PLoS Medicine最新文献

{"title":"Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.","authors":"D. Moore-Palhares, A. Dasgupta, M. Saifuddin, Maria Lourdes Anzola Pena, S. Prasla, L. Ho, Lin Lu, Joseph Kung, Evan McNabb, L. Sannachi, D. Vesprini, Hanbo Chen, Irene Karam, Hany Soliman, Ewa Szumacher, E. Chow, Sonal Gandhi, Maureen Trudeau, B. Curpen, G. Stanisz, Michael C. Kolios, G. Czarnota","doi":"10.1371/journal.pmed.1004408","DOIUrl":"https://doi.org/10.1371/journal.pmed.1004408","url":null,"abstract":"BACKGROUND\u0000Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer.\u0000\u0000\u0000METHODS AND FINDINGS\u0000This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fr","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"37 32","pages":"e1004408"},"PeriodicalIF":15.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140966558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.","authors":"Daniel Moore-Palhares, Archya Dasgupta, Murtuza Saifuddin, Maria Lourdes Anzola Pena, Shopnil Prasla, Ling Ho, Lin Lu, Joseph Kung, Evan McNabb, Lakshmanan Sannachi, Danny Vesprini, Hanbo Chen, Irene Karam, Hany Soliman, Ewa Szumacher, Edward Chow, Sonal Gandhi, Maureen Trudeau, Belinda Curpen, Greg J Stanisz, Michael Kolios, Gregory J Czarnota","doi":"10.1371/journal.pmed.1004408","DOIUrl":"10.1371/journal.pmed.1004408","url":null,"abstract":"<p><strong>Background: </strong>Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer.</p><p><strong>Methods and findings: </strong>This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitation","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004408"},"PeriodicalIF":15.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140960458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global, regional, and national burden of heatwave-related mortality from 1990 to 2019: A three-stage modelling study.","authors":"Qi Zhao, Shanshan Li, Tingting Ye, Yao Wu, Antonio Gasparrini, Shilu Tong, Aleš Urban, Ana Maria Vicedo-Cabrera, Aurelio Tobias, Ben Armstrong, Dominic Royé, Eric Lavigne, Francesca de'Donato, Francesco Sera, Haidong Kan, Joel Schwartz, Mathilde Pascal, Niilo Ryti, Patrick Goodman, Paulo Hilario Nascimento Saldiva, Michelle L Bell, Yuming Guo","doi":"10.1371/journal.pmed.1004364","DOIUrl":"10.1371/journal.pmed.1004364","url":null,"abstract":"<p><strong>Background: </strong>The regional disparity of heatwave-related mortality over a long period has not been sufficiently assessed across the globe, impeding the localisation of adaptation planning and risk management towards climate change. We quantified the global mortality burden associated with heatwaves at a spatial resolution of 0.5°×0.5° and the temporal change from 1990 to 2019.</p><p><strong>Methods and findings: </strong>We collected data on daily deaths and temperature from 750 locations of 43 countries or regions, and 5 meta-predictors in 0.5°×0.5° resolution across the world. Heatwaves were defined as location-specific daily mean temperature ≥95th percentiles of year-round temperature range with duration ≥2 days. We first estimated the location-specific heatwave-mortality association. Secondly, a multivariate meta-regression was fitted between location-specific associations and 5 meta-predictors, which was in the third stage used with grid cell-specific meta-predictors to predict grid cell-specific association. Heatwave-related excess deaths were calculated for each grid and aggregated. During 1990 to 2019, 0.94% (95% CI: 0.68-1.19) of deaths [i.e., 153,078 cases (95% eCI: 109,950-194,227)] per warm season were estimated to be from heatwaves, accounting for 236 (95% eCI: 170-300) deaths per 10 million residents. The ratio between heatwave-related excess deaths and all premature deaths per warm season remained relatively unchanged over the 30 years, while the number of heatwave-related excess deaths per 10 million residents per warm season declined by 7.2% per decade in comparison to the 30-year average. Locations with the highest heatwave-related death ratio and rate were in Southern and Eastern Europe or areas had polar and alpine climates, and/or their residents had high incomes. The temporal change of heatwave-related mortality burden showed geographic disparities, such that locations with tropical climate or low incomes were observed with the greatest decline. The main limitation of this study was the lack of data from certain regions, e.g., Arabian Peninsula and South Asia.</p><p><strong>Conclusions: </strong>Heatwaves were associated with substantial mortality burden that varied spatiotemporally over the globe in the past 30 years. The findings indicate the potential benefit of governmental actions to enhance health sector adaptation and resilience, accounting for inequalities across communities.</p>","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004364"},"PeriodicalIF":15.