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Our engagement project aimed to improve our understanding of the issue of antimicrobial use and antimicrobial resistance (AMR) among adult Thai communities, and co-create locally relevant solutions to AMR, especially those focusing on raising awareness to improve related policies in Thailand.<\/jats:p>\n                  <jats:p>We conducted a series of online and in-person \u2018conversations\u2019 according to Wellcome\u2019s \u2018Responsive Dialogues\u2019 engagement approach, designed to bring together different voices to understand complex AMR problems and find potential solutions. This approach enabled key AMR stakeholders and policy makers to hear directly from communities and members of the public, and vice versa. Conversations events took place between 25 November 2020 and 8 July 2022, and we engaged 179 AMR key stakeholders and members of the public across Thailand.<\/jats:p>\n                  <jats:p>The issues found were: there were quite a lot of misunderstandings around antimicrobials and AMR; participants felt that communications and engagement around antimicrobial resistance had limited reach and impact; asking for and taking antibiotics for self-limiting ailments is a social norm in Thailand; and there appeared to be a wide availability of cheap antimicrobials. To mitigate the spread of AMR, participants suggested that the messages around AMR should be tailored to the target audience, there should be more initiatives to increase general health literacy, there should be increased availability of AMR related information at the local level and there should be increased local leadership of AMR mitigation efforts.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial registration\u00a0<\/jats:bold>\n                    Thaiclinicaltrials.org registration: TCTR20210528003 (28\/05\/2021).\n                  <\/jats:p>","DOI":"10.1186\/s13756-024-01416-2","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T08:01:37Z","timestamp":1720080097000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Embedding community and public voices in co-created solutions to mitigate antimicrobial resistance (AMR) in Thailand using the \u2018Responsive Dialogues\u2019 public engagement framework"],"prefix":"10.1186","volume":"13","author":[{"given":"Tassawan","family":"Poomchaichote","sequence":"first","affiliation":[]},{"given":"Niyada","family":"Kiatying-Angsulee","sequence":"additional","affiliation":[]},{"given":"Kanpong","family":"Boonthaworn","sequence":"additional","affiliation":[]},{"given":"Bhensri","family":"Naemiratch","sequence":"additional","affiliation":[]},{"given":"Supanat","family":"Ruangkajorn","sequence":"additional","affiliation":[]},{"given":"Ravikanya","family":"Prapharsavat","sequence":"additional","affiliation":[]},{"given":"Chaiwat","family":"Thirapantu","sequence":"additional","affiliation":[]},{"given":"Karnjariya","family":"Sukrung","sequence":"additional","affiliation":[]},{"given":"Direk","family":"Limmathurotsakul","sequence":"additional","affiliation":[]},{"given":"Anne","family":"Osterrieder","sequence":"additional","affiliation":[]},{"given":"Phaik Yeong","family":"Cheah","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,7,4]]},"reference":[{"issue":"7","key":"1416_CR1","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1179\/2047773215y.0000000030[publishedOnlineFirst:20150907]","volume":"109","author":"F Prestinaci","year":"2015","unstructured":"Prestinaci F, Pezzotti P, Pantosti A. 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However, they face implementation challenges including data accessibility and literacy. Data dashboards offer a method to address these challenges, thereby promoting data-informed practice. This paper reports on a pilot of The School Health Research Network Data Dashboard with secondary schools.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The Dashboard was piloted by three secondary schools (recruited by size; free school meal entitlement) in Wales, UK. Interviews with school staff (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u20097) and public health practitioners (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u20096) were conducted. Data were analysed thematically. Research design, including interview questions, analytical interpretation and code, and theme development utilised Complex Adaptive Systems as the conceptual framework.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>School staff had access to multiple data sets for health promotion but often lacked the time and capacity to utilise them. The Dashboard was perceived to be a user-friendly method of enhancing data accessibility and usability in secondary schools, providing appropriate training and guidance for school staff was available to avoid data misinterpretation. National roll-out of the Dashboard was supported if it aligned with the needs of schools and the wider education system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The Dashboard presents an opportunity for data-informed health and well-being practice and could also support schools to meet education system requirements, providing school staff receive appropriate training. This paper offers novel practical, policy-relevant insights on the interaction of digital dashboards with school systems, capacity constraints, and professional learning needs and valuable insights for public health systems seeking to support data-informed practice in educational settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12889-026-26647-3","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T07:25:10Z","timestamp":1771399510000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Piloting a data dashboard to support data-informed health promotion in secondary schools: qualitative analysis of stakeholder interviews"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5288-6614","authenticated-orcid":false,"given":"J.","family":"Van Godwin","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1284-9645","authenticated-orcid":false,"given":"S.","family":"Long","sequence":"additional","affiliation":[]},{"given":"B.","family":"Bowen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3388-8902","authenticated-orcid":false,"given":"H.","family":"Reed","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4671-2797","authenticated-orcid":false,"given":"N.","family":"Page","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7949-4039","authenticated-orcid":false,"given":"M.","family":"Svobodova","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3380-4966","authenticated-orcid":false,"given":"M.","family":"Boffey","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9484-1729","authenticated-orcid":false,"given":"F.","family":"Rice","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0254-3397","authenticated-orcid":false,"given":"Y.","family":"Shenderovich","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8976-9825","authenticated-orcid":false,"given":"R.","family":"Bevan-Jones","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-3681","authenticated-orcid":false,"given":"S.","family":"Murphy","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6215-0870","authenticated-orcid":false,"given":"J.","family":"Segrott","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"issue":"9801","key":"26647_CR1","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1016\/S0140-6736(11)60827-1","volume":"378","author":"C Kieling","year":"2011","unstructured":"Kieling C, Baker-Henningham H, Belfer M, Conti G, Ertem I, Omigbodun O, et al. 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has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and \u03b1+thalassaemia, with the protective association of Sl2 greatest in children with normal \u03b1-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.<\/jats:p>","DOI":"10.7554\/elife.31579","type":"journal-article","created":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T20:00:11Z","timestamp":1524600011000},"source":"Crossref","is-referenced-by-count":28,"title":["Two complement receptor one alleles have opposing associations with cerebral malaria and interact with \u03b1+thalassaemia"],"prefix":"10.7554","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-4365","authenticated-orcid":true,"given":"D Herbert","family":"Opi","sequence":"first","affiliation":[{"name":"Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya"},{"name":"Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, 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Kenya"}]},{"given":"Neema","family":"Mturi","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya"}]},{"given":"Norbert","family":"Peshu","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya"}]},{"given":"Kathryn","family":"Maitland","sequence":"additional","affiliation":[{"name":"Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya"},{"name":"Department of Medicine, Imperial College, London, United Kingdom"}]},{"given":"Ahmed","family":"Raza","sequence":"additional","affiliation":[{"name":"Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom"}]},{"given":"Dominic P","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Human Genetics, 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links exist between co-transcriptional RNA processing and the transcribing RNAPII. In particular, pre-mRNA splicing was reported to be associated with slowed RNAPII elongation. Here, we identify a site of ubiquitination (K1246) in the catalytic subunit of RNAPII close to the DNA entry path. Ubiquitination was increased in the absence of the Bre5-Ubp3 ubiquitin protease complex. Bre5 binds RNA in vivo, with a preference for exon 2 regions of intron-containing pre-mRNAs and poly(A) proximal sites. Ubiquitinated RNAPII showed similar enrichment. The absence of Bre5 led to impaired splicing and defects in RNAPII elongation in vivo on a splicing reporter construct. Strains expressing RNAPII with a K1246R mutation showed reduced co-transcriptional splicing. We propose that ubiquinitation of RNAPII is induced by RNA processing events and linked to transcriptional pausing, which is released by Bre5-Ubp3 associated with the nascent transcript.<\/jats:p>","DOI":"10.7554\/elife.27082","type":"journal-article","created":{"date-parts":[[2017,10,13]],"date-time":"2017-10-13T08:00:24Z","timestamp":1507881624000},"source":"Crossref","is-referenced-by-count":20,"title":["RNA polymerase II stalling at pre-mRNA splice sites is enforced by ubiquitination of the catalytic subunit"],"prefix":"10.7554","volume":"6","author":[{"given":"Laura","family":"Milligan","sequence":"first","affiliation":[{"name":"Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Scotland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8226-7272","authenticated-orcid":true,"given":"Camille","family":"Sayou","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, 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                   <ns3:bold>Background<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>The long-term impact of elevated blood pressure on mortality outcomes has been recently revisited due to proposed changes in cut-offs for hypertension. This study aimed at assessing the association between high blood pressure levels and 10-year mortality using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) and the American College of Cardiology and the American Heart Association (ACC\/AHA) 2017 blood pressure guidelines.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>Data of the PERU MIGRANT Study, a prospective ongoing cohort, was used. The outcome of interest was 10-year all-cause mortality, and exposures were blood pressure categories according to the JNC-7 and ACC\/AHA 2017 guidelines. Log-rank test, Kaplan-Meier and Cox regression models were used to assess the associations of interest controlling for confounders. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>A total of 976 records, mean age of 60.4 (SD: 11.4), 513 (52.6%) women, were analyzed. Hypertension prevalence at baseline almost doubled from 16.0% (95% CI 13.7%\u201318.4%) to 31.3% (95% CI 28.4%\u201334.3%), using the JNC-7 and ACC\/AHA 2017 definitions, respectively. Sixty-three (6.4%) participants died during the 10-year follow-up, equating to a mortality rate of 3.6 (95% CI 2.4\u20134.7) per 1000 person-years. Using JNC-7, and compared to those with normal blood pressure, those with pre-hypertension and hypertension had 2-fold and 3.5-fold increased risk of death, respectively. Similar mortality effect sizes were estimated using ACC\/AHA 2017 for stage 1 and stage 2 hypertension.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>Blood pressure levels under two different definitions increased the risk of 10-year all-cause mortality. Hypertension prevalence doubled using ACC\/AHA 2017 compared to JNC-7. The choice of blood pressure cut-offs to classify hypertension categories need to be balanced against the patients benefit and the capacities of the health system to adequately handle a large proportion of new patients.<\/ns3:p>","DOI":"10.12688\/f1000research.73900.2","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T12:40:13Z","timestamp":1673959213000},"page":"1134","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood pressure and 10-year all-cause mortality: Findings from the PERU MIGRANT Study"],"prefix":"10.12688","volume":"10","author":[{"given":"Aida","family":"Hidalgo-Benites","sequence":"first","affiliation":[]},{"given":"Valeria","family":"Senosain-Leon","sequence":"additional","affiliation":[]},{"given":"Rodrigo M.","family":"Carrillo-Larco","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Ruiz-Alejos","sequence":"additional","affiliation":[]},{"given":"Robert H.","family":"Gilman","sequence":"additional","affiliation":[]},{"given":"Liam","family":"Smeeth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-5468","authenticated-orcid":false,"given":"J. Jaime","family":"Miranda","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-1376","authenticated-orcid":false,"given":"Antonio","family":"Bernab\u00e9-Ortiz","sequence":"additional","affiliation":[]}],"member":"2560","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1603-1658","DOI":"10.1016\/S0140-6736(16)31460-X","article-title":"Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.","volume":"388","year":"2016","journal-title":"Lancet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2224-2260","DOI":"10.1016\/S0140-6736(12)61766-8","article-title":"A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990\u20132010: a systematic analysis for the Global Burden of Disease Study 2010.","volume":"380","author":"S Lim","year":"2012","journal-title":"Lancet."},{"key":"ref4","first-page":"37-55","article-title":"Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants.","volume":"389","year":"2017","journal-title":"Lancet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1206-1252","DOI":"10.1161\/01.HYP.0000107251.49515.c2","article-title":"Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.","volume":"42","author":"A Chobanian","year":"2003","journal-title":"Hypertension."