Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
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Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States
Adang LA , Bonkowsky JL , Boelens JJ , Mallack E , Ahrens-Nicklas R , Bernat JA , Bley A , Burton B , Darling A , Eichler F , Eklund E , Emrick L , Escolar M , Fatemi A , Fraser JL , Gaviglio A , Keller S , Patterson MC , Orchard P , Orthmann-Murphy J , Santoro JD , Schöls L , Sevin C , Srivastava IN , Rajan D , Rubin JP , Van Haren K , Wasserstein M , Zerem A , Fumagalli F , Laugwitz L , Vanderver A . Cytotherapy 2024 Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care. |
Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda
Monod M , Brizzi A , Galiwango RM , Ssekubugu R , Chen Y , Xi X , Kankaka EN , Ssempijja V , Abeler-Dörner L , Akullian A , Blenkinsop A , Bonsall D , Chang LW , Dan S , Fraser C , Golubchik T , Gray RH , Hall M , Jackson JC , Kigozi G , Laeyendecker O , Mills LA , Quinn TC , Reynolds SJ , Santelli J , Sewankambo NK , Spencer SEF , Ssekasanvu J , Thomson L , Wawer MJ , Serwadda D , Godfrey-Faussett P , Kagaayi J , Grabowski MK , Ratmann O . Nat Microbiol 2023 9 (1) 35-54 HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep-sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted: whereas HIV transmission to girls and women (aged 15-24 years) from older men declined by about one-third, transmission to women (aged 25-34 years) from men that were 0-6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programmes to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa. |
Patient characteristics during early transmission of SARS-CoV-2, Palau, January 13-February 24, 2022
Eilers B , Adelbai-Fraser MD , Collado JR , Van Dyke M , Firestone M , Guinn AS , Dillon MT , Brostrom R , Kinzer MH , Muñoz N , Okumura K , Brown V , Ademokun O , Udui R , Uherbelau GJ , Hancock WT . Emerg Infect Dis 2023 29 (9) 1939-1941 Palau had no reported evidence of COVID-19 community spread until January 2022. We chart reviewed hospitalized patients who had a positive SARS-CoV-2 test result during early community transmission. Booster vaccinations and early outpatient treatment decreased hospitalizations. Inadequate hospital infection control practices contributed to iatrogenic COVID-19 and preventable deaths. |
Estimating typhoid incidence from community-based serosurveys: A multicohort study in Bangladesh, Nepal, Pakistan and Ghana (preprint)
Aiemjoy K , Seidman JC , Saha S , Munira SJ , Islam Sajib MS , Sium SMA , Sarkar A , Alam N , Zahan FN , Kabir MS , Tamrakar D , Vaidya K , Shrestha R , Shakya J , Katuwal N , Shrestha S , Yousafzai MT , Iqbal J , Dehraj IF , Ladak Y , Maria N , Adnan M , Pervaiz S , Carter AS , Longley AT , Fraser C , Ryan ET , Nodoushani A , Fasano A , Leonard MM , Kenyon V , Bogoch II , Jeon HJ , Haselbeck A , Park SE , Zellweger RM , Marks F , Owusu-Dabo E , Adu-Sarkodie Y , Owusu M , Teunis P , Luby SP , Garrett DO , Qamar FN , Saha SK , Charles RC , Andrews JR . medRxiv 2022 2021.10.20.21265277 Background The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown.Methods We collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.Findings The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children <5 years ranged between 58.5 per 100 person-years (95% CI: 42.1 - 81.4) in Dhaka, Bangladesh to 6.6 (95% CI: 4.3-9.9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.Interpretation The approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.Funding This work was supported by the Bill and Melinda Gates Foundation (INV-000572).Evidence before this study Previous studies have identified serologic responses to two antigens (Hemolysin E [HlyE] and Salmonella lipopolysaccharide [LPS]) as promising diagnostic markers of acute typhoidal Salmonella infection. We reviewed the evidence for seroepidemiology tools for enteric fever available as of November 01, 2021, by searching the National Library of Medicine article database and medRxiv for preprint publications, published in English, using the terms “enteric fever”, “typhoid fever”, “Salmonella Typhi”, “Salmonella Paratyphi”, “typhoidal Salmonella”, “Hemolysin E”, “Salmonella lipopolysaccharide”, “seroconversion”, “serosurveillance”, “seroepidemiology”, “seroprevalence” and “seropositivity.” We found no studies using HlyE or LPS as markers to measure the incidence or prevalence of enteric fever in a population. Anti-Vi IgG responses were used as a marker of population seroprevalence in cross-sectional studies conducted in South Africa, Fiji, and Nepal, but were not used to calculate population-based incidence estimates.Added value of this study We developed and validated a method to estimate typhoidal Salmonella incidence in cross-sectional population samples using antibody responses measured from dried blood spots. First, using longitudinal dried blood spots collected from over 1400 blood culture-confirmed cases in four countries, we modeled the longitudinal dynamics of antibody responses for up to two years following infection, accounting for heterogeneity in antibody responses and age-dependence. We found that longitudinal antibody responses were highly consistent across four countries on two continents and did not differ by clinical severity. We then used these antibody kinetic parameters to estimate incidence in population-based samples in six communities across the four countries, where concomitant population-based incidence was measured using blood cultures. Seroincidence estimates were much higher than blood-culture-based