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"User-defined outcomes of the Danish cardiovascular screening (DANCAVAS) trial: A post hoc analyses of a population-based, randomised controlled trial.","authors":"Axel Cosmus Pyndt Diederichsen, Anna Mejldal, Rikke Søgaard, Jesper Hallas, Jess Lambrechtsen, Flemming Hald Steffensen, Lars Frost, Kenneth Egstrup, Martin Busk, Grazina Urbonaviciene, Marek Karon, Lars Melholt Rasmussen, Jes Sanddal Lindholt","doi":"10.1371/journal.pmed.1004403","DOIUrl":"10.1371/journal.pmed.1004403","url":null,"abstract":"<p><strong>Background: </strong>The Danish cardiovascular screening (DANCAVAS) trial, a nationwide trial designed to investigate the impact of cardiovascular screening in men, did not decrease all-cause mortality, an outcome decided by the investigators. However, the target group may have varied preferences. In this study, we aimed to evaluate whether men aged 65 to 74 years requested a CT-based cardiovascular screening examination and to assess its impact on outcomes determined by their preferences.</p><p><strong>Methods and findings: </strong>This is a post hoc study of the randomised DANCAVAS trial. All men 65 to 74 years of age residing in specific areas of Denmark were randomised (1:2) to invitation-to-screening (16,736 men, of which 10,471 underwent screening) or usual-care (29,790 men). The examination included among others a non-contrast CT scan (to assess the coronary artery calcium score and aortic aneurysms). Positive findings prompted preventive treatment with atorvastatin, aspirin, and surveillance/surgical evaluation. The usual-care group remained unaware of the trial and the assignments. The user-defined outcome was based on patient preferences and determined through a survey sent in January 2023 to a random sample of 9,095 men from the target group, with a 68.0% response rate (6,182 respondents). Safety outcomes included severe bleeding and mortality within 30 days after cardiovascular surgery. Analyses were performed on an intention-to-screen basis. Prevention of stroke and myocardial infarction was the primary motivation for participating in the screening examination. After a median follow-up of 6.4 years, 1,800 of 16,736 men (10.8%) in the invited-to-screening group and 3,420 of 29,790 (11.5%) in the usual-care group experienced an event (hazard ratio (HR), 0.93 (95% confidence interval (CI), 0.88 to 0.98; p = 0.010); number needed to invite at 6 years, 148 (95% CI, 80 to 986)). A total of 324 men (1.9%) in the invited-to-screening group and 491 (1.7%) in the usual-care group had an intracranial bleeding (HR, 1.17; 95% CI, 1.02 to 1.35; p = 0.029). Additionally, 994 (5.9%) in the invited-to-screening group and 1,722 (5.8%) in the usual-care group experienced severe gastrointestinal bleeding (HR, 1.02; 95% CI, 0.95 to 1.11; p = 0.583). No differences were found in mortality after cardiovascular surgery. The primary limitation of the study is that exclusive enrolment of men aged 65 to 74 renders the findings non-generalisable to women or men of other age groups.</p><p><strong>Conclusion: </strong>In this comprehensive population-based cardiovascular screening and intervention program, we observed a reduction in the user-defined outcome, stroke and myocardial infarction, but entail a small increased risk of intracranial bleeding.</p><p><strong>Trial registration: </strong>ISRCTN Registry number, ISRCTN12157806 https://www.isrctn.com/ISRCTN12157806.</p>","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004403"},"PeriodicalIF":15.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11132442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.","authors":"De-Shen Wang, Chao Ren, Shan-Shan Li, William Pat Fong, Xiao-Jun Wu, Jian Xiao, Bin-Kui Li, Yun Zheng, Pei-Rong Ding, Gong Chen, Miao-Zhen Qiu, Zhi-Qiang Wang, Feng-Hua Wang, Hui-Yan Luo, Feng Wang, Xiao-Zhong Wang, Ling-Yun Wang, De-Jin Xie, Tao Chen, Li-Ren Li, Zhen-Hai Lu, Xiao-Hui Zhai, Tian-Shu Liu, Ying Yuan, Jia-Qi Chen, Qiong Tan, Zhi-Zhong Pan, De-Sen Wan, Rong Zhang, Yun-Fei Yuan, Rui-Hua Xu, Yu-Hong Li","doi":"10.1371/journal.pmed.1004389","DOIUrl":"10.1371/journal.pmed.1004389","url":null,"abstract":"<p><strong>Background: </strong>It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM.</p><p><strong>Methods and findings: </strong>This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004389"},"PeriodicalIF":15.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case-area targeted interventions during a large-scale cholera epidemic: A prospective cohort study in Northeast Nigeria.","authors":"Jennifer OKeeffe, Lindsay Salem-Bango, Michael R Desjardins, Daniele Lantagne, Chiara Altare, Gurpreet Kaur, Thomas Heath, Kanaganathan Rangaiya, Patricia Oke-Oghene Obroh, Ahmadu Audu, Baptiste Lecuyot, Timothée Zoungrana, Emmanuel Emeka Ihemezue, Solomon Aye, Mustafa Sikder, Shannon Doocy, Qiulin Wang, Melody Xiao, Paul B Spiegel","doi":"10.1371/journal.pmed.1004404","DOIUrl":"10.1371/journal.pmed.1004404","url":null,"abstract":"<p><strong>Background: </strong>Cholera outbreaks are on the rise globally, with conflict-affected settings particularly at risk. Case-area targeted interventions (CATIs), a strategy whereby teams provide a package of interventions to case and neighboring households within a predefined \"ring,\" are increasingly employed in cholera responses. However, evidence on their ability to attenuate incidence is limited.