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e426-e483","DOI":"10.1161\/CIR.0000000000000597","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines.","volume":"138","author":"P Whelton","year":"2018","journal-title":"Circulation."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"956-960","DOI":"10.1016\/j.amjmed.2017.12.049","article-title":"Baseline Blood Pressure, the 2017 ACC\/AHA High Blood Pressure Guidelines, and Long-Term Cardiovascular Risk in SPRINT.","volume":"131","author":"M Vaduganathan","year":"2018","journal-title":"Am. J. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"399-410","DOI":"10.23736\/S0026-4725.19.04965-X","article-title":"Implications of the new 2017 American College of Cardiology\/American Aeart Association Guidelines for Hypertension.","volume":"67","author":"W Aronow","year":"2019","journal-title":"Minerva Cardioangiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"6382","DOI":"10.1038\/s41598-019-42809-3","article-title":"Status of Hypertension in Tehran: Potential impact of the ACC\/AHA 2017 and JNC7 Guidelines, 2012\u20132015.","volume":"9","author":"S Asgari","year":"2019","journal-title":"Sci. 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Health."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1471-2261-9-23","article-title":"The effect on cardiovascular risk factors of migration from rural to urban areas in Peru: PERU MIGRANT Study.","volume":"9","author":"J Miranda","year":"2009","journal-title":"BMC Cardiovasc. Disord."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1752-f","DOI":"10.1093\/ije\/dyx116","article-title":"Cohort Profile: The PERU MIGRANT Study-A prospective cohort study of rural dwellers, urban dwellers and rural-to-urban migrants in Peru.","volume":"46","author":"R Carrillo-Larco","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.16811350.v3","article-title":"PERU MIGRANT Study. Figshare.","author":"J Miranda","year":"2021","journal-title":"Dataset."},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.008548","article-title":"Nationwide Impact of the 2017 American College of Cardiology\/American Heart Association Blood Pressure Guidelines on Stroke Survivors.","volume":"7","author":"A Lekoubou","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1-3","DOI":"10.6515\/ACS.201801_34(1).20171218A","article-title":"Our Stance towards the 2017 ACC\/AHA High Blood Pressure Clinical Practice Guideline: Has the Pendulum Swung Too Far?.","volume":"34","author":"T Wang","year":"2018","journal-title":"Acta Cardiol. Sin."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"74-80","DOI":"10.1097\/HPC.0000000000000045","article-title":"Agreement Between Cardiovascular Disease Risk Scores in Resource-Limited Settings: Evidence from 5 Peruvian Sites.","volume":"14","author":"J Bazo-Alvarez","year":"2015","journal-title":"Crit. Pathw. Cardiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"771-778","DOI":"10.3949\/ccjm.85a.18028","article-title":"2017 ACC\/AHA hypertension guidelines: Toward tighter control.","volume":"85","author":"R Blonsky","year":"2018","journal-title":"Cleve. Clin. J. Med."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.jash.2018.01.004","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. A report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines.","volume":"12","author":"R Brook","year":"2018","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1187-1197","DOI":"10.1016\/j.jacc.2018.05.074","article-title":"2017 ACC\/AHA Blood Pressure Treatment Guideline Recommendations and Cardiovascular Risk.","volume":"72","author":"L Colantonio","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"374-378","DOI":"10.1038\/s41591-020-0754-2","article-title":"Effect of salt substitution on community-wide blood pressure and hypertension incidence.","volume":"26","author":"A Bernabe-Ortiz","year":"2020","journal-title":"Nat. Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"507-520","DOI":"10.1001\/jama.2013.284427","article-title":"2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).","volume":"311","author":"P James","year":"2014","journal-title":"JAMA."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"327-334","DOI":"10.1161\/HYPERTENSIONAHA.118.12291","article-title":"Cardiovascular Disease and Mortality in Adults Aged >\/=60 Years According to Recommendations by the American College of Cardiology\/American Heart Association and American College of Physicians\/American Academy of Family Physicians.","volume":"73","author":"B Jaeger","year":"2019","journal-title":"Hypertension."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"572-581","DOI":"10.1001\/jamacardio.2018.1240","article-title":"Estimating the Association of the 2017 and 2014 Hypertension Guidelines With Cardiovascular Events and Deaths in US Adults: An Analysis of National DataAssociation of the 2014 and 2017 Hypertension Guidelines With Cardiovascular Events and Deaths in US AdultsAssociation of the 2014 and 2017 Hypertension Guidelines With Cardiovascular Events and Deaths in US Adults.","volume":"3","author":"J Bundy","year":"2018","journal-title":"JAMA Cardiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"114-119","DOI":"10.4103\/aam.aam_6_17","article-title":"A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria.","volume":"16","author":"A Olowofela","year":"2017","journal-title":"Ann. Afr. 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We do now understand the age cut-off at year 30 and thank the authors for clarification. Nonetheless, we are wondering how the new categorization is justified. With regards to blood pressure and mortality, we would think that particularly the age group 60+ might be at high risk and thus, more detailed analysis (i.e., splitting into further age group 60-69, 70-79, etc.) might be of interest. We kindly ask the authors for more details on the stratification choice. Overall, though, we still recommend including age as a covariate measured on a continuous scale to improve the power of the analysis.<\/b>  \n<b><i>Response:<\/i><\/b> The categorization of the age variable is due to the fact that the sampling approach was stratified by age in that way (i.e., 30-39, 40-49, 50-59, and 60+). For instance, even we can adjust for that variable in different forms (i.e., using different cut-offs or in a continuous fashion), the best way would be to adjust for the form the variable was stratified. This was explained in the \u201cSettings and participants\u201d subheading in the Methods section. In addition, this was added in the Statistical analysis subheading:  \u201c\n<i>Potential confounders were selected under epidemiological criteria. Since the selection of the participant\u2019s sample was stratified by age (i.e., 30-39, 40-49, 50-59, 60+), such variable was included in that form in adjusted models.<\/i>\u201d  \n<b>2. Current guidelines used to report the results of observational studies such as STROBE clearly state that inferential measures should not be used for description of the study population. In line with that, we strongly suggest to delete all p-values from tables 1-3 and to simply describe the characteristics of the study participants. Further, and also as advanced by current guidelines, the use of p-values is not an appropriate criterion for selecting which confounders to adjust for in the analysis. Consequently, we advocate that any statement about potential associations based on single p-values should be avoided.<\/b>  \n<b><i>Response:<\/i><\/b> We have deleted p-values from tables 1 to 3 as suggested. We have not selected confounders based on p-values, but in an epidemiological approach (pre-specified model).  \n<b>3. We thank the authors for rewriting the Statistical analysis section where they refer to the Kaplan-Meier estimator. In the text it now reads that the evaluation of the proportional hazard assumption is based on visual inspection of a graph. For higher transparency and better understanding, we would suggest to include the graph in the article or as supporting material.<\/b>  \n<b><i>Response:<\/i><\/b>\n<b> <\/b>We have included the figure in the manuscript as requested. We believe the figure does not add more information. Thus, we think the figure should be included in online material but F1000Research does not accept supplemental material. We leave the final decision to include the figure to the reviewer and the editor.  \n<b>4. We are pleased to see that the authors followed our recommendation and changed the term \u201cbivariate model\u201d. Though, the term \u201cbivariable model\u201d is still somewhat misleading and rather uncommon to use. We would suggest to simply refer to an \u201cassociation\u201d.<\/b>  \n<b><i>Response:<\/i><\/b> We have deleted the word bivariable from the text of the manuscript.  \n<b>5. As suggested by the authors, we have reviewed the Public health relevance section for more information on how their study provides input e.g. for local decision making or public health implications. From our point of view, the article still lacks precise guidance in which way the estimates\/results from the study presented in the article can be used for decision making with respect to benefits and risks for patients with newly diagnosed hypertension. Consequently, we highly recommend that the authors explain the implications of their study in more detail and that they provide concrete ideas of possible future activities.<\/b>  \n<b><i>Response:<\/i><\/b> This is an observational study looking at the association between two different guidelines for hypertension definition and all-cause mortality, and not a clinical trial to do decision making. However, according to our results, we have added some lines:  \n<i>\u201cTreatment must be guaranteed for hypertension (using JNC-7) and stage 2 hypertension (ACC\/AHA 2017) to reduce mortality risk. If this effect can be seen in pre-hypertension (JNC-7) and stage 1 hypertension (ACC\/AHA 2017) should be further assessed.\u201d<\/i>  \n<b>6. In our first review we noted that the authors were not consistent in their writing and with the vocabulary used in the tables, e.g. &quot;stage 1&quot; vs. &quot;stage-1&quot; vs. &quot;stage I&quot; (same applies for \u201cstage 2\u201d). In the reviewed article we still find inconsistencies, particularly comparing the Public health relevance section with the rest of the text.<\/b>  \n<b><i>Response:<\/i><\/b> We have reviewed through manuscript, tables and figures to keep consistency.","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v2#referee-comment-9541","order":1,"name":"referee-comment-9541","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"RMC-L is supported by a Wellcome Trust International Training Fellowship, London, UK (214185\/Z\/18\/Z). AB-O (103994\/Z\/14\/Z) and JJM (074833\/Z\/04\/Z, 20517\/Z\/16\/Z) were supported by the Wellcome Trust, London, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]},{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T03:29:33Z","timestamp":1767151773106,"version":"build-2238731810"},"reference-count":23,"publisher":"Springer Science and Business Media 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cardiovascular disease risk factors recorded at a single visit. However, the comparative utility of single versus sequential risk factor measurements for stroke prediction is unclear. Risk factors were recorded on three separate visits on 13,753 individuals in the prospective China Kadoorie Biobank. All participants were stroke-free at baseline (2004\u20132008), first resurvey (2008), and second resurvey (2013\u20132014), and were followed-up for incident cases of first stroke in the 3\u00a0years following the second resurvey. To reflect the models currently used in clinical practice, sex-specific Cox models were developed to estimate 3-year risks of stroke using single measurements recorded at second resurvey and were retrospectively applied to risk factor data from previous visits. Temporal trends in the Cox-generated risk estimates from 2004 to 2014 were analyzed using linear mixed effects models. To assess the value of more flexible machine learning approaches and the incorporation of longitudinal data, we developed gradient boosted tree (GBT) models for 3-year prediction of stroke using both single measurements and sequential measurements of risk factor inputs. Overall, Cox-generated estimates for 3-year stroke risk increased by 0.3% per annum in men and 0.2% per annum in women, but varied substantially between individuals. The risk estimates at second resurvey were highly correlated with the annual increase of risk for each individual (men: r\u2009=\u20090.91, women: r\u2009=\u20090.89), and performance of the longitudinal GBT models was comparable with both Cox and GBT models that considered measurements from only a single visit (AUCs: 0.779\u20130.811 in men, 0.724\u20130.756 in women). These results provide support for current clinical guidelines, which recommend using risk factor measurements recorded at a single visit for stroke prediction.<\/jats:p>","DOI":"10.1038\/s41598-021-95244-8","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:16:11Z","timestamp":1632960971000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Utility of single versus sequential measurements of risk factors for prediction of stroke in Chinese 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We describe mechanisms of iron dysregulation in severe anaemia that might contribute to increased risk and pathogenesis of invasive bacteria, recent advances in knowledge of how iron deficiency and severe anaemia impair immune responses to bacterial infections and vaccines, and the gaps in our understanding of mechanisms underlying severe anaemia, iron deficiency, and the risk of invasive bacterial infections.