case estimates across all six sites, suggestive of a high incidence of asymptomatic or unrecognized infections. Still, the rank order of seroincidence and culture-based incidence rates were the same, with the highest rates in Bangladesh and lowest in Ghana.Implications of all the available evidence Many a -risk low- and middle-income countries lack data on typhoid incidence needed to inform and evaluate vaccine introduction. Even in countries where incidence estimates are available, data are typically geographically and temporally sparse due to the resources necessary to initiate and sustain blood culture surveillance. We found that typhoidal Salmonella infection incidence can be estimated from community-based serosurveys using dried blood spots, representing an efficient and scalable approach for generating the typhoid burden data needed to inform typhoid control programs in resource-constrained settings.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was funded by th eBill and Melinda Gates Foundation (grant INV-000572)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Institutional Review Boards in the United States (Centers for Disease Control and Prevention; Stanford University Institutional Review Board), Bangladesh (Bangladesh Institute of Child Health Ethical Review Committee), Nepal (Nepal Health Research Council Ethical Review Board), Pakistan (AKU Ethic Review Committee and Pakistan National Bioethics Committee), Korea (International Vaccine Institute IRB), Belgium (Institute of Tropical Medicine Antwerp Institutional Review Board) and Ghana (Komfo Anokye Teaching Hospital, Committee on Human Research, Publication and Ethics) approved the study forms and protocols.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors |
Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial – BCPP/ Ya Tsie trial (preprint)
Magosi LE , Zhang Y , Golubchik T , DeGruttola V , Tchetgen Tchetgen E , Novitsky V , Moore J , Bachanas P , Segolodi T , Lebelonyane R , Pretorius Holme M , Moyo S , Makhema J , Lockman S , Fraser C , Essex MM , Lipsitch M . medRxiv 2021 2021.06.19.21259186 Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 – 56.7] versus 3% [0.1 – 27.3]) than at baseline (7% [1.5 – 25.3] versus 5% [0.9 – 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis study was supported by the National Institute of General Medical Sciences (U54GM088558); the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610); and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The trial was approved by the Botswana Health Research and Development Committee, the institutional review board of the Centers for Disease Control and Prevention and the Harvard School of Public Health Office of Regulatory Affairs and Research Compliance; and was monitored by a data and safety monitoring board and Westat. Written informed consent for enrollment in the trial and viral HIV genotyping was obtained from all participants.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll relevant data are within the paper and the Supplemental Notes, figures and tables. HIV-1 reads are available on reasonable request through the PANGEA consortium (www.pangea-hiv.org) |
Interim impact evaluation of the hepatitis C virus elimination program in Georgia (preprint)
Walker JG , Fraser H , Lim AG , Gvinjilia L , Hagan L , Kuchuloria T , Martin NK , Nasrullah M , Shadaker S , Aladashvili M , Asatiani A , Baliashvili D , Butsashvili M , Chikovani I , Khonelidze I , Kirtadze I , Kuniholm MH , Otiashvili D , Stvilia K , Tsertsvadze T , Hickman M , Morgan J , Gamkrelidze A , Kvaratskhelia V , Averhoff F , Vickerman P . bioRxiv 2018 270579 Background and Aims Georgia has one of the highest hepatitis C virus (HCV) prevalence rates in the world, with >5% of the adult population (~150,000 people) chronically infected. In April 2015, the Georgian government, in collaboration with CDC and other partners, launched a national program to eliminate HCV through scaling up HCV treatment and prevention interventions, with the aim of achieving a 90% reduction in prevalence by 2020. We evaluate the interim impact of the HCV treatment program as of 31 October 2017, and assess the feasibility of achieving the elimination goal by 2020.Method We developed a dynamic HCV transmission model to capture the current and historical epidemic dynamics of HCV in Georgia, including the main drivers of transmission. Using the 2015 national sero-survey and prior surveys conducted among people who inject drugs (PWID) from 1997-2015, the model was calibrated to data on HCV prevalence by age, gender and PWID status, and the age distribution of PWID. We use the model to project the interim impact of treatment strategies currently being undertaken as part of the ongoing Georgia HCV elimination program, while accounting for treatment failure/loss to follow up, in order to determine whether they are on track to achieving their HCV elimination target by 2020, or whether strategies need to be modified to ensure success.Results A treatment rate of 2,050 patients/month was required from the beginning of the national program to achieve a 90% reduction in prevalence by the end of 2020, with equal treatment rates of PWID and the general population. From May 2015 to October 2017, 40,420 patients were treated, an average of ~1,350 per month; although the treatment rate has recently declined from a peak of 4,500/month in September 2016 to 2100/month in November-December 2016, and 1000/month in August-October 2017, with a sustained virological response rate (SVR) of 98% per-protocol or 78% intent to treat. The model projects that the treatments undertaken up to October 2017 have reduced adult chronic prevalence by 26% (18-35%) to 3.7% (2.9-5.1%), reduced total incidence by 25% (15-35%), and prevented 1845 (751-3969) new infections and 93 (31-177) HCV-related deaths. If the treatment rate of 1000 patients initiated per month continues, prevalence will have halved by 2020, and reduce by 90% by 2026. In order to reach a 90% reduction by 2020, the treatment rate must increase 3.5-fold to 4000/month.Conclusion The Georgia HCV elimination program has accomplished an impressive scale up of treatment, which has already impacted on prevalence and incidence, and averted deaths due to HCV. However, extensive scale up is needed to achieve a 90% reduction in prevalence by 2020. |