</p><p><strong>Methods and findings: </strong>We conducted a prospective observational cohort study in 3 conflict-affected states in Nigeria in 2021. Enumerators within rapid response teams observed CATI implementation during a cholera outbreak and collected data on household demographics; existing water, sanitation, and hygiene (WASH) infrastructure; and CATI interventions. Descriptive statistics showed that CATIs were delivered to 46,864 case and neighbor households, with 80.0% of cases and 33.5% of neighbors receiving all intended supplies and activities, in a context with operational challenges of population density, supply stock outs, and security constraints. We then applied prospective Poisson space-time scan statistics (STSS) across 3 models for each state: (1) an unadjusted model with case and population data; (2) an environmentally adjusted model adjusting for distance to cholera treatment centers and existing WASH infrastructure (improved water source, improved latrine, and handwashing station); and (3) a fully adjusted model adjusting for environmental and CATI variables (supply of Aquatabs and soap, hygiene promotion, bedding and latrine disinfection activities, ring coverage, and response timeliness). We ran the STSS each day of our study period to evaluate the space-time dynamics of the cholera outbreaks. Compared to the unadjusted model, significant cholera clustering was attenuated in the environmentally adjusted model (from 572 to 18 clusters) but there was still risk of cholera transmission. Two states still yielded significant clusters (range 8-10 total clusters, relative risk of 2.2-5.5, 16.6-19.9 day duration, including 11.1-56.8 cholera cases). Cholera clustering was completely attenuated in the fully adjusted model, with no significant anomalous clusters across time and space. Associated measures including quantity, relative risk, significance, likelihood of recurrence, size, and duration of clusters reinforced the results. Key limitations include selection bias, remote data monitoring, and the lack of a control group.</p><p><strong>Conclusions: </strong>CATIs were associated with significant reductions in cholera clustering in Northeast Nigeria despite operational challenges. Our results provide a strong justification for rapid implementation and scale-up CATIs in cholera-response, particularly in conflict settings where WASH access is often limited.</p>","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004404"},"PeriodicalIF":15.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11149837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cyclical cascade of HIV care: Temporal care engagement trends within a population-wide cohort.","authors":"Jonathan Euvrard, Venessa Timmerman, Claire Marriott Keene, Florence Phelanyane, Alexa Heekes, Brian D Rice, Anna Grimsrud, Peter Ehrenkranz, Andrew Boulle","doi":"10.1371/journal.pmed.1004407","DOIUrl":"10.1371/journal.pmed.1004407","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The traditional HIV treatment cascade aims to visualise the journey of each person living with HIV from diagnosis, through initiation on antiretroviral therapy (ART) to treatment success, represented by virological suppression. This representation has been a pivotal tool in highlighting and quantifying sequential gaps along the care continuum. There is longstanding recognition, however, that this may oversimplify the complexity of real-world engagement with HIV services in settings with mature high-burden HIV epidemics. A complementary \"cyclical\" cascade has been proposed to represent the processes of disengagement at different points on the care continuum, with multiple pathways to re-engagement, although the feasibility of implementing this at scale has been uncertain. This study aimed to populate, refine, and explore the utility of a cyclical representation of the HIV cascade, using routine data from a high-burden HIV setting.