model of BRCAness

Osteosarcoma (OS) is an aggressive sarcoma, where novel treatment approaches are required. Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) patterns reminiscent of BRCA1 or BRCA2 mutant tumours. This raises the possibility that PARP inhibitors (PARPi), used to treat BRCA1/2 mutant cancers, could be used to target OS. Using high-throughput drug sensitivity screening we generated chemosensitivity profiles for 79 small molecule inhibitors, including three clinical PARPi. Drug screening was performed in 88 tumour cell lines, including 18 OS TCLs. This identified known sensitivity effects in OS TCLs, such as sensitivity to FGFR inhibitors. When compared to BRCA1/2 mutant TCLs, OS TCLs, with the exception of LM7, were PARPi resistant, including those with previously determined BRCAness LoH profiles. Post-screen validation experiments confirmed PARPi sensitivity in LM7 cells as well as a defect in the ability to form nuclear RAD51 foci in response to DNA damage. LM7 provides one OS model for the study of PARPi sensitivity through a potential defect in RAD51-mediated DNA repair. The drug sensitivity dataset we generated in 88 TCLs could also serve as a resource for the study of drug sensitivity effects in OS

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Protocol for a systematic review of the diagnostic test accuracy of tests for IgE-mediated food allergy

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of updating the guidelines on the diagnosis and management of food allergy. The existing guidelines are based on a systematic review of the literature until 30 September 2012. Therefore, a new systematic review must be undertaken to inform the new guidelines. This systematic review aims to assess the accuracy of index tests to support the diagnosis of IgE-mediated food allergy. Methods: The databases Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID) will be searched for diagnostic test accuracy studies from 1 October 2012 to 30 June 2021. Inclusion and exclusion criteria will be used to select appropriate studies. Data from these studies will be extracted and tabulated, and then reviewed for risk of bias and applicability using the QUADAS-2 tool. All evaluations will be done in duplicate. Studies with a high risk of bias and low applicability will be excluded. Meta-analysis will be performed if there are three or more studies of the same index test and food. Results: A protocol for the systematic review and meta-analyses is presented and was registered using Prospero prior to commencing the literature search. Discussion: Oral food challenges are the reference standard for diagnosis but involve considerable risks and resources. This protocol for systematic review aims to assess the accuracy of various tests to diagnose food allergy, which can be useful in both clinical and research settings