Growing gender disparity in HIV infection in Africa: sources and policy implications (preprint)
Monod M , Brizzi A , Galiwango RM , Ssekubugu R , Chen Y , Xi X , Kankaka EN , Ssempijja V , Dorner LA , Akullian A , Blenkinsop A , Bonsall D , Chang LW , Dan S , Fraser C , Golubchik T , Gray RH , Hall M , Jackson JC , Kigozi G , Laeyendecker O , Mills LA , Quinn TC , Reynolds SJ , Santelli J , Sewankambo NK , Spencer SEF , Ssekasanvu J , Thomson L , Wawer MJ , Serwadda D , Godfrey-Faussett P , Kagaayi J , Grabowski MK , Ratmann O . medRxiv 2023 17 HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years, but as new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance and longitudinal deep-sequence viral phylogenetics to assess how HIV incidence and the population groups driving transmission have evolved over a 15 year period from 2003 to 2018 in Uganda. HIV viral suppression increased more rapidly in women than men, resulting in 1.5-2 fold higher suppression rates in women with HIV by 2018 across age groups. Incidence declined more slowly in women than men, increasing pre-existing gender imbalance in HIV burden. Age-specific transmission flows shifted; the share of transmission to girls and women aged 15-24 years from older men declined by approximately one third, whereas the contribution of transmission to women aged 25-34 years from men aged 0-6 years older doubled from 2003 to 2018. We estimated closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018 and ended gender disparities in incidence. This study suggests that male-targeted HIV programs to increase HIV suppression are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. |
Correction: Building capacity for injury prevention: a process evaluation of a replication of the Cardiff Violence Prevention Programme in the Southeastern USA
Mercer Kollar LM , Sumner SA , Bartholow B , Wu DT , More JC , Mays EW , Atkins EV , Fraser DA , Flood CE , Shepherd JP . Inj Prev 2021 27 (1) 101 The article is previously published with incorrect and missing information. The updates are as follows: | | The last sentence in the third paragraph of ‘Building hospital capacity for data collection’ in ‘Results’ section has been updated as ‘A one-way ANOVA revealed a significant difference between April 2015 and April 2016 triage times, F(1,2734)=5.33, p=0.02. Triage times were on average 16.2 s longer in April 2016 compared with April 2015. No post-hoc analyses were done to control for other, non-CMST-related changes that occurred during the triage process (eg, additional triage screen) from April 2015 to April 2016.’ | Below statement has been added in the sixth paragraph of the ‘Discussion’ section after ‘Nurse participation in the satisfaction … a different US hospital.’ | The statistically significant increase in triage time of 16.2 s, which is unlikely to be clinically significant, may reflect other non-CMST-related triage process changes - such as addition of another triage screen - that were not accounted for in the analyses. |
Factors driving norovirus transmission in long-term care facilities: A case-level analysis of 107 outbreaks
Chen Y , Lopman BA , Hall AJ , Kambhampati AK , Roberts L , Mason J , Vilen K , Salehi E , Fraser A , Adams C . Epidemics 2023 42 100671 Norovirus is the most common cause of gastroenteritis outbreaks in long-term care facilities (LTCFs) in the United States, causing a high burden of disease in both residents and staff. Understanding how case symptoms and characteristics contribute to norovirus transmission can lead to more informed outbreak control measures in LTCFs. We examined line lists for 107 norovirus outbreaks that took place in LTCFs in five U.S. states from 2015 to 2019. We estimated the individual effective reproduction number, R(i), to quantify individual case infectiousness and examined the contribution of vomiting, diarrhea, and being a resident (vs. staff) to case infectiousness. The associations between case characteristics and R(i) were estimated using a multivariable, log-linear mixed model with inverse variance weighting. We found that cases with vomiting infected 1.28 (95 % CI: 1.11, 1.48) times the number of secondary cases compared to cases without vomiting, and LTCF residents infected 1.31 (95 % CI: 1.15, 1.50) times the number of secondary cases compared to staff. There was no difference in infectiousness between cases with and without diarrhea (1.07; 95 % CI: 0.90, 1.29). This suggests that vomiting, particularly by LTCF residents, was a primary driver of norovirus transmission. These results support control measures that limit exposure to vomitus during norovirus outbreaks in LTCFs. |
Implementation of a Nationwide Knowledge-Based COVID-19 Contact Tracing Training Program, 2020.