<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.18829.1","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T08:09:56Z","timestamp":1675325396000},"page":"48","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Severe anaemia, iron deficiency, and susceptibility to invasive bacterial infections"],"prefix":"10.12688","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5726-1776","authenticated-orcid":false,"given":"Kelvin 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This typically involves manual delineation to measure the rectus femoris cross-sectional area (RFCSA), which is a subjective, time-consuming, and laborious task that requires significant expertise. We aimed to develop and evaluate an AI tool that performs automated recognition and measurement of RFCSA to support non-expert operators in measurement of the RFCSA using muscle ultrasound. Twenty patients were recruited between Feb 2023 and July 2023 and were randomized sequentially to operators using AI (n\u2009=\u200910) or non-AI (n\u2009=\u200910). Muscle loss during ICU stay was similar for both methods: 26\u2009\u00b1\u200915% for AI and 23\u2009\u00b1\u200911% for the non-AI, respectively (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.13). In total 59 ultrasound examinations were carried out (30 without AI and 29 with AI). When assisted by our AI tool, the operators showed less variability between measurements with higher intraclass correlation coefficients (ICCs 0.999 95% CI 0.998\u20130.999 vs. 0.982 95% CI 0.962\u20130.993) and lower Bland Altman limits of agreement (\u00b1\u20091.9% vs. \u00b1\u20096.6%) compared to not using the AI tool. The time spent on scans reduced significantly from a median of 19.6 min (IQR 16.9\u201321.7) to 9.4 min (IQR 7.2\u201311.7) compared to when using the AI tool (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). AI-assisted muscle ultrasound removes the need for manual tracing, increases reproducibility and saves time. This system may aid monitoring muscle size in ICU patients assisting rehabilitation programmes.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-64564-w","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T15:21:54Z","timestamp":1719415314000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Clinical evaluation of AI-assisted muscle ultrasound for monitoring muscle wasting in ICU patients"],"prefix":"10.1038","volume":"14","author":[{"given":"Phung Tran Huy","family":"Nhat","sequence":"first","affiliation":[]},{"given":"Nguyen","family":"Van Hao","sequence":"additional","affiliation":[]},{"given":"Lam Minh","family":"Yen","sequence":"additional","affiliation":[]},{"given":"Nguyen Hoang","family":"Anh","sequence":"additional","affiliation":[]},{"given":"Dong 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This study evaluated the sequential effects of prior infection, heterologous boosting with mRNA-1273 (Moderna), and the occurrence of Omicron vaccine-breakthrough infection (VBI) thereafter.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We evaluated anti-spike IgG (Abbott) and neutralising (cPASS\/GenScript) antibody (nAb) titers up to one year after mRNA-1273 boost in two-dose-CoronaVac-primed Indonesian healthcare workers (August 2021-August 2022). We used linear mixed modeling to estimate the rate of change in antibody levels, and logistic regression to examine associations between antibody levels and VBI.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Of 138 participants, 52 (37.7%) had a prior infection and 78 (56.5%) received an mRNA-1273 booster. After two-dose CoronaVac, antibody titers had significantly declined within 180\u00a0days, irrespective of prior infection. After mRNA-1273 booster, anti-spike IgG (1.47% decline\/day) and Omicron B.1.1.529\/BA.2 nAbs declined between day 28\u201390, and IgG titers plateaued between day 90\u2013360. During the BA.1\/BA.2 wave (February\u2013March 2022), 34.6% (27\/78) of individuals experienced a VBI (median 181\u00a0days after mRNA-1273), although none developed severe illness. VBI was associated with low pre-VBI anti-spike IgG and B.1.1.529\/BA.2 nAbs, which were restored post-VBI.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>mRNA-1273 booster after two-dose CoronaVac did not prevent BA.1\/BA.2 VBI. Periodic vaccine boosters may be warranted against emerging SARS-CoV-2 variants.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12879-024-09644-y","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T09:03:13Z","timestamp":1722502993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Anti-SARS-CoV-2 antibody dynamics after primary vaccination with two-dose inactivated whole-virus vaccine, heterologous mRNA-1273 vaccine booster, and Omicron breakthrough infection in Indonesian health care workers"],"prefix":"10.1186","volume":"24","author":[{"given":"Suwarti","family":"Suwarti","sequence":"first","affiliation":[]},{"given":"Gilbert","family":"Lazarus","sequence":"additional","affiliation":[]},{"given":"Sabighoh","family":"Zanjabila","sequence":"additional","affiliation":[]},{"given":"Robert","family":"Sinto","sequence":"additional","affiliation":[]},{"given":"Fransiska","family":"Fransiska","sequence":"additional","affiliation":[]},{"given":"Theresia","family":"Deborah","sequence":"additional","affiliation":[]},{"given":"Dwi","family":"Oktavia","sequence":"additional","affiliation":[]},{"given":"Junaidah","family":"Junaidah","sequence":"additional","affiliation":[]},{"given":"Santayana","family":"Santayana","sequence":"additional","affiliation":[]},{"given":"Henry","family":"Surendra","sequence":"additional","affiliation":[]},{"given":"Jeng","family":"Yuliana","sequence":"additional","affiliation":[]},{"given":"Herlina","family":"Pardosi","sequence":"additional","affiliation":[]},{"given":"Nunung","family":"Nuraeni","sequence":"additional","affiliation":[]},{"given":"Saraswati","family":"Soebianto","sequence":"additional","affiliation":[]},{"given":"Novi Dwi","family":"Susilowati","sequence":"additional","affiliation":[]},{"given":"Decy","family":"Subekti","sequence":"additional","affiliation":[]},{"given":"Ariel","family":"Pradipta","sequence":"additional","affiliation":[]},{"given":"J. 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All participants provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"768"},{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T21:03:41Z","timestamp":1774559021143,"version":"3.50.1"},"reference-count":74,"publisher":"Society for Neuroscience","issue":"44","license":[{"start":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T00:00:00Z","timestamp":1651536000000},"content-version":"vor","delay-in-days":225,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["109117\/Z\/15\/Z"],"award-info":[{"award-number":["109117\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["202747\/Z\/16\/Z"],"award-info":[{"award-number":["202747\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["102645\/Z\/13\/Z"],"award-info":[{"award-number":["102645\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["219433\/Z\/19\/Z"],"award-info":[{"award-number":["219433\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2021,11,3]]},"abstract":"<jats:p>The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (<jats:italic>Kcna6<jats:sup>lacZ<\/jats:sup><\/jats:italic>) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of \u201cmeganeurites,\u201d and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (<jats:italic>Kcna6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce pathologic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using<jats:italic>lacZ<\/jats:italic>. Nonetheless, in<jats:italic>Kcna6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>In recent decades, the expansion of technologies to experimentally manipulate the rodent genome has contributed significantly to the field of neuroscience. While introduction of enzymatic or fluorescent reporter proteins to label neuronal populations is now commonplace, often potential toxicity effects are not fully considered. We show a role of Kv1.6 in acute and neuropathic pain states through analysis of two mouse models lacking Kv1.6 potassium channels: one with additional expression of LacZ and one without. We show that LacZ reporter enzymes induce unintended defects in sensory neurons, with an impact on behavioral data outcomes. To summarize we highlight the importance of Kv1.6 in recovery of normal sensory function following nerve injury, and careful interpretation of data from LacZ reporter models.<\/jats:p>","DOI":"10.1523\/jneurosci.0187-21.2021","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T17:50:31Z","timestamp":1632160231000},"page":"9141-9162","source":"Crossref","is-referenced-by-count":7,"title":["Studying Independent<i>Kcna6<\/i>Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation"],"prefix":"10.1523","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9501-1762","authenticated-orcid":false,"given":"Liam J.","family":"Peck","sequence":"first","affiliation":[]},{"given":"Ryan","family":"Patel","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Diaz","sequence":"additional","affiliation":[]},{"given":"Yolanda 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This study aimed at assessing the association between high blood pressure levels and 10-year mortality using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) and the American College of Cardiology and the American Heart Association (ACC\/AHA) 2017 blood pressure guidelines. Methods Data analysis of the PERU MIGRANT Study, a prospective ongoing cohort, was used. The outcome of interest was 10-year all-cause mortality, and exposures were blood pressure categories according to the JNC-7 and ACC\/AHA 2017 guidelines. Log-rank test, Kaplan-Meier and Cox regression models were used to assess the associations of interest controlling for confounders. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated. Results A total of 976 records, mean age of 60.4 (SD: 11.4), 513 (52.6%) women, were analyzed. Hypertension prevalence at baseline almost doubled from 16.0% (95% CI 13.7%\u201318.4%) to 31.3% (95% CI 28.4%\u201334.3%), using the JNC-7 and ACC\/AHA 2017 definitions, respectively. Sixty-three (6.4%) participants died during the 10-year follow-up, equating to a mortality rate of 3.6 (95% CI 2.4\u20134.7) per 1000 person-years. Using JNC-7, and compared to those with normal blood pressure, those with pre-hypertension and hypertension had 2.1-fold and 5.1-fold increased risk of death, respectively. Similar mortality effect sizes were estimated using ACC\/AHA 2017 for stage-1 and stage-2 hypertension. Conclusions Blood pressure levels under two different definitions increased the risk of 10-year all-cause mortality. Hypertension prevalence doubled using ACC\/AHA 2017 compared to JNC-7. The choice of blood pressure cut-offs to classify hypertension categories need to be balanced against the patients benefit and the capacities of the health system to adequately handle a large proportion of new patients.<\/ns5:p>","DOI":"10.12688\/f1000research.73900.4","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T07:10:12Z","timestamp":1700464212000},"page":"1134","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Blood pressure and 10-year all-cause mortality: Findings from the PERU MIGRANT Study"],"prefix":"10.12688","volume":"10","author":[{"given":"Aida","family":"Hidalgo-Benites","sequence":"first","affiliation":[]},{"given":"Valeria","family":"Senosain-Leon","sequence":"additional","affiliation":[]},{"given":"Rodrigo M.","family":"Carrillo-Larco","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Ruiz-Alejos","sequence":"additional","affiliation":[]},{"given":"Robert H.","family":"Gilman","sequence":"additional","affiliation":[]},{"given":"Liam","family":"Smeeth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-5468","authenticated-orcid":false,"given":"J. 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A report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines.","volume":"12","author":"R Brook","year":"2018","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1187-1197","DOI":"10.1016\/j.jacc.2018.05.074","article-title":"2017 ACC\/AHA Blood Pressure Treatment Guideline Recommendations and Cardiovascular Risk.","volume":"72","author":"L Colantonio","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"374-378","DOI":"10.1038\/s41591-020-0754-2","article-title":"Effect of salt substitution on community-wide blood pressure and hypertension incidence.","volume":"26","author":"A Bernabe-Ortiz","year":"2020","journal-title":"Nat. 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AB-O (103994\/Z\/14\/Z) and JJM (074833\/Z\/04\/Z, 20517\/Z\/16\/Z) were supported by the Wellcome Trust, London, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]},{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:09:34Z","timestamp":1772168974317,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.73900.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000}},{"DOI":"10.12688\/f1000research.73900.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000}}],"reference-count":32,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["214185\/Z\/18\/Z"],"award-info":[{"award-number":["214185\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["074833\/Z\/04\/Z"],"award-info":[{"award-number":["074833\/Z\/04\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["103994\/Z\/14\/Z"],"award-info":[{"award-number":["103994\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome","award":["20517\/Z\/16\/Z"],"award-info":[{"award-number":["20517\/Z\/16\/Z"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    <ns3:bold>Background<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>The long-term impact of elevated blood pressure on mortality outcomes has been recently revisited due to proposed changes in cut-offs for hypertension. This study aimed at assessing the association between high blood pressure levels and 10-year mortality using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) and the American College of Cardiology and the American Heart Association (ACC\/AHA) 2017 blood pressure guidelines.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Methods<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>Data of the PERU MIGRANT Study, a prospective ongoing cohort, was used. The outcome of interest was 10-year all-cause mortality, and exposures were blood pressure categories according to the JNC-7 and ACC\/AHA 2017 guidelines. Log-rank test, Kaplan-Meier and Cox regression models were used to assess the associations of interest controlling for confounders. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Results<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>A total of 976 records, mean age of 60.4 (SD: 11.4), 513 (52.6%) women, were analyzed. Hypertension prevalence at baseline almost doubled from 16.0% (95% CI 13.7%\u201318.4%) to 31.3% (95% CI 28.4%\u201334.3%), using the JNC-7 and ACC\/AHA 2017 definitions, respectively. Sixty-three (6.4%) participants died during the 10-year follow-up, equating to a mortality rate of 3.6 (95% CI 2.4\u20134.7) per 1000 person-years. Using JNC-7, and compared to those with normal blood pressure, those with pre-hypertension and hypertension had 2-fold and 3.5-fold increased risk of death, respectively. Similar mortality effect sizes were estimated using ACC\/AHA 2017 for stage 1 and stage 2 hypertension.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Conclusions<\/ns3:bold>\n                  <\/ns3:p>\n                  <ns3:p>Blood pressure levels under two different definitions increased the risk of 10-year all-cause mortality. Hypertension prevalence doubled using ACC\/AHA 2017 compared to JNC-7. The choice of blood pressure cut-offs to classify hypertension categories need to be balanced against the patients benefit and the capacities of the health system to adequately handle a large proportion of new patients.