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods and findings: &lt;/strong&gt;This observational cohort study leveraged person-level data on all people living with HIV in the Western Cape (WC), South Africa, who accessed public health services in the 2 years prior to 31 December 2023. Programme data from disease registers were complemented by data from pharmacy and laboratory systems. At study closure, 494 370 people were included, constituting 93% of those of those estimated to be living with HIV in the province, of whom 355 104 were on ART. Substantial disengagement from HIV care was evident at every point on the cascade. Early treatment emerged as a period of higher risk of disengagement, but it did not account for the majority of disengagement. Almost all those currently disengaged had prior experience of treatment. While re-engagement was also common, overall treatment coverage had increased slowly over 5 years. The transition to dolutegravir-based regimens was dramatic with good virological outcomes for those in care, notwithstanding a clearly discernible impact of the Coronavirus Disease 2019 (COVID-19) pandemic on viral load (VL) testing. People currently engaged and disengaged in care are similar with respect to age and gender. Those who died or disengaged recently were previously distributed across a range of cascade statuses, and a substantial proportion of those newly initiating and re-initiating treatment were no longer on treatment 6 months later. The main limitation of this study was incomplete evidence of HIV testing, linkage to HIV-specific services, and out-of-facility mortality.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Using routine data, it was possible to populate and automate a cyclical cascade of HIV care that continuously captured the nonlinear care journeys of individuals living with HIV. In this generalised mature HIV epidemic, most people are treatment experienced. Disengagement is common and occurs at various points along the cascade, making it challenging to identify high-impact intervention opport","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004407"},"PeriodicalIF":15.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11125544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deworming and micronutrient status by community open defecation prevalence: An observational study using nationally representative data from India, 2016-2018.","authors":"Suman Chakrabarti, Sitara S R Ajjampur, Hugh Sharma Waddington, Avinash Kishore, Phuong H Nguyen, Samuel Scott","doi":"10.1371/journal.pmed.1004402","DOIUrl":"10.1371/journal.pmed.1004402","url":null,"abstract":"<p><strong>Background: </strong>Micronutrient deficiencies are widespread in India. Soil-transmitted helminth (STH) infections are acquired by interaction with soil and water contaminated by human feces and lead to blood loss and poor micronutrient absorption. The current recommendation for control of STH-related morbidity is targeted deworming, yet little is known about the effectiveness of deworming on micronutrient status in varying sanitation contexts. Ranging between 1% and 40% prevalence across Indian states, open defecation (OD) remains high despite India's investments at elimination by promoting community-wide sanitation. This variation provides an opportunity to study the relationship between deworming, micronutrient status, and OD at-scale.</p><p><strong>Methods and findings: </strong>Cross-sectional datasets that were representative for India were obtained the Comprehensive National Nutrition Survey in 2016 to 2018 (n = 105,060 individuals aged 1 to 19 years). Consumption of deworming medication was described by age and community OD level. Logistic regression models were used to examine the relationship between deworming, cluster OD, and their interactions, with anemia and micronutrient deficiencies (iron, zinc, vitamin A, folate, and vitamin B12), controlling for age, sex, wealth, diet, and seasonality. These regression models further allowed us to identify a minimum OD rate after which deworming becomes ineffective. In sensitivity analyses, the association between deworming and deficiencies were tested in subsamples of communities classified into 3 OD levels based on statistical tertiles: OD free (0% of households in the community practicing OD), moderate OD (>0% and <30%), or high OD (at least 30%). Average deworming coverage and OD prevalence in the sample were 43.4% [IQR 26.0, 59.0] and 19.1% [IQR 0, 28.5], respectively. Controlling for other determinants of nutritional status, adolescents living in communities with higher OD levels had lower coverage of deworming and higher prevalence of anemia, zinc, vitamin A, and B12 deficiencies. Compared to those who were not dewormed, dewormed children and adolescents had lower odds of anemia (adjusted odds ratio 0.72, (95% CI [0.67, 0.78], p < 0.001) and deficiencies of iron 0.78, (95% CI [0.74, 0.82], p < 0.001) and folate 0.69, (95% CI [0.64,0.74], p<0.001)) in OD free communities. These protective effects remained significant for anemia but diminished for other micronutrient deficiencies in communities with moderate or high OD. Analysis of community OD indicated a threshold range of 30% to 60%, above which targeted deworming was no longer significantly associated with lower anemia, iron, and folate deficiency. The primary limitations of the study included potential for omitted variables bias and inability to capture longitudinal effects.