Ruebush E , Dennison A , Lane JT , Harper-Hardy P , Poulin A , Prather B , Wright S , Harvey D , Fraser MR . Public Health Rep 2022 137 333549221101327 In the United States, the public health response to control COVID-19 required rapid expansion of the contact tracing workforce from approximately 2200 personnel prepandemic to more than 100 000 during the pandemic. We describe the development and implementation of a free nationwide training course for COVID-19 contact tracers that launched April 28, 2020, and summarize participant characteristics and evaluation findings through December 31, 2020. Uptake of the online asynchronous training was substantial: 90 643 registrants completed the course during the first 8 months. In an analysis of a subset of course participants (n = 13 697), 7724 (56.4%) reported having no prepandemic public health experience and 7178 (52.4%) reported currently serving as case investigators, contact tracers, or both. Most participants who completed a course evaluation reported satisfaction with course utility (94.8%; 59 497 of 62 753) and improved understanding of contact tracing practice (93.0%; 66 107 of 71 048). These findings suggest that the course successfully reached the intended audience of new public health practitioners. Lessons learned from this implementation indicate that an introductory course level is appropriate for a national knowledge-based training that aims to complement jurisdiction-specific training. In addition, offering a range of implementation options can promote course uptake among public health agency staff. This course supported the emerging needs of the public health practice community by training a workforce to fill an important gap during the COVID-19 pandemic and could serve as a feasible model for enhancing workforce knowledge for future and ongoing public health threats. |
Estimating typhoid incidence from community-based serosurveys: a multicohort study
Aiemjoy K , Seidman JC , Saha S , Munira SJ , Islam Sajib MS , Sium SMA , Sarkar A , Alam N , Zahan FN , Kabir MS , Tamrakar D , Vaidya K , Shrestha R , Shakya J , Katuwal N , Shrestha S , Yousafzai MT , Iqbal J , Dehraj IF , Ladak Y , Maria N , Adnan M , Pervaiz S , Carter AS , Longley AT , Fraser C , Ryan ET , Nodoushani A , Fasano A , Leonard MM , Kenyon V , Bogoch II , Jeon HJ , Haselbeck A , Park SE , Zellweger RM , Marks F , Owusu-Dabo E , Adu-Sarkodie Y , Owusu M , Teunis P , Luby SP , Garrett DO , Qamar FN , Saha SK , Charles RC , Andrews JR . Lancet Microbe 2022 3 (8) e578-e587 BACKGROUND: The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence. METHODS: We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys. FINDINGS: The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates. INTERPRETATION: The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time. FUNDING: Bill & Melinda Gates Foundation. TRANSLATIONS: For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section. |
Connecting the dots: Public health, clinical, and community connections to improve contraception access
Pliska ES , Barfield WD , Fraser MR . Am J Public Health 2022 112 S508-s510 Reproductive well-being and equity require systems working together to develop trust and authentic, power-sharing relationships with communities, particularly those that have been historically marginalized. This includes addressing structural racism and healing from it; promoting equity, including equitable access to health care services; and engaging communities as decision makers in policy development, program design, and quality care.1,2 Appropriate contraception access that includes receiving the desired care and support that one needs is critical for promoting optimal and equitable reproductive health.3 |
User perceptions and use of an enhanced electronic health record in Rwanda with and without clinical alerts: Cross-sectional survey
Fraser HSF , Mugisha M , Remera E , Ngenzi JL , Richards J , Santas X , Naidoo W , Seebregts C , Condo J , Umubyeyi A . JMIR Med Inform 2022 10 (5) e32305 BACKGROUND: Electronic health records (EHRs) have been implemented in many low-resource settings but lack strong evidence for usability, use, user confidence, scalability, and sustainability. OBJECTIVE: This study aimed to evaluate staff use and perceptions of an EHR widely used for HIV care in >300 health facilities in Rwanda, providing evidence on factors influencing current performance, scalability, and sustainability. METHODS: A randomized, cross-sectional, structured interview survey of health center staff was designed to assess functionality, use, and attitudes toward the EHR and clinical alerts. This study used the associated randomized clinical trial study sample (56/112, 50% sites received an enhanced EHR), pulling 27 (50%) sites from each group. Free-text comments were analyzed thematically using inductive coding. RESULTS: Of the 100 participants, 90 (90% response rate) were interviewed at 54 health centers: 44 (49%) participants were