<\/ns3:p>","DOI":"10.12688\/f1000research.73900.3","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T04:45:08Z","timestamp":1681274708000},"page":"1134","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood pressure and 10-year all-cause mortality: Findings from the PERU MIGRANT Study"],"prefix":"10.12688","volume":"10","author":[{"given":"Aida","family":"Hidalgo-Benites","sequence":"first","affiliation":[]},{"given":"Valeria","family":"Senosain-Leon","sequence":"additional","affiliation":[]},{"given":"Rodrigo M.","family":"Carrillo-Larco","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Ruiz-Alejos","sequence":"additional","affiliation":[]},{"given":"Robert H.","family":"Gilman","sequence":"additional","affiliation":[]},{"given":"Liam","family":"Smeeth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-5468","authenticated-orcid":false,"given":"J. Jaime","family":"Miranda","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-1376","authenticated-orcid":false,"given":"Antonio","family":"Bernab\u00e9-Ortiz","sequence":"additional","affiliation":[]}],"member":"2560","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1603-1658","DOI":"10.1016\/S0140-6736(16)31460-X","article-title":"Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.","volume":"388","year":"2016","journal-title":"Lancet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2224-2260","DOI":"10.1016\/S0140-6736(12)61766-8","article-title":"A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990\u20132010: a systematic analysis for the Global Burden of Disease Study 2010.","volume":"380","author":"S Lim","year":"2012","journal-title":"Lancet."},{"key":"ref4","first-page":"37-55","article-title":"Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants.","volume":"389","year":"2017","journal-title":"Lancet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1206-1252","DOI":"10.1161\/01.HYP.0000107251.49515.c2","article-title":"Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.","volume":"42","author":"A Chobanian","year":"2003","journal-title":"Hypertension."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e426-e483","DOI":"10.1161\/CIR.0000000000000597","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines.","volume":"138","author":"P Whelton","year":"2018","journal-title":"Circulation."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"956-960","DOI":"10.1016\/j.amjmed.2017.12.049","article-title":"Baseline Blood Pressure, the 2017 ACC\/AHA High Blood Pressure Guidelines, and Long-Term Cardiovascular Risk in SPRINT.","volume":"131","author":"M Vaduganathan","year":"2018","journal-title":"Am. 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Chil."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"668-670","DOI":"10.1177\/2047487318799489","article-title":"New 2017 ACC\/AHA hypertension guideline: Implications for a Latin American country like Peru.","volume":"26","author":"A Hern\u00e1ndez-V\u00e1squez","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1256-1264","DOI":"10.1161\/HYPERTENSIONAHA.106.083592","article-title":"Predictive utility of pulse pressure and other blood pressure measures for cardiovascular outcomes.","volume":"49","author":"W Mosley","year":"2007","journal-title":"Hypertension."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"345-354","DOI":"10.1177\/2047487319862066","article-title":"Associations of blood pressure categories defined by 2017 ACC\/AHA guidelines with mortality in China: Pooled results from three prospective cohorts.","volume":"27","author":"N Liu","year":"2020","journal-title":"Eur. J. Prev. 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(Greenwich)."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"775-781","DOI":"10.1001\/jamacardio.2017.1421","article-title":"Systolic Blood Pressure Reduction and Risk of Cardiovascular Disease and Mortality: A Systematic Review and Network Meta-analysis.","volume":"2","author":"J Bundy","year":"2017","journal-title":"JAMA Cardiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"e035190","DOI":"10.1136\/bmjopen-2019-035190","article-title":"Association between blood pressure levels and cardiovascular deaths: a 20-year follow-up study in rural China.","volume":"10","author":"M Wang","year":"2020","journal-title":"BMJ Open."},{"key":"ref19","first-page":"e123-e133","article-title":"Trends in cardiometabolic risk factors in the Americas between 1980 and 2014: a pooled analysis of population-based surveys.","volume":"8","year":"2020","journal-title":"Lancet Glob. 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Figshare.","author":"J Miranda","year":"2021","journal-title":"Dataset."},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.008548","article-title":"Nationwide Impact of the 2017 American College of Cardiology\/American Heart Association Blood Pressure Guidelines on Stroke Survivors.","volume":"7","author":"A Lekoubou","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1-3","DOI":"10.6515\/ACS.201801_34(1).20171218A","article-title":"Our Stance towards the 2017 ACC\/AHA High Blood Pressure Clinical Practice Guideline: Has the Pendulum Swung Too Far?.","volume":"34","author":"T Wang","year":"2018","journal-title":"Acta Cardiol. 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Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"507-520","DOI":"10.1001\/jama.2013.284427","article-title":"2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).","volume":"311","author":"P James","year":"2014","journal-title":"JAMA."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"327-334","DOI":"10.1161\/HYPERTENSIONAHA.118.12291","article-title":"Cardiovascular Disease and Mortality in Adults Aged >\/=60 Years According to Recommendations by the American College of Cardiology\/American Heart Association and American College of Physicians\/American Academy of Family Physicians.","volume":"73","author":"B Jaeger","year":"2019","journal-title":"Hypertension."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"572-581","DOI":"10.1001\/jamacardio.2018.1240","article-title":"Estimating the Association of the 2017 and 2014 Hypertension Guidelines With Cardiovascular Events and Deaths in US Adults: An Analysis of National DataAssociation of the 2014 and 2017 Hypertension Guidelines With Cardiovascular Events and Deaths in US AdultsAssociation of the 2014 and 2017 Hypertension Guidelines With Cardiovascular Events and Deaths in US Adults.","volume":"3","author":"J Bundy","year":"2018","journal-title":"JAMA Cardiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"114-119","DOI":"10.4103\/aam.aam_6_17","article-title":"A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria.","volume":"16","author":"A Olowofela","year":"2017","journal-title":"Ann. Afr. Med."}],"updated-by":[{"DOI":"10.12688\/f1000research.73900.4","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000}}],"container-title":["F1000Research"],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T08:50:13Z","timestamp":1701247813000},"score":9.6997795,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3"}},"issued":{"date-parts":[[2023,4,12]]},"references-count":32,"URL":"https:\/\/doi.org\/10.12688\/f1000research.73900.3","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.146604.r221681","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.146604.r221681","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"published":{"date-parts":[[2023,4,12]]},"assertion":[{"value":"Approved with reservations, Approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.142808.r160523, Annika Hoyer, Dina Voeltz, Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, Bielefeld, 24 Jan 2023, version 2, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v2#referee-response-160523","order":0,"name":"referee-response-160523","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Antonio Bernabe-Ortiz<\/b>; \n<i>Posted: 04 Apr 2023<\/i>; \n<b>1. We do now understand the age cut-off at year 30 and thank the authors for clarification. Nonetheless, we are wondering how the new categorization is justified. With regards to blood pressure and mortality, we would think that particularly the age group 60+ might be at high risk and thus, more detailed analysis (i.e., splitting into further age group 60-69, 70-79, etc.) might be of interest. We kindly ask the authors for more details on the stratification choice. Overall, though, we still recommend including age as a covariate measured on a continuous scale to improve the power of the analysis.<\/b>  \n<b><i>Response:<\/i><\/b> The categorization of the age variable is due to the fact that the sampling approach was stratified by age in that way (i.e., 30-39, 40-49, 50-59, and 60+). For instance, even we can adjust for that variable in different forms (i.e., using different cut-offs or in a continuous fashion), the best way would be to adjust for the form the variable was stratified. This was explained in the \u201cSettings and participants\u201d subheading in the Methods section. In addition, this was added in the Statistical analysis subheading:  \u201c\n<i>Potential confounders were selected under epidemiological criteria. Since the selection of the participant\u2019s sample was stratified by age (i.e., 30-39, 40-49, 50-59, 60+), such variable was included in that form in adjusted models.<\/i>\u201d  \n<b>2. Current guidelines used to report the results of observational studies such as STROBE clearly state that inferential measures should not be used for description of the study population. In line with that, we strongly suggest to delete all p-values from tables 1-3 and to simply describe the characteristics of the study participants. Further, and also as advanced by current guidelines, the use of p-values is not an appropriate criterion for selecting which confounders to adjust for in the analysis. Consequently, we advocate that any statement about potential associations based on single p-values should be avoided.<\/b>  \n<b><i>Response:<\/i><\/b> We have deleted p-values from tables 1 to 3 as suggested. We have not selected confounders based on p-values, but in an epidemiological approach (pre-specified model).  \n<b>3. We thank the authors for rewriting the Statistical analysis section where they refer to the Kaplan-Meier estimator. In the text it now reads that the evaluation of the proportional hazard assumption is based on visual inspection of a graph. For higher transparency and better understanding, we would suggest to include the graph in the article or as supporting material.<\/b>  \n<b><i>Response:<\/i><\/b>\n<b> <\/b>We have included the figure in the manuscript as requested. We believe the figure does not add more information. Thus, we think the figure should be included in online material but F1000Research does not accept supplemental material. We leave the final decision to include the figure to the reviewer and the editor.  \n<b>4. We are pleased to see that the authors followed our recommendation and changed the term \u201cbivariate model\u201d. Though, the term \u201cbivariable model\u201d is still somewhat misleading and rather uncommon to use. We would suggest to simply refer to an \u201cassociation\u201d.<\/b>  \n<b><i>Response:<\/i><\/b> We have deleted the word bivariable from the text of the manuscript.  \n<b>5. As suggested by the authors, we have reviewed the Public health relevance section for more information on how their study provides input e.g. for local decision making or public health implications. From our point of view, the article still lacks precise guidance in which way the estimates\/results from the study presented in the article can be used for decision making with respect to benefits and risks for patients with newly diagnosed hypertension. Consequently, we highly recommend that the authors explain the implications of their study in more detail and that they provide concrete ideas of possible future activities.<\/b>  \n<b><i>Response:<\/i><\/b> This is an observational study looking at the association between two different guidelines for hypertension definition and all-cause mortality, and not a clinical trial to do decision making. However, according to our results, we have added some lines:  \n<i>\u201cTreatment must be guaranteed for hypertension (using JNC-7) and stage 2 hypertension (ACC\/AHA 2017) to reduce mortality risk. If this effect can be seen in pre-hypertension (JNC-7) and stage 1 hypertension (ACC\/AHA 2017) should be further assessed.\u201d<\/i>  \n<b>6. In our first review we noted that the authors were not consistent in their writing and with the vocabulary used in the tables, e.g. &quot;stage 1&quot; vs. &quot;stage-1&quot; vs. &quot;stage I&quot; (same applies for \u201cstage 2\u201d). In the reviewed article we still find inconsistencies, particularly comparing the Public health relevance section with the rest of the text.<\/b>  \n<b><i>Response:<\/i><\/b> We have reviewed through manuscript, tables and figures to keep consistency.","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3#referee-comment-9541","order":1,"name":"referee-comment-9541","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.146604.r221681, Margarita Gutierrez, University of the Philippines Manila College of Pharmacy, Manila, 09 Nov 2023, version 3, 2 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3#referee-response-221681","order":2,"name":"referee-response-221681","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Antonio Bernabe-Ortiz<\/b>; \n<i>Posted: 13 Nov 2023<\/i>; \n<b>Sample Size and Generalizability: While the study provides valuable insights, it is important to ensure that the sample size and characteristics of the study population are representative of the broader population. A larger and more diverse sample could enhance the generalizability of the findings.<\/b> \n<b><i>Response:<\/i><\/b> This is a secondary analysis of an existing dataset. The idea of the original study was to compare the cardiometabolic profile of three different populations (urban, rural-to-urban migrants, and rural dwellers). Even, we tried to take a random sample of participants for each population group, such selection was done in specific study sites using an age- and sex-stratification approach. Based on that, it is not possible to increase the sample size of the study.  \n<b>Confounding Factors: The study controlled for confounding factors, but it is essential to consider potential unmeasured confounders that might affect the relationship between blood pressure and mortality. A more comprehensive assessment of confounding variables, including lifestyle factors and comorbidities, would strengthen the study.