</p><p><strong>Conclusions: </strong>Moderate to high rates of OD significantly modify the association between deworming and micronutrient status in Ind","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004402"},"PeriodicalIF":15.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11125536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicted impact of banning nonessential, energy-dense food and beverages in schools in Mexico: A microsimulation study.","authors":"Ana Basto-Abreu, Martha Carnalla, Francisco Reyes-Sánchez, Alan Reyes-García, Michelle M Haby, Isabel Junquera-Badilla, Lianca Sartoris-Ayala, Juan A Rivera, Barry M Popkin, Tonatiuh Barrientos-Gutiérrez","doi":"10.1371/journal.pmed.1004394","DOIUrl":"10.1371/journal.pmed.1004394","url":null,"abstract":"<p><strong>Background: </strong>Childhood obesity is a growing concern worldwide. School-based interventions have been proposed as effective means to improve nutritional knowledge and prevent obesity. In 2023, Mexico approved a reform to the General Education Law to strengthen the ban of sales and advertising of nonessential energy-dense food and beverages (NEDFBs) in schools and surroundings. We aimed to predict the expected one-year change in total caloric intake and obesity prevalence by introducing the ban of NEDFBs sales in schools, among school-aged children and adolescents (6 to 17 years old) in Mexico.</p><p><strong>Methods and findings: </strong>We used age-specific equations to predict baseline fat-free mass (FFM) and fat mass (FM) and then estimated total energy intake (TEI) per day. The TEI after the intervention was estimated under 4 scenarios: (1) using national data to inform the intervention effect; (2) varying law compliance; (3) using meta-analytic data to inform the intervention effect size on calories; and (4) using national data to inform the intervention effect by sex and socioeconomic status (SES). We used Hall's microsimulation model to estimate the potential impact on body weight and obesity prevalence of children and adolescents 1 year after implementing the intervention in Mexican schools. We found that children could reduce their daily energy intake by 33 kcal/day/person (uncertainty interval, UI, [25, 42] kcal/day/person), reducing on average 0.8 kg/person (UI [0.6, 1.0] kg/person) and 1.5 percentage points (pp) in obesity (UI [1.1, 1.9] pp) 1 year after implementing the law. We showed that compliance will be key to the success of this intervention: considering a 50% compliance the intervention effect could reduce 0.4 kg/person (UI [0.3, 0.5] kg/person). Our sensitivity analysis showed that the ban could reduce body weight by 1.3 kg/person (UI [0.8, 1.8] kg/person) and up to 5.4 kg/person (UI [3.4, 7.5] kg/person) in the best-case scenario. Study limitations include assuming that obesity and the contribution of NEDFBs consumed at school remain constant over time, assuming full compliance, and not considering the potential effect of banning NEDFBs in stores near schools.</p><p><strong>Conclusions: </strong>Even in the most conservative scenario, banning sales of NEDFBs in schools is expected to significantly reduce obesity, but achieving high compliance will be key to its success.</p><p><strong>Why was this study done?: </strong>- School-based interventions have been recognized as effective means to improve nutritional knowledge and prevent obesity-related diseases.- In December 2023, the Chamber of Representatives of Mexico approved an amendment that strengthens and updates the General Education Law (Article 75) and nutritional guidelines to ban the sales and advertising of nonessential energy-dense food and beverages (NEDFBs) in schools.</p><p><strong>What did the researchers do and find?: </strong>- We used age-spec","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004394"},"PeriodicalIF":15.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.","authors":"Andria Mousa, Gina Cuomo-Dannenburg, Hayley A Thompson, R Matthew Chico, Khalid B Beshir, Colin J Sutherland, David Schellenberg, Roly Gosling, Michael Alifrangis, Emma Filtenborg Hocke, Helle Hansson, Ana Chopo-Pizarro, Wilfred F Mbacham, Innocent M Ali, Mike Chaponda, Cally Roper, Lucy C Okell","doi":"10.1371/journal.pmed.1004376","DOIUrl":"10.1371/journal.pmed.1004376","url":null,"abstract":"<p><strong>Background: </strong>Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings.</p><p><strong>Methods and findings: </strong>We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common.</p><p><strong>Conclusions: </strong>These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.</p>","PeriodicalId":49008,"journal":{"name":"PLoS Medicine","volume":"21 5","pages":"e1004376"},"PeriodicalIF":15.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11081503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}