clinical and 46 (51%) were technical. The EHR top uses were to access client data easily or quickly (62/90, 69%), update patient records (56/89, 63%), create new patient records (49/88, 56%), generate various reports (38/85, 45%), and review previous records (43/89, 48%). In addition, >90% (81/90) of respondents agreed that the EHR made it easier to make informed decisions, was worth using, and has improved patient information quality. Regarding availability, (66/88) 75% said they could always or almost always count on the EHR being available, whereas (6/88) 7% said never/almost never. In intervention sites, staff were significantly more likely to update existing records (P=.04), generate summaries before (P<.001) or during visits (P=.01), and agree that "the EHR provides useful alerts, and reminders" (P<.01). CONCLUSIONS: Most users perceived the EHR as well accepted, appropriate, and effective for use in low-resource settings despite infrastructure limitation in 25% (22/88) of the sites. The implementation of EHR enhancements can improve the perceived usefulness and use of key functions. Successful scale-up and use of EHRs in small health facilities could improve clinical documentation, care, reporting, and disease surveillance in low- and middle-income countries. |
Costs of seasonal influenza vaccination in South Africa
Fraser H , Tombe-Mdewa W , Kohli-Lynch C , Hofman K , Tempia S , McMorrow M , Lambach P , Ramkrishna W , Cohen C , Hutubessy R , Edoka I . Influenza Other Respir Viruses 2022 16 (5) 873-880 BACKGROUND: Influenza accounts for a substantial number of deaths and hospitalisations annually in South Africa. To address this disease burden, the South African National Department of Health introduced a trivalent inactivated influenza vaccination programme in 2010. METHODS: We adapted and populated the WHO Seasonal Influenza Immunization Costing Tool (WHO SIICT) with country-specific data to estimate the cost of the influenza vaccination programme in South Africa. Data were obtained through key-informant interviews at different levels of the health system and through a review of existing secondary data sources. Costs were estimated from a public provider perspective and expressed in 2018 prices. We conducted scenario analyses to assess the impact of different levels of programme expansion and the use of quadrivalent vaccines on total programme costs. RESULTS: Total financial and economic costs were estimated at approximately USD 2.93 million and USD 7.91 million, respectively, while financial and economic cost per person immunised was estimated at USD 3.29 and USD 8.88, respectively. Expanding the programme by 5% and 10% increased economic cost per person immunised to USD 9.36 and USD 9.52 in the two scenarios, respectively. Finally, replacing trivalent inactivated influenza vaccine (TIV) with quadrivalent vaccine increased financial and economic costs to USD 4.89 and USD 10.48 per person immunised, respectively. CONCLUSION: We adapted the WHO SIICT and provide estimates of the total costs of the seasonal influenza vaccination programme in South Africa. These estimates provide a basis for planning future programme expansion and may serve as inputs for cost-effectiveness analyses of seasonal influenza vaccination programmes. |
Efficacy of EPA-registered disinfectants against two human norovirus surrogates and Clostridioides difficile endospores
Huang J , Park GW , Jones RM , Fraser A , Vinjé J , Jiang X . J Appl Microbiol 2022 132 (6) 4289-4299 AIMS: To determine the efficacy of a panel of nine EPA-registered disinfectants against two human norovirus (HuNoV) surrogates [feline calicivirus (FCV) and Tulane virus (TuV)] and Clostridioides difficile endospores. METHODS AND RESULTS: Nine EPA-registered products, five of which contained H(2) O(2) as active ingredient, were tested against infectious FCV, TuV, and C. difficile endospores using two ASTM methods, a suspension and carrier test. Efficacy claims against FCV were confirmed for 8 of 9 products. The most efficacious product containing H(2) O(2) as ingredient, achieved a >5.1 log reduction of FCV and >3.1 log reduction of TuV after 5 min, and >6.0 log reduction of C. difficile endospores after 10 min. Of the five products containing H(2) O(2) , no strong correlation (R(2) =0.25, p=0.03) was observed between disinfection efficacy and H(2) O(2) concentration. Addition of 0.025% ferrous sulfate to 1% H(2) O(2) solution improved efficacy against FCV, TuV, and C. difficile. CONCLUSION: Disinfectants containing H(2) O(2) are the most efficacious disinfection products against FCV, TuV and C. difficile endospores. Product formulation, rather than the concentration of H(2) O(2) in a product, impacts the efficacy of a disinfection product. SIGNIFICANCE AND IMPACT OF STUDY: H(2) O(2) -based disinfectants are efficacious against surrogate viruses for HuNoV and C. difficile endospores. |
Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial - BCPP/ Ya Tsie trial.