<\/b> \n<b><i>Response:<\/i><\/b> We agree with the reviewer. Our adjusted model was built using epidemiological criteria and information available in the dataset. As a result, we did not include variables, important to control the model, but not present in the database. We have clarified that in the Statistical analysis section. In addition, we have added a comment about that in the Strengths and Limitations section: \n<i>\u201c<\/i>\n<i>Second, some variables, relevant to understand the relationship between hypertension and all-cause mortality, were not available (e.g., diet patterns, salt consumption, among others).\u201d<\/i> &nbsp; \n<b>Long-Term Follow-Up: Ten years is a substantial follow-up period, but extending the observation period further could provide additional insights into the relationship between blood pressure and long-term mortality.<\/b> \n<b><i>Response:<\/i><\/b> As pointed out by the reviewer, extending observation period would be ideal, but currently, that is not possible. Available information was used for this manuscript.  \n<b>Clinical Implications: The authors should provide recommendations for healthcare practitioners based on their findings. This could include guidance on blood pressure management strategies, especially considering the increased prevalence of hypertension when using ACC\/AHA 2017 guidelines.<\/b> \n<b>Response:<\/b> We would like to add a comment to provide recommendation for healthcare practitioners. However, this is an observational study looking at the association between two different guidelines for hypertension definition and all-cause mortality, and not a clinical trial to do decision making. Nevertheless, we have included a couple of sentences have been added: \n<i>\u201cFrom the clinical perspective, a tailored follow-up of those individuals with pre-hypertension may be required to decide appropriate treatment, even high-risk stratification may be considered. In addition to that, a combination of population-wide interventions may be also needed.\u201d<\/i>  \n<b>Discussion of Potential Biases: The study should address potential biases, such as selection bias or measurement bias, and explain how these were minimized or managed.<\/b> \n<b><i>Response:<\/i><\/b> Thanks for the suggestion. We have added that in the Strengths and Limitations section: \n<i>\u201c<\/i>\n<i>Fourth, selection bias can be an issue as studied population groups were selected in specific sites and may not be totally representative of the general population. In addition, measurement bias may be present. However, standard procedures were used to assess blood pressure levels.\u201d<\/i>  \n<b>Public Health Impact: The study mentions the capacity of healthcare systems to manage a larger number of hypertensive patients. A discussion of the potential public health impact of increased hypertension prevalence and its associated resource implications would be valuable.<\/b> Response: We have discussed this point in our manuscript. We have extended some topics: \n<i>\u201c<\/i>\n<i>Peru is a middle-income country with a fragile and fragmented healthcare system, with poor response to the challenges of chronic conditions. Increasing the number of people with hypertension may benefit those with blood pressure levels in the range 130\u2013139\/80\u201389 mm Hg, but would represent a major investment (i.e., human resources, budget and time) so that these patients can receive adequate treatment, management, and follow-up.\u201d<\/i>","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v3#referee-comment-10564","order":3,"name":"referee-comment-10564","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"RMC-L is supported by a Wellcome Trust International Training Fellowship, London, UK (214185\/Z\/18\/Z). AB-O (103994\/Z\/14\/Z) and JJM (074833\/Z\/04\/Z, 20517\/Z\/16\/Z) were supported by the Wellcome Trust, London, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]},{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:09:34Z","timestamp":1772168974333,"version":"3.50.1"},"reference-count":32,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T00:00:00Z","timestamp":1636416000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["074833\/Z\/04\/Z"],"award-info":[{"award-number":["074833\/Z\/04\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["214185\/Z\/18\/Z"],"award-info":[{"award-number":["214185\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["103994\/Z\/14\/Z"],"award-info":[{"award-number":["103994\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome","award":["20517\/Z\/16\/Z"],"award-info":[{"award-number":["20517\/Z\/16\/Z"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background<\/ns4:bold>\n                  <\/ns4:p>\n                  <ns4:p>The long-term impact of elevated blood pressure on mortality outcomes has been recently revisited due to proposed changes in cut-offs for hypertension. This study aimed at assessing the association between high blood pressure levels and 10-year mortality using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) and the American College of Cardiology and the American Heart Association (ACC\/AHA) 2017 blood pressure guidelines.<\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods<\/ns4:bold>\n                  <\/ns4:p>\n                  <ns4:p>Data analysis of the PERU MIGRANT Study, a prospective ongoing cohort, was used. The outcome of interest was 10-year all-cause mortality, and exposures were blood pressure categories according to the JNC-7 and ACC\/AHA 2017 guidelines. Log-rank test, Kaplan-Meier and Cox regression models were used to assess the associations of interest controlling for confounders. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated.<\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results<\/ns4:bold>\n                  <\/ns4:p>\n                  <ns4:p>A total of 976 records, mean age of 60.4 (SD: 11.4), 513 (52.6%) women, were analyzed. Hypertension prevalence at baseline almost doubled from 16.0% (95% CI 13.7%\u201318.4%) to 31.3% (95% CI 28.4%\u201334.3%), using the JNC-7 and ACC\/AHA 2017 definitions, respectively. Sixty three (6.4%) participants died during the 10-year follow-up, equating to a mortality rate of 3.6 (95% CI 2.4\u20134.7) per 1000 person-years. Using JNC-7, and compared to those with normal blood pressure, those with pre-hypertension and hypertension had 2.1-fold and 5.1-fold increased risk of death, respectively. Similar mortality effect sizes were estimated using ACC\/AHA 2017 for stage-1 and stage-2 hypertension.<\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions<\/ns4:bold>\n                  <\/ns4:p>\n                  <ns4:p>Blood pressure levels under two different definitions increased the risk of 10-year all-cause mortality. Hypertension prevalence doubled using ACC\/AHA 2017 compared to JNC-7. The choice of blood pressure cut-offs to classify hypertension categories need to be balanced against the patients benefit and the capacities of the health system to adequately handle a large proportion of new patients.<\/ns4:p>","DOI":"10.12688\/f1000research.73900.1","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T10:05:08Z","timestamp":1636452308000},"page":"1134","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Blood pressure and 10-year all-cause mortality: Findings from the PERU MIGRANT Study"],"prefix":"10.12688","volume":"10","author":[{"given":"Aida","family":"Hidalgo-Benites","sequence":"first","affiliation":[]},{"given":"Valeria","family":"Senosain-Leon","sequence":"additional","affiliation":[]},{"given":"Rodrigo M.","family":"Carrillo-Larco","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"Ruiz-Alejos","sequence":"additional","affiliation":[]},{"given":"Robert H.","family":"Gilman","sequence":"additional","affiliation":[]},{"given":"Liam","family":"Smeeth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-5468","authenticated-orcid":false,"given":"J. Jaime","family":"Miranda","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-1376","authenticated-orcid":false,"given":"Antonio","family":"Bernab\u00e9-Ortiz","sequence":"additional","affiliation":[]}],"member":"2560","published-online":{"date-parts":[[2021,11,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1603-1658","DOI":"10.1016\/S0140-6736(16)31460-X","article-title":"Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.","volume":"388","year":"2016","journal-title":"Lancet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2224-2260","DOI":"10.1016\/S0140-6736(12)61766-8","article-title":"A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990\u20132010: a systematic analysis for the Global Burden of Disease Study 2010.","volume":"380","author":"S Lim","year":"2012","journal-title":"Lancet."},{"key":"ref4","first-page":"37-55","article-title":"Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants.","volume":"389","year":"2017","journal-title":"Lancet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1206-1252","DOI":"10.1161\/01.HYP.0000107251.49515.c2","article-title":"Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.","volume":"42","author":"A Chobanian","year":"2003","journal-title":"Hypertension."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e426-e483","DOI":"10.1161\/CIR.0000000000000597","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines.","volume":"138","author":"P Whelton","year":"2018","journal-title":"Circulation."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"956-960","DOI":"10.1016\/j.amjmed.2017.12.049","article-title":"Baseline Blood Pressure, the 2017 ACC\/AHA High Blood Pressure Guidelines, and Long-Term Cardiovascular Risk in SPRINT.","volume":"131","author":"M Vaduganathan","year":"2018","journal-title":"Am. J. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"399-410","DOI":"10.23736\/S0026-4725.19.04965-X","article-title":"Implications of the new 2017 American College of Cardiology\/American Aeart Association Guidelines for Hypertension.","volume":"67","author":"W Aronow","year":"2019","journal-title":"Minerva Cardioangiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"6382","DOI":"10.1038\/s41598-019-42809-3","article-title":"Status of Hypertension in Tehran: Potential impact of the ACC\/AHA 2017 and JNC7 Guidelines, 2012\u20132015.","volume":"9","author":"S Asgari","year":"2019","journal-title":"Sci. Rep."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"109-118","DOI":"10.1161\/CIRCULATIONAHA.117.032582","article-title":"Potential US Population Impact of the 2017 ACC\/AHA High Blood Pressure Guideline.","volume":"137","author":"P Muntner","year":"2018","journal-title":"Circulation."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s11906-019-0906-2","article-title":"Impact of the 2017 American College of Cardiology\/American Heart Association Blood Pressure Guidelines on the Next Blood Pressure Guidelines in Asia.","volume":"21","author":"N Nakagawa","year":"2019","journal-title":"Curr. Hypertens. Rep."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"545-556","DOI":"10.4067\/S0034-98872019000500545","article-title":"Changes in the prevalence of hypertension in Peru using the new guideline of the American College of Cardiology.","volume":"147","author":"A Hernandez-Vasquez","year":"2019","journal-title":"Rev. Med. Chil."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"668-670","DOI":"10.1177\/2047487318799489","article-title":"New 2017 ACC\/AHA hypertension guideline: Implications for a Latin American country like Peru.","volume":"26","author":"A Hern\u00e1ndez-V\u00e1squez","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1256-1264","DOI":"10.1161\/HYPERTENSIONAHA.106.083592","article-title":"Predictive utility of pulse pressure and other blood pressure measures for cardiovascular outcomes.","volume":"49","author":"W Mosley","year":"2007","journal-title":"Hypertension."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"345-354","DOI":"10.1177\/2047487319862066","article-title":"Associations of blood pressure categories defined by 2017 ACC\/AHA guidelines with mortality in China: Pooled results from three prospective cohorts.","volume":"27","author":"N Liu","year":"2020","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"678-685","DOI":"10.1111\/jch.12375","article-title":"Brachial pulse pressure and cardiovascular or all-cause mortality in the general population: a meta-analysis of prospective observational studies.","volume":"16","author":"L Zhao","year":"2014","journal-title":"J. Clin. Hypertens. (Greenwich)."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"775-781","DOI":"10.1001\/jamacardio.2017.1421","article-title":"Systolic Blood Pressure Reduction and Risk of Cardiovascular Disease and Mortality: A Systematic Review and Network Meta-analysis.","volume":"2","author":"J Bundy","year":"2017","journal-title":"JAMA Cardiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"e035190","DOI":"10.1136\/bmjopen-2019-035190","article-title":"Association between blood pressure levels and cardiovascular deaths: a 20-year follow-up study in rural China.","volume":"10","author":"M Wang","year":"2020","journal-title":"BMJ Open."},{"key":"ref19","first-page":"e123-e133","article-title":"Trends in cardiometabolic risk factors in the Americas between 1980 and 2014: a pooled analysis of population-based surveys.","volume":"8","year":"2020","journal-title":"Lancet Glob. Health."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1471-2261-9-23","article-title":"The effect on cardiovascular risk factors of migration from rural to urban areas in Peru: PERU MIGRANT Study.","volume":"9","author":"J Miranda","year":"2009","journal-title":"BMC Cardiovasc. Disord."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1752-f","DOI":"10.1093\/ije\/dyx116","article-title":"Cohort Profile: The PERU MIGRANT Study-A prospective cohort study of rural dwellers, urban dwellers and rural-to-urban migrants in Peru.","volume":"46","author":"R Carrillo-Larco","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.16811350.v3","article-title":"PERU MIGRANT Study. Figshare.","author":"J Miranda","year":"2021","journal-title":"Dataset."},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.008548","article-title":"Nationwide Impact of the 2017 American College of Cardiology\/American Heart Association Blood Pressure Guidelines on Stroke Survivors.","volume":"7","author":"A Lekoubou","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1-3","DOI":"10.6515\/ACS.201801_34(1).20171218A","article-title":"Our Stance towards the 2017 ACC\/AHA High Blood Pressure Clinical Practice Guideline: Has the Pendulum Swung Too Far?.","volume":"34","author":"T Wang","year":"2018","journal-title":"Acta Cardiol. Sin."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"74-80","DOI":"10.1097\/HPC.0000000000000045","article-title":"Agreement Between Cardiovascular Disease Risk Scores in Resource-Limited Settings: Evidence from 5 Peruvian Sites.","volume":"14","author":"J Bazo-Alvarez","year":"2015","journal-title":"Crit. Pathw. Cardiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"771-778","DOI":"10.3949\/ccjm.85a.18028","article-title":"2017 ACC\/AHA hypertension guidelines: Toward tighter control.","volume":"85","author":"R Blonsky","year":"2018","journal-title":"Cleve. Clin. J. Med."