Magosi LE , Zhang Y , Golubchik T , DeGruttola V , TchetgenTchetgen E , Novitsky V , Moore J , Bachanas P , Segolodi T , Lebelonyane R , PretoriusHolme M , Moyo S , Makhema J , Lockman S , Fraser C , Essex MM , Lipsitch M . Elife 2022 11 Background: Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. Methods: To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV-intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana. We sequenced HIV viral whole genomes from 5,114 trial participants among the 30 trial communities. Results: Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 - 56.7] versus 3% [0.1 - 27.3]) than at baseline (7% [1.5 - 25.3] versus 5% [0.9 - 22.9]) compatible with a benefit from treatment-as-prevention. Conclusion: Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies. Funding: This study was supported by the National Institute of General Medical Sciences (U54GM088558); the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610); and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911). |
Hygienic monitoring in long-term care facilities using ATP, crAssphage, and human noroviruses to direct environmental surface cleaning
Cannon JL , Park GW , Anderson B , Leone C , Chao M , Vinjé J , Fraser AM . Am J Infect Control 2022 50 (3) 289-294 BACKGROUND: Norovirus and C. difficile are associated with diarrheal illnesses and deaths in long-term care (LTC) facilities and can be transmitted by contaminated environmental surfaces. Hygienic monitoring tools such as adenosine triphosphate (ATP) bioluminescence and indicators of fecal contamination can help to identify LTC facility surfaces with cleaning deficiencies. METHODS: High-touch surfaces in 11 LTC facilities were swabbed and tested for contamination by norovirus, a fecal indicator virus, crAssphage, and ATP which detects organic debris. High levels of contamination were defined as log ATP relative light unit values or crAssphage log genomic copy values in the 75th percentile of values obtained from each facility. RESULTS: Over 90% of surfaces tested positive for crAssphage or gave failing ATP scores. Norovirus contamination was not detected. Handrails, equipment controls, and patient beds were 4 times more likely than other surfaces or locations to have high levels of crAssphage. Patient bed handrails and tables and chairs in patient lounges had high levels of both ATP and crAssphage. CONCLUSIONS: Surfaces with high levels of ATP and crAssphage were identified. Quantifying levels of contamination longitudinally and before and after cleaning might enhance infection prevention and control procedures for reducing diarrheal illnesses in LTC facilities. |
Lack of association of post-discharge prophylactic antibiotics with decreased risk of surgical site infection following spinal fusion
Olsen MA , Greenberg JK , Peacock K , Nickel KB , Fraser VJ , Warren DK . J Antimicrob Chemother 2022 77 (4) 1178-1184 OBJECTIVES: To determine the prevalence and factors associated with post-discharge prophylactic antibiotic use after spinal fusion and whether use was associated with decreased risk of surgical site infection (SSI). METHODS: Persons aged 10-64 years undergoing spinal fusion between 1 January 2010 and 30 June 2015 were identified in the MarketScan Commercial Database. Complicated patients and those coded for infection from 30 days before to 2 days after the surgical admission were excluded. Outpatient oral antibiotics were identified within 2 days of surgical discharge. SSI was defined using ICD-9-CM diagnosis codes within 90 days of surgery. Generalized linear models were used to determine factors associated with post-discharge prophylactic antibiotic use and with SSI. RESULTS: The cohort included 156 446 fusion procedures, with post-discharge prophylactic antibiotics used in 9223 (5.9%) surgeries. SSIs occurred after 2557 (1.6%) procedures. Factors significantly associated with post-discharge prophylactic antibiotics included history of lymphoma, diabetes, 3-7 versus 1-2 vertebral levels fused, and non-infectious postoperative complications. In multivariable analysis, post-discharge prophylactic antibiotic use was not associated with SSI risk after spinal fusion (relative risk 0.98; 95% CI 0.84-1.14). CONCLUSIONS: Post-discharge prophylactic oral antibiotics after spinal fusion were used more commonly in patients with major medical comorbidities, more complex surgeries and those with postoperative complications during the surgical admission. After adjusting for surgical complexity and infection risk factors, post-discharge prophylactic antibiotic use was not associated with decreased SSI risk. These results suggest that prolonged prophylactic antibiotic use should be avoided after spine surgery, given the lack of benefit and potential for harm. |
Histopathology of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities in a murine model