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.jash.2018.01.004","article-title":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. A report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines.","volume":"12","author":"R Brook","year":"2018","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1187-1197","DOI":"10.1016\/j.jacc.2018.05.074","article-title":"2017 ACC\/AHA Blood Pressure Treatment Guideline Recommendations and Cardiovascular Risk.","volume":"72","author":"L Colantonio","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"374-378","DOI":"10.1038\/s41591-020-0754-2","article-title":"Effect of salt substitution on community-wide blood pressure and hypertension incidence.","volume":"26","author":"A Bernabe-Ortiz","year":"2020","journal-title":"Nat. Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"507-520","DOI":"10.1001\/jama.2013.284427","article-title":"2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).","volume":"311","author":"P James","year":"2014","journal-title":"JAMA."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"327-334","DOI":"10.1161\/HYPERTENSIONAHA.118.12291","article-title":"Cardiovascular Disease and Mortality in Adults Aged >\/=60 Years According to Recommendations by the American College of Cardiology\/American Heart Association and American College of Physicians\/American Academy of Family Physicians.","volume":"73","author":"B Jaeger","year":"2019","journal-title":"Hypertension."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"572-581","DOI":"10.1001\/jamacardio.2018.1240","article-title":"Estimating the Association of the 2017 and 2014 Hypertension Guidelines With Cardiovascular Events and Deaths in US Adults: An Analysis of National DataAssociation of the 2014 and 2017 Hypertension Guidelines With Cardiovascular Events and Deaths in US AdultsAssociation of the 2014 and 2017 Hypertension Guidelines With Cardiovascular Events and Deaths in US Adults.","volume":"3","author":"J Bundy","year":"2018","journal-title":"JAMA Cardiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"114-119","DOI":"10.4103\/aam.aam_6_17","article-title":"A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria.","volume":"16","author":"A Olowofela","year":"2017","journal-title":"Ann. Afr. Med."}],"updated-by":[{"DOI":"10.12688\/f1000research.73900.4","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000}},{"DOI":"10.12688\/f1000research.73900.3","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000}},{"DOI":"10.12688\/f1000research.73900.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000}}],"container-title":["F1000Research"],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T04:45:20Z","timestamp":1681274720000},"score":9.6997795,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1"}},"issued":{"date-parts":[[2021,11,9]]},"references-count":32,"URL":"https:\/\/doi.org\/10.12688\/f1000research.73900.1","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.77589.r144138","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.77589.r144138","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"published":{"date-parts":[[2021,11,9]]},"assertion":[{"value":"Approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.77589.r144138, Annika Hoyer, Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, Bielefeld, 22 Jul 2022, version 1, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1#referee-response-144138","order":0,"name":"referee-response-144138","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Antonio Bernabe-Ortiz<\/b>; \n<i>Posted: 02 Jan 2023<\/i>; \n<b>REVIEWER 1 - ANNIKA HOYER<\/b>  The article is well written and spreads light on the association between blood pressure and mortality depending on the cut-off for defining high blood pressure in the Peruvian population. However, we have some comments and suggestions that may improve the article:  \n<b>In the introduction, it was written that &quot;prevalence of hypertension was estimated to be 24.1% and 20.1% in men and women, respectively&quot;. It would be helpful to add the year that corresponds to these prevalence's.<\/b>  \n<b><i>Response:<\/i><\/b> We have rewritten the sentence to clarify this point. Now, it reads: \u201c\n<i>\u2026and the prevalence of hypertension in 2015 was estimated to be 24.1% and 20.1% in men and women, respectively.<\/i>\u201d &nbsp; \n<b>In the introduction, we would suggest to briefly discuss the reasons that initially led to a reformulation of the definition of hypertension, i.e., what were the motives of the ACC\/AHA to change the cut-off levels, and why did they introduce four instead of three categories?<\/b>  \n<b><i>Response:<\/i><\/b> Although the focus of the paper was not to define the motivations of the ACC\/AHA to change the cut-off levels, we have introduced some lines regarding this point. Now, it reads: \u201c\n<i>In 2017, as part of the ongoing review process of full guidelines commissioned in about 6-year cycles, the American College of Cardiology and the American Heart Association (ACC\/AHA 2017) changed the proposed cut-off points used for defining hypertension, \u2026<\/i>\u201d  \n<b>In the &quot;Settings and participants&quot; section, it remains unclear what is meant by an &quot;age and stratified sampling approach&quot; which is used to select participants of the PERU MIGRANT study. This should be clarified.<\/b>  \n<b><i>Response:<\/i><\/b> Thanks for noticing these typos. We have corrected this section to better clarify this point. Now, it reads: \u201c\n<i>Participants were randomly selected using an age- (30\u201339, 40\u201349, 50\u201359, and 60+) and sex- stratified sampling approach, utilizing the most up-to-date census in the study area.<\/i>\u201d  \n<b>What is the reason for splitting age into two categories (&lt; 50 vs. &gt;= 50)? With respect to the power of the analysis, it would be far better to include age as a covariate measured on a continuous scale.<\/b>  \n<b><i>Response: <\/i><\/b>Age is considered as confounder in our models. However, we have changed the categorization of age in four categories based on the stratification of the sample (30-39, 40-49, 50-69, and 60+ years). We have accordingly modified paper results. Overall, HR reduced after controlling for age in 4 categories, but are yet consistent.  \n<b>We were also wondering about the reason for the age cut-off at year 30? Is there a reason why no children, adolescents and any other people below 30 years are excluded?<\/b>  \n<b><i>Response:<\/i><\/b> The original study at baseline recruited participants aged 30 years and over, and this was done because cardiovascular conditions are most common among subjects aged \u2265 30 years. This is a secondary analysis of that data and for instance no data of other age group was available.  \n<b>We would strongly recommend to delete all p-values from tables 1-3 and to purely report on the characteristics of the population. This would be in line with current guidelines used to report the results of observational studies (e.g., STROBE).<\/b>  \n<b><i>Response: <\/i><\/b>We have decided to keep the p-values in Tables 1 to 3 as they are important to show association of variables with the exposures and outcome of interest, and for instance, the role of potential confounders. We ask the editor to decide about this topic if relevant.  \n<b>We are a bit confused about the term &quot;Kaplan-Meier test&quot; and would suggest that the authors explain in more detail what specific kind of statistical test they used. If they are interested in the association between the exposure and outcome, it would be also possible to assess the estimated hazard ratios (HR) and their confidence intervals based on the proportional hazard regression approach.<\/b>  \n<b><i>Response:<\/i><\/b> We have rewritten this section to clarify this point. It now reads: \u201c\n<i>A plot of the Kaplan-Meier estimator was used to evaluate the assumption of proportional hazards graphically, whereas such assessment was done in post-hoc analysis using the Schoenfeld residuals.<\/i>\u201d  \n<b>Drawing conclusions about potential associations between variables based on univariate p-values (tables 1-3) alone should be viewed critically because the PERU MIGRANT study is a cohort study. That means that there are indeed confounding variables that are not adjusted for in tables 1-3. Again, we would recommend to delete all p-values from tables 1-3, to simply describe the characteristics of the study participants and to avoid statements about potential associations based on single p-values.<\/b>  \n<b><i>Response: <\/i><\/b>We only described the findings in our Results section. To avoid confusion, we have rewritten this section as follows: \u201c\n<i>In both definitions, high blood pressure levels were more frequent among males, older subjects, migrant and urban dwellers, as well as those with obesity and those with type 2 diabetes mellitus<\/i>\u201d.  \n<b>The term &quot;bivariate model&quot; should be avoided when only the association between two variables is meant because in a bivariate analysis, the outcome consists of two variables.<\/b>  \n<b><i>Response:<\/i><\/b> We have changed the term by using \u201cbivariable model\u201d. &nbsp; \n<b>With respect to the Cox model, we would suggest to interpret the HR in terms of hazards and not risks. That means, a HR of 5.1 indicates a 5.1-fold increased hazard (and not a risk). It should also be added compared to which group the hazard is increased (or decreased).<\/b>  \n<b><i>Response:<\/i><\/b> We have rewritten this section as suggested: \u201c\n<i>Using the JNC-7 guideline and compared to those with normal blood pressure, those with pre-hypertension and hypertension had 2-fold and 3.4-fold increased hazard of death, respectively. On the other hand, using the ACC\/AHA 2017 definition and compared to those with normal blood pressure, stage 1 and stage 2 hypertension were associated with a 2.5- and 3.5-fold increase in the hazard of mortality.<\/i>\u201d  \n<b>We were wondering if the authors took account for possible left truncation which maybe occurred because the minimum age of entry is 30 years.<\/b>  \n<b><i>Response:<\/i><\/b> Although left truncation can be present as minimum age at study entry was 30 years, we believe the effect can be negligible as the prevalence of hypertension in Peruvian population aged &lt;30 years is very low (&lt;3%). However, we have added that in the limitations section: \u201c\n<i>Third, although left truncation can be present as subjects &lt;30 years were excluded, the potential effect of such limitation may be negligible as the prevalence of hypertension is low in that age group.<\/i>\u201d  \n<b>When discussing the AIC and BIC for the models, the authors should be more precise and state which models were compared and which result refers to which comparison.<\/b>  \n<b><i>Response:<\/i><\/b> We have clarified this point in the Statistical analysis section: \u201c\n<i>Using full-adjusted models, Akaike and Bayesian information criteria (AIC and BIC) as well as the Nelson-Aalen graphs were utilized to compare both blood pressure level definitions and their impact on mortality.<\/i>\u201d In addition, this has been also clarified in the Results section: \u201c\n<i>When comparing adjusted models, AIC and BIC were very similar (AIC was 741.3 for JNC-7 vs. 742.2 for ACC\/AHA 2017, whereas BIC was 824.1 for JNC-7 vs. 829.9 for ACC\/AHA 2017), highlighting no difference between models.<\/i>\u201d  \n<b>In the section where the authors compare their findings with other studies, the dates of the studies mentioned should be added.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section accordingly. We have added dates of recruitment of the studies.  \n<b>In the introduction and conclusion, the authors highlight that three different population groups were separately considered. Though, in the result section this is not further taken up. We would recommend that the authors explain why the distinction is yet so important and if the findings of their study differ with regards to the different groups.<\/b>  \n<b><i>Response:<\/i><\/b> We have not included population groups in the Introduction section. However, we have included such information in the Methods section as it is needed to describe the cohort used in the analysis, and in the Discussion section, especially in the Strength and Limitations section. We have dropped this section as it does not affect the interpretation of the results.  \n<b>From our point of view, the conclusion that 46% of deaths could be avoided using the JNC-7 definition, and 66.7% using the ACC\/AHA 2017 guideline if hypertension is treated, seem a bit speculative. Could deaths be really prevented if people are classified as being hypertensive? We think such a conclusion cannot be drawn from a cohort study and the analysis done by the authors because it is not known if hypertension was the reason for all reported deaths. Only associations are seen. This should be discussed in more detail. We would also suggest to weaken this conclusion.<\/b>  \n<b><i>Response:<\/i><\/b> This section highlighted by the reviewer is not a conclusion, it is only a finding described taking into account the limitations of the study (only observational). However, based on the comment, we have deleted this section. &nbsp; \n<b>We would suggest that the authors explain the implications of their study in more detail. As a concluding remark, they have written that their estimates can be used to inform local decision making. We were wondering how this can be achieved based on the estimated HRs because they do not differ that much between the two definitions of hypertension. It would be helpful to describe in which way these estimates can be used for decision making with respect to benefits and risks for patients with newly diagnosed hypertension.<\/b>  \n<b><i>Response:<\/i><\/b> We believe all these topics are discussed in the Public Health Relevance section: (1) the increase in the prevalence of hypertension, and the use of medications would start at a lower blood pressure level, with the subsequent increase in care costs at the health system which will be translated to the patient. So, countries like Peru are not prepared for that change, and for instance, it will require appropriate strategies to face them. In addition, we also discuss in this section the increase of side effects due to the greater use of anti-hypertensive medication.  \n<b>The authors may want to add a decimal separator (e.g. 1,000 person years).<\/b>  \n<b><i>Response:<\/i><\/b> This will depend on the journal style and not necessarily on us. The paper has been adapted for review by editors, so we believe this may be not important at all.  \n<b>With regards to abbreviations: They should be introduced when first used (e.g. page 9 &quot;CV risk scores&quot;), and only introduced when needed (e.g. STEPs is never referred to again). First, the full name should be spelled and then the abbreviation should be added in brackets (e.g., Systolic Blood Pressure Intervention Trial Study (SPRINT)). Abbreviations in the abstract should be avoided (e.g., HR).<\/b>  \n<b><i>Response:<\/i><\/b> The meaning of SPRINT Study is in the introduction of the paper. The use of abbreviations in the abstract depends on the journal style. We have nevertheless described the meaning of such abbreviations. &nbsp; \n<b>The authors should be consistent in their writing and with the vocabulary used in the tables. E.g. &quot;stage 1&quot; vs. &quot;stage-1&quot; vs. &quot;stage I&quot; (same applies for \u201cstage 2\u201d)<\/b> \n<b>and &quot;Las Pampas de San Juan de Miraflores&quot; vs. <\/b>\n<b>&quot;San Juan de Miraflores&quot;.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified the manuscript to be consistent with our terms. &nbsp; \n<b>Abstract: The data of the PERU MIGRANT Study was used, not the analysis, we think.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section. &nbsp; \n<b>Page 3, Settings and Participants: The sentence \u201cIn Lima, a highly urbanized city, Las Pampas de San Juan de Miraflores was selected as the urban environment,\u201d should be rephrased as follows \u201cLas Pampas de San Juan de Miraflores, a highly urbanized city in Lima, Peru, was selected as the urban environment....\u201d.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section as suggested. &nbsp; \n<b>Page 4: There is a typo in the Procedures section. It should be read \u201cmeasured\u201d instead of \u201cmeasure\u201d in the following sentence: \u201cBlood pressure was measured in seated position after a resting period of five minutes.\u201d<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section as suggested. &nbsp; \n<b>Page 4: Another typo is found in the Ethics section. Instead of \u201cin UK\u201d the authors should write \u201cin the UK\u201d at the end of the first sentence of the mentioned paragraph.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section as suggested. &nbsp; \n<b>Page 7: When discussing the main findings, we would suggest reformulating the following sentence on page 7 to \u201cHigh blood pressure levels have been found to increase the risk of 10-year all-cause mortality (please add a reference) \u2026\u201d.<\/b>  \n<b><i>Response:<\/i><\/b> This sentence is not part of a reference but instead the interpretation of our findings. We have clarified that by adding an introduction phase as follows: \u201c\n<i>According to our findings, high blood pressure levels increased the risk of 10-year all-cause mortality, \u2026<\/i>\u201d","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1#referee-comment-9179","order":1,"name":"referee-comment-9179","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Antonio Bernabe-Ortiz<\/b>; \n<i>Posted: 04 Jan 2023<\/i>; The article is well written and spreads light on the association between blood pressure and mortality depending on the cut-off for defining high blood pressure in the Peruvian population. However, we have some comments and suggestions that may improve the article:  \n<b>In the introduction, it was written that &quot;prevalence of hypertension was estimated to be 24.1% and 20.1% in men and women, respectively&quot;. It would be helpful to add the year that corresponds to these prevalence's.<\/b>  \n<b><i>Response:<\/i><\/b> We have rewritten the sentence to clarify this point. Now, it reads: \u201c\n<i>\u2026and the prevalence of hypertension in 2015 was estimated to be 24.1% and 20.1% in men and women, respectively.<\/i>\u201d &nbsp; \n<b>In the introduction, we would suggest to briefly discuss the reasons that initially led to a reformulation of the definition of hypertension, i.e., what were the motives of the ACC\/AHA to change the cut-off levels, and why did they introduce four instead of three categories?<\/b>  \n<b><i>Response:<\/i><\/b> Although the focus of the paper was not to define the motivations of the ACC\/AHA to change the cut-off levels, we have introduced some lines regarding this point. Now, it reads: \u201c\n<i>In 2017, as part of the ongoing review process of full guidelines commissioned in about 6-year cycles, the American College of Cardiology and the American Heart Association (ACC\/AHA 2017) changed the proposed cut-off points used for defining hypertension, \u2026<\/i>\u201d  \n<b>In the &quot;Settings and participants&quot; section, it remains unclear what is meant by an &quot;age and stratified sampling approach&quot; which is used to select participants of the PERU MIGRANT study. This should be clarified.<\/b> \n<b><i>Response:<\/i><\/b> Thanks for notice these typos. We have corrected this section to better clarify this point. Now, it reads: \u201c\n<i>Participants were randomly selected using an age- (30\u201339, 40\u201349, 50\u201359, and 60+) and sex- stratified sampling approach, utilizing the most up-to-date census in the study area.<\/i>\u201d  \n<b>What is the reason for splitting age into two categories (&lt; 50 vs. &gt;= 50)? With respect to the power of the analysis, it would be far better to include age as a covariate measured on a continuous scale.<\/b>  \n<b><i>Response: <\/i><\/b>Age is considered as confounder in our models. However, we have changed the categorization of age in four categories based on the stratification of the sample (30-39, 40-49, 50-69, and 60+ years). We have accordingly modified paper results. Overall, HR reduced after controlling for age in 4 categories, but are yet consistent.  \n<b>We were also wondering about the reason for the age cut-off at year 30? Is there a reason why no children, adolescents and any other people below 30 years are excluded?<\/b>  \n<b><i>Response:<\/i><\/b> The original study at baseline recruited participants aged 30 years and over, and this was done because cardiovascular conditions are most common among subjects aged \u2265 30 years. This is a secondary analysis of that data and for instance no data of other age group was available.  \n<b>We would strongly recommend to delete all p-values from tables 1-3 and to purely report on the characteristics of the population. This would be in line with current guidelines used to report the results of observational studies (e.g., STROBE).<\/b>  \n<b><i>Response: <\/i><\/b>We have decided to keep the p-values in Tables 1 to 3 as they are important to show association of variables with the exposures and outcome of interest, and for instance, the role of potential confounders. We ask the editor to decide about this topic if relevant.  \n<b>We are a bit confused about the term &quot;Kaplan-Meier test&quot; and would suggest that the authors explain in more detail what specific kind of statistical test they used. If they are interested in the association between the exposure and outcome, it would be also possible to assess the estimated hazard ratios (HR) and their confidence intervals based on the proportional hazard regression approach.<\/b> \n<b><i>Response:<\/i><\/b> We have rewritten this section to clarify this point. It now reads: \u201c\n<i>A plot of the Kaplan-Meier estimator was used to evaluate the assumption of proportional hazards graphically, whereas such assessment was done in post-hoc analysis using the Schoenfeld residuals.<\/i>\u201d  \n<b>Drawing conclusions about potential associations between variables based on univariate p-values (tables 1-3) alone should be viewed critically because the PERU MIGRANT study is a cohort study. That means that there are indeed confounding variables that are not adjusted for in tables 1-3. Again, we would recommend to delete all p-values from tables 1-3, to simply describe the characteristics of the study participants and to avoid statements about potential associations based on single p-values.<\/b>  \n<b><i>Response: <\/i><\/b>We only described the findings in our Results section. To avoid confusion, we have rewritten this section as follows: \u201c\n<i>In both definitions, high blood pressure levels were more frequent among males, older subjects, migrant and urban dwellers, as well as those with obesity and those with type 2 diabetes mellitus<\/i>\u201d.  \n<b>The term &quot;bivariate model&quot; should be avoided when only the association between two variables is meant because in a bivariate analysis, the outcome consists of two variables.<\/b>  \n<b><i>Response:<\/i><\/b> We have changed the term by using \u201cbivariable model\u201d. &nbsp; \n<b>With respect to the Cox model, we would suggest to interpret the HR in terms of hazards and not risks. That means, a HR of 5.1 indicates a 5.1-fold increased hazard (and not a risk). It should also be added compared to which group the hazard is increased (or decreased).<\/b>  \n<b><i>Response:<\/i><\/b> We have rewritten this section as suggested: \u201c\n<i>Using the JNC-7 guideline and compared to those with normal blood pressure, those with pre-hypertension and hypertension had 2-fold and 3.4-fold increased hazard of death, respectively. On the other hand, using the ACC\/AHA 2017 definition and compared to those with normal blood pressure, stage 1 and stage 2 hypertension were associated with a 2.5- and 3.5-fold increase in the hazard of mortality.<\/i>\u201d  \n<b>We were wondering if the authors took account for possible left truncation which maybe occurred because the minimum age of entry is 30 years.<\/b>  \n<b><i>Response:<\/i><\/b> Although left truncation can be present as minimum age at study entry was 30 years, we believe the effect can be negligible as the prevalence of hypertension in Peruvian population aged &lt;30 years is very low (&lt;3%). However, we have added that in the limitations section: \u201c\n<i>Third, although left truncation can be present as subjects &lt;30 years were excluded, the potential effect of such limitation may be negligible as the prevalence of hypertension is low in that age group.<\/i>\u201d  \n<b>When discussing the AIC and BIC for the models, the authors should be more precise and state which models were compared and which result refers to which comparison.<\/b>  \n<b><i>Response:<\/i><\/b> We have clarified this point in the Statistical analysis section: \u201c\n<i>Using full-adjusted models, Akaike and Bayesian information criteria (AIC and BIC) as well as the Nelson-Aalen graphs were utilized to compare both blood pressure level definitions and their impact on mortality.<\/i>\u201d In addition, this has been also clarified in the Results section: \u201c\n<i>When comparing adjusted models, AIC and BIC were very similar (AIC was 741.3 for JNC-7 vs. 742.2 for ACC\/AHA 2017, whereas BIC was 824.1 for JNC-7 vs. 829.9 for ACC\/AHA 2017), highlighting no difference between models.<\/i>\u201d  \n<b>In the section where the authors compare their findings with other studies, the dates of the studies mentioned should be added.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section accordingly. We have added dates of recruitment of the studies.  \n<b>In the introduction and conclusion, the authors highlight that three different population groups were separately considered. Though, in the result section this is not further taken up. We would recommend that the authors explain why the distinction is yet so important and if the findings of their study differ with regards to the different groups.<\/b>  \n<b><i>Response:<\/i><\/b> We have not included population groups in the Introduction section. However, we have included such information in the Methods section as it is needed to describe the cohort used in the analysis, and in the Discussion section, especially in the Strength and Limitations section. We have dropped this section as it does not affect the interpretation of the results.  \n<b>From our point of view, the conclusion that 46% of deaths could be avoided using the JNC-7 definition, and 66.7% using the ACC\/AHA 2017 guideline if hypertension is treated, seem a bit speculative. Could deaths be really prevented if people are classified as being hypertensive? We think such a conclusion cannot be drawn from a cohort study and the analysis done by the authors because it is not known if hypertension was the reason for all reported deaths. Only associations are seen. This should be discussed in more detail. We would also suggest to weaken this conclusion.<\/b>  \n<b><i>Response:<\/i><\/b> This section highlighted by the reviewer is not a conclusion, it is only a finding described taking into account the limitations of the study (only observational). However, based on the comment, we have deleted this section. &nbsp; \n<b>We would suggest that the authors explain the implications of their study in more detail. As a concluding remark, they have written that their estimates can be used to inform local decision making. We were wondering how this can be achieved based on the estimated HRs because they do not differ that much between the two definitions of hypertension. It would be helpful to describe in which way these estimates can be used for decision making with respect to benefits and risks for patients with newly diagnosed hypertension.<\/b>  \n<b><i>Response:<\/i><\/b> We believe all these topics are discussed in the Public Health Relevance section: (1) the increase in the prevalence of hypertension, and the use of medications would start at a lower blood pressure level, with the subsequent increase in care costs at the health system which will be translated to the patient. So, countries like Peru are not prepared for that change, and for instance, it will require appropriate strategies to face them. In addition, we also discuss in this section the increase of side effects due to the greater use of anti-hypertensive medication.  \n<b>The authors may want to add a decimal separator (e.g. 1,000 person years).<\/b>  \n<b><i>Response:<\/i><\/b> This will depend on the journal style and not necessarily on us. The paper has been adapted for review by editors, so we believe this may be not important at all.  \n<b>With regards to abbreviations: They should be introduced when first used (e.g. page 9 &quot;CV risk scores&quot;), and only introduced when needed (e.g. STEPs is never referred to again). First, the full name should be spelled and then the abbreviation should be added in brackets (e.g., Systolic Blood Pressure Intervention Trial Study (SPRINT)). Abbreviations in the abstract should be avoided (e.g., HR).<\/b>  \n<b><i>Response:<\/i><\/b> The meaning of SPRINT Study is in the introduction of the paper. The use of abbreviations in the abstract depends on the journal style. We have nevertheless described the meaning of such abbreviations. &nbsp; \n<b>The authors should be consistent in their writing and with the vocabulary used in the tables. E.g. &quot;stage 1&quot; vs. &quot;stage-1&quot; vs. &quot;stage I&quot; (same applies for \u201cstage 2\u201d)<\/b> \n<b>and &quot;Las Pampas de San Juan de Miraflores&quot; vs. <\/b>\n<b>&quot;San Juan de Miraflores&quot;.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified the manuscript to be consistent with our terms. &nbsp; \n<b>Abstract: The data of the PERU MIGRANT Study was used, not the analysis, we think.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section. &nbsp; \n<b>Page 3, Settings and Participants: The sentence \u201cIn Lima, a highly urbanized city, Las Pampas de San Juan de Miraflores was selected as the urban environment,\u201d should be rephrased as follows \u201cLas Pampas de San Juan de Miraflores, a highly urbanized city in Lima, Peru, was selected as the urban environment....\u201d.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section as suggested. &nbsp; \n<b>Page 4: There is a typo in the Procedures section. It should be read \u201cmeasured\u201d instead of \u201cmeasure\u201d in the following sentence: \u201cBlood pressure was measured in seated position after a resting period of five minutes.\u201d<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section as suggested. &nbsp; \n<b>Page 4: Another typo is found in the Ethics section. Instead of \u201cin UK\u201d the authors should write \u201cin the UK\u201d at the end of the first sentence of the mentioned paragraph.<\/b>  \n<b><i>Response:<\/i><\/b> We have modified this section as suggested. &nbsp; \n<b>Page 7: When discussing the main findings, we would suggest reformulating the following sentence on page 7 to \u201cHigh blood pressure levels have been found to increase the risk of 10-year all-cause mortality (please add a reference) \u2026\u201d.<\/b>  \n<b><i>Response:<\/i><\/b> This sentence is not part of a reference but instead the interpretation of our findings. We have clarified that by adding an introduction phase as follows: \u201c\n<i>According to our findings, high blood pressure levels increased the risk of 10-year all-cause mortality, \u2026<\/i>\u201d","URL":"https:\/\/f1000research.com\/articles\/10-1134\/v1#referee-comment-9188","order":2,"name":"referee-comment-9188","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"RMC-L is supported by a Wellcome Trust International Training Fellowship, London, UK (214185\/Z\/18\/Z). AB-O (103994\/Z\/14\/Z) and JJM (074833\/Z\/04\/Z, 20517\/Z\/16\/Z) were supported by the Wellcome Trust, London, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]},{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T21:01:51Z","timestamp":1774558911147,"version":"3.50.1"},"reference-count":39,"publisher":"Springer Science and Business Media 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degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55\u201390 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/s41433-022-02097-0","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T10:04:07Z","timestamp":1653473047000},"page":"1275-1283","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration\u2014the PINNACLE trial protocol"],"prefix":"10.1038","volume":"37","author":[{"given":"Janice","family":"Sutton","sequence":"first","affiliation":[]},{"given":"Martin J.","family":"Menten","sequence":"additional","affiliation":[]},{"given":"Sophie","family":"Riedl","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9168-0894","authenticated-orcid":false,"given":"Hrvoje","family":"Bogunovi\u0107","sequence":"additional","affiliation":[]},{"given":"Oliver","family":"Leingang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1690-9043","authenticated-orcid":false,"given":"Philipp","family":"Anders","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3372-7885","authenticated-orcid":false,"given":"Ahmed M.","family":"Hagag","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2899-6279","authenticated-orcid":false,"given":"Sebastian","family":"Waldstein","sequence":"additional","affiliation":[]},{"given":"Amber","family":"Wilson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-8900","authenticated-orcid":false,"given":"Angela J.","family":"Cree","sequence":"additional","affiliation":[]},{"given":"Ghislaine","family":"Traber","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2110-1690","authenticated-orcid":false,"given":"Lars G.","family":"Fritsche","sequence":"additional","affiliation":[]},{"given":"Hendrik","family":"Scholl","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Rueckert","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-7311","authenticated-orcid":false,"given":"Ursula","family":"Schmidt-Erfurth","sequence":"additional","affiliation":[]},{"given":"Sobha","family":"Sivaprasad","sequence":"additional","affiliation":[]},{"given":"Toby","family":"Prevost","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5541-4305","authenticated-orcid":false,"given":"Andrew","family":"Lotery","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"2097_CR1","doi-asserted-by":"publisher","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","volume":"2","author":"WL Wong","year":"2014","unstructured":"Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng C-Y, et al. 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DR is a co-founder and shareholder of IXICO Plc. SS has attended advisory board meetings and received research grants and is a consultant for Genentech Inc.\/F. Hoffmann-La Roche Ltd, Allergen, Bayer and Novartis, Oxurion, Ophtea, Optos, Oculis, Apellis, Eyebio, Gyroscope. SW is a consultant to Bayer, Roche, Santen, B\u00f6hringer Ingelheim and Novartis. USE receives grant support from Genentech, Kodiak, Novartis, RetInSight and Roche and is a consultant for Apellis. HB has received research grants from Heidelberg Engineering and Apellis, and speaker fees from Bayer, Roche, and Apellis. HS is a member of the Scientific Advisory Board of: Astellas Pharma Global Development, Inc.\/Astellas Institute for Regenerative Medicine; Boehringer Ingelheim Pharma GmbH & Co; Gyroscope Therapeutics Ltd.; Janssen Research & Development, LLC (Johnson & Johnson); Novartis Pharma AG (CORE); Okuvision GmbH; and Third Rock Ventures, LLC. 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suboptimal; as such, new effective treatments for distressing voices are needed. AVATAR therapy involves voice-hearers engaging in a series of facilitated dialogues with a digital embodiment of the distressing voice. This randomized phase 2\/3 trial assesses the efficacy of two forms of AVATAR therapy, AVATAR-Brief (AV-BRF) and AVATAR-Extended (AV-EXT), both combined with treatment as usual (TAU) compared to TAU alone, and conducted an intention-to-treat analysis. We recruited 345 participants with psychosis; data were available for 300 participants (86.9%) at 16 weeks and 298 (86.4%) at 28 weeks. The primary outcome was voice-related distress at both time points, while voice severity and voice frequency were key secondary outcomes. Voice-related distress improved, compared with TAU, in both forms at 16 weeks but not at 28 weeks. Distress at 16 weeks was as follows: AV-BRF, effect \u22121.05 points, 96.5% confidence interval (CI)\u2009=\u2009\u22122.110 to 0, <jats:italic>P<\/jats:italic>\u2009=\u20090.035, Cohen\u2019s <jats:italic>d<\/jats:italic>\u2009=\u20090.38 (CI\u2009=\u20090 to 0.767); AV-EXT \u22121.60 points, 96.5% CI\u2009=\u2009\u22123.133 to \u22120.058, <jats:italic>P<\/jats:italic>\u2009=\u20090.029, Cohen\u2019s <jats:italic>d<\/jats:italic>\u2009=\u20090.58 (CI\u2009=\u20090.021 to 1.139). Distress at 28 weeks was: AV-BRF, \u22120.62 points, 96.5% CI\u2009=\u2009\u22121.912 to 0.679, <jats:italic>P<\/jats:italic>\u2009=\u20090.316, Cohen\u2019s <jats:italic>d<\/jats:italic>\u2009=\u20090.22 (CI\u2009=\u2009\u22120.247 to 0.695); AV-EXT \u22121.06 points, 96.5% CI\u2009=\u2009\u22122.700 to 0.586, <jats:italic>P<\/jats:italic>\u2009=\u20090.175, Cohen\u2019s <jats:italic>d<\/jats:italic>\u2009=\u20090.38 (CI\u2009=\u2009\u22120.213 to 0.981). Voice severity improved in both forms, compared with TAU, at 16 weeks but not at 28 weeks whereas frequency was reduced in AV-EXT but not in AV-BRF at both time points. There were no related serious adverse events. These findings provide partial support for our primary hypotheses. AV-EXT met our threshold for a clinically significant change, suggesting that future work should be primarily guided by this protocol. 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Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome was the rate of viral clearance (derived under a linear mixed-effects model from the daily log\n                      <jats:sub>10<\/jats:sub>\n                      viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]), assessed in a modified intention-to-treat population (mITT). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial was registered at ClinicalTrials.gov (NCT05041907) on 13\/09\/2021.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients given favipiravir and patients receiving no study drug; a -1% (95% credible interval: -14 to 14%) difference. High dose favipiravir was well-tolerated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Favipiravir does not accelerate viral clearance in early symptomatic COVID-19. The viral clearance rate estimated\u00a0from quantitative measurements of oropharyngeal eluate viral densities assesses the antiviral efficacy of drugs in vivo with comparatively few studied\u00a0patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12879-023-08835-3","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T06:02:18Z","timestamp":1705298538000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial"],"prefix":"10.1186","volume":"24","author":[{"given":"Viravarn","family":"Luvira","sequence":"first","affiliation":[]},{"given":"William H. 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All methods were performed in accordance with the relevant guidelines and regulations (e.g. Declaration of Helsinki).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"89"},{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:17:41Z","timestamp":1772165861419,"version":"3.50.1"},"reference-count":22,"publisher":"Springer Science and Business Media 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To achieve the World Health Organization\u2019s goals for HCV elimination, there is a need for substantial scale-up in testing, treatment, and a reduction in new infections. Data on the population impact of scaling up treatment is not available in Pakistan, nor is there reliable data on the incidence of infection\/reinfection. This project will fill this gap by providing important empirical data on the incidence of infection (primary and reinfection) in Pakistan. Then, by using this data in epidemic models, the study will determine whether response rates achieved with affordable therapies (sofosbuvir plus daclatasvir) will be sufficient to eliminate HCV in Pakistan.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This prospective multi-centre cohort study will screen 25,000 individuals for HCV antibody (Ab) and RNA (if Ab-positive) at various centers in Pakistan- Karachi (Sindh) and Punjab, providing estimates of the disease prevalence. HCV positive patients will be treated with sofosbuvir and daclatasvir for 12-weeks, (extended to 24-weeks in those with cirrhosis) and the proportion responding to this first-line treatment estimated. Patients who test HCV Ab negative will be recalled 12\u00a0months later to test for new HCV infections, providing estimates of the incidence rate. Patients diagnosed with HCV (~\u20094,000) will be treated and tested for Sustained Virological Response (SVR). Questionnaires to assess risk factors, productivity, health care usage and quality of life will be completed at both the initial screening and at 12-month follow-up, allowing mathematical modelling and economic analysis to assess the current treatment strategies. Viral resistance will be analysed and patients who have successfully completed treatment will be retested 12\u00a0months later to estimate the rate of re-infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The HepFREEPak study will provide evidence on the efficacy of available and widely used treatment options in Pakistan. It will also provide data on the incidence rate of primary infections and re-infections. Data on incidence risk factors will allow us to model and incorporate heterogeneity of risk and how that affects screening and treatment strategies. These data will identify any gaps in current test-and-treat programs to achieve HCV elimination in Pakistan.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study registration<\/jats:title>\n                    <jats:p>This study was registered on clinicaltrials.gov (NCT04943588) on June 29, 2021.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12889-023-17290-3","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T05:02:47Z","timestamp":1702875767000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HepFREEPak: protocol for a multi-centre, prospective observational study examining efficacy and impact of current therapies for the treatment of hepatitis C in Pakistan and reporting resistance to antiviral drugs: study protocol"],"prefix":"10.1186","volume":"23","author":[{"given":"Ambreen","family":"Arif","sequence":"first","affiliation":[]},{"given":"Aliya","family":"Hasnain","sequence":"additional","affiliation":[]},{"given":"Auj","family":"Chaudhry","sequence":"additional","affiliation":[]},{"given":"Muhammad","family":"Asim","sequence":"additional","affiliation":[]},{"given":"Muhammad Nabeel","family":"Shafqat","sequence":"additional","affiliation":[]},{"given":"Abeer","family":"Altaf","sequence":"additional","affiliation":[]},{"given":"Noor","family":"Saba","sequence":"additional","affiliation":[]},{"given":"Polychronis","family":"Kemos","sequence":"additional","affiliation":[]},{"given":"M. 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The study was approved by the National Bioethics Committee (NBC) Pakistan (Ref: No.4\u201387\/NBC-677\/21\/439) on 9th Sep 2021.This study was registered on clinicaltrials.gov (NCT04943588) on June 29, 2021.At enrollment, written informed consent will be obtained from all eligible participants after explaining details of the study and available treatment options and this will be confirmed by an independent witness.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MAA, is supported by Sir Henry Dale Fellowship jointly funded by the Royal Society and Wellcome Trust (220171\/Z\/20\/Z). EB, has received consultancy fees from Roche, AstraZeneca and Vaccitech. PV, has received unrestricted research funding from Gilead that is unrelated to this study. GRF, has received consultancy and speaker fees from Abbvie, Biomarin, CSL Behring, GSK, Gilead and Pfizer. None of the other authors have any competing interests to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2529"}],"items-per-page":20,"query":{"start-index":0,"search-terms":null}}}