Fraser K , Hubbs A , Yanamala N , Mercer RR , Stueckle TA , Jensen J , Eye T , Battelli L , Clingerman S , Fluharty K , Dodd T , Casuccio G , Bunker K , Lersch TL , Kashon ML , Orandle M , Dahm M , Schubauer-Berigan MK , Kodali V , Erdely A . Part Fibre Toxicol 2021 18 (1) 47 BACKGROUND: Multi-walled carbon nanotubes and nanofibers (CNT/F) have been previously investigated for their potential toxicities; however, comparative studies of the broad material class are lacking, especially those with a larger diameter. Additionally, computational modeling correlating physicochemical characteristics and toxicity outcomes have been infrequently employed, and it is unclear if all CNT/F confer similar toxicity, including histopathology changes such as pulmonary fibrosis. Male C57BL/6 mice were exposed to 40 µg of one of nine CNT/F (MW #1-7 and CNF #1-2) commonly found in exposure assessment studies of U.S. facilities with diameters ranging from 6 to 150 nm. Human fibroblasts (0-20 µg/ml) were used to assess the predictive value of in vitro to in vivo modeling systems. RESULTS: All materials induced histopathology changes, although the types and magnitude of the changes varied. In general, the larger diameter MWs (MW #5-7, including Mitsui-7) and CNF #1 induced greater histopathology changes compared to MW #1 and #3 while MW #4 and CNF #2 were intermediate in effect. Differences in individual alveolar or bronchiolar outcomes and severity correlated with physical dimensions and how the materials agglomerated. Human fibroblast monocultures were found to be insufficient to fully replicate in vivo fibrosis outcomes suggesting in vitro predictive potential depends upon more advanced cell culture in vitro models. Pleural penetrations were observed more consistently in CNT/F with larger lengths and diameters. CONCLUSION: Physicochemical characteristics, notably nominal CNT/F dimension and agglomerate size, predicted histopathologic changes and enabled grouping of materials by their toxicity profiles. Particles of greater nominal tube length were generally associated with increased severity of histopathology outcomes. Larger particle lengths and agglomerates were associated with more severe bronchi/bronchiolar outcomes. Spherical agglomerated particles of smaller nominal tube dimension were linked to granulomatous inflammation while a mixture of smaller and larger dimensional CNT/F resulted in more severe alveolar injury. |
Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation
Young TL , Mostovenko E , Denson JL , Begay JG , Lucas SN , Herbert G , Zychowski K , Hunter R , Salazar R , Wang T , Fraser K , Erdely A , Ottens AK , Campen MJ . Part Fibre Toxicol 2021 18 (1) 34 BACKGROUND: Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. RESULTS: C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. CONCLUSIONS: Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption. |
Evaluation of phylogenetic methods for inferring the direction of HIV transmission: HPTN 052.
Zhang Y , Wymant C , Laeyendecker O , Grabowski MK , Hall M , Hudelson S , Piwowar-Manning E , McCauley M , Gamble T , Hosseinipour MC , Kumarasamy N , Hakim JG , Kumwenda J , Mills LA , Santos BR , Grinsztejn B , Pilotto JH , Chariyalertsak S , Makhema J , Chen YQ , Cohen MS , Fraser C , Eshleman SH . Clin Infect Dis 2021 72 (1) 30-37 BACKGROUND: Phylogenetic analysis can be used to assess human immunodeficiency virus (HIV) transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction. METHODS: Complete next-generation sequencing (NGS) data were obtained for 105 unique index-partner sample pairs from 32 couples enrolled in the HIV Prevention Trials Network (HPTN) 052 study (up to 2 samples/person). Index samples were obtained up to 5.5 years before partner infection; partner samples were obtained near the time of seroconversion. The bioinformatics method, phyloscanner, was used to infer transmission direction. Analyses were performed using samples from individual sample pairs, samples from all couples (1 sample/person; group analysis), and all available samples (multisample group analysis). Analysis was also performed using NGS data from defined regions of the HIV genome (gag, pol, env). RESULTS: Using whole-genome NGS data, transmission direction was inferred correctly (index to partner) for 98 of 105 (93.3%) of the individual sample pairs, 99 of 105 (94.3%) sample pairs using group analysis, and 31 of the 32 couples (96.9%) using multisample group analysis. There were no cases where the incorrect transmission direction (partner to index) was inferred. The accuracy of the method was higher with greater time between index and partner sample collection. Pol region sequences performed better than env or gag sequences for inferring transmission direction. CONCLUSIONS: We demonstrate the potential of a phylogenetic method to infer the direction of HIV transmission between 2 individuals using whole-genome and pol NGS data. |
Analytical performance specifications for 25-hydroxyvitamin D examinations
Cavalier E , Fraser CG , Bhattoa HP , Heijboer AC , Makris K , Ulmer CZ , Vesper HW , Vasikaran S , Lukas P , Delanaye P , Carobene A . Nutrients 2021 13 (2) Currently the 25-hydroxy vitamin D (25(OH)D) concentration is thought to be the best estimate of the vitamin D status of an individual. Unfortunately, its measurement remains complex, despite recent technological advances. We evaluated the biological variation (BV) of 25(OH)D in order to set analytical performance specifications (APS) for measurement uncertainty (MU). Six European laboratories recruited 91 healthy participants. The 25(OH)D concentrations in K(3)-EDTA plasma were examined weekly for up to 10 weeks in duplicate on a Lumipulse G1200 (Fujirebio, Tokyo, Japan). The linear regression of the mean 25(OH)D concentrations at each blood collection showed that participants were not in a steady state. The dissection of the 10-sample collection into two subsets, namely collections 1-5 and 6-10, did not allow for correction of the lack of homogeneity: estimates of the within-subject BV ranged from 5.8% to 7.1% and the between-subject BV ranged from 25.0% to 39.2%. Methods that would differentiate a difference induced by 25(OH)D supplementation at p < 0.05 should have MU < 13.6%, while at p < 0.01, the MU should be <9.6%. The development of APS using BV assumes a steady state of patients. The findings in this study suggest that patients are not in steady state. Therefore, APS that are based on MU appear to be more appropriate. |
Antimicrobial resistance control efforts in Africa: a survey of the role of Civil Society Organisations
Fraser JL , Alimi YH , Varma JK , Muraya T , Kujinga T , Carter VK , Schultsz C , Del Rio Vilas VJ . Glob Health Action 2021 14 (1) 1868055 Background: Antimicrobial resistance (AMR) is a growing public health threat in Africa. AMR prevention and control requires coordination across multiple sectors of government and civil society partners. Objectives: To assess the current role, needs, and capacities of CSOs working in AMR in Africa. Methods: We conducted an online survey of 35 CSOs working in 37 countries across Africa. The survey asked about priorities for AMR, current AMR-specific activities, monitoring practices, training needs, and preferences for sharing information on AMR. Further data were gathered on the main roles of the organisations, the length of time engaged in and budget spent on AMR-related activities, and their involvement in the development and implementation of National Action Plans (NAPs). Results were assessed against The Africa Centres for Disease Control and Prevention (Africa CDC) Framework for Antimicrobial Resistance (2018-2023). Results: CSOs with AMR-related activities are working in all four areas of Africa CDC's Framework: improving surveillance, delaying emergence, limiting transmission, and mitigating harm from infections caused by AMR microorganisms. Engagement with the four objectives is mainly through advocacy, followed by accountability and service delivery. There were limited monitoring activities reported by CSOs, with only seven (20%) providing an example metric used to monitor their activities related to AMR, and 27 (80%) CSOs reporting having no AMR-related strategy. Half the CSOs reported engaging with the development and implementation of NAPs; however, only three CSOs are aligning their work with these national strategies. Conclusion: CSOs across Africa are supporting AMR prevention and control, however, there is potential for more engagement. Africa CDC and other government agencies should support the training of CSOs in strategies to control AMR. Tailored training programmes can build knowledge of AMR, capacity for monitoring processes, and facilitate further identification of CSOs' contribution to the AMR Framework and alignment with NAPs and regional strategies. |
Healthcare-associated outbreaks of bacterial infections in Africa, 2009-2018: A review
Fraser JL , Mwatondo A , Alimi YH , Varma JK , Vilas VJDR . Int J Infect Dis 2020 103 469-477 BACKGROUND: Healthcare-associated infections (HAIs) are a major global public health problem, increasing the transmission of drug-resistant infections. In Africa, the prevalence of HAIs among all hospital inpatients is estimated to be between 3% and 15%, but outbreaks are infrequently reported. Failure to detect and/or report outbreaks can increase the risk of ongoing infections and recurrent outbreaks. METHODS: A search of the PubMed, Web of Science, Cochrane Library, and other outbreak databases was performed to identify published literature on bacterial HAI outbreaks in Africa (January 2009 to December 2018). Details of the outbreak characteristics, hospital environment, and the control measures implemented were extracted. RESULTS: Twenty-two studies published over the 10-year period were identified. These reported 31 distinct outbreaks and a total of 31 causative pathogens, including Klebsiella pneumoniae (six outbreaks, 19%), Staphylococcus aureus (six outbreaks, 19%), and Enterococcus (five outbreaks, 16%). Most outbreaks were reported from university (n = 8, 26%) and tertiary hospitals (n = 11, 55%), from South Africa (n = 9, 41%) and Tunisia (n = 4, 18%). Interventions to control the outbreaks were described in 27 (90%) outbreaks, and all instituted or recommended enhancing hand hygiene and education. CONCLUSIONS: Few facilities in Africa reported HAI outbreaks over the 10-year period, suggesting substantial under-detection and under-reporting. The quality and timeliness of reporting require improvement to ensure changes in public health practice. |
A cost-effectiveness analysis of South Africa's seasonal influenza vaccination programme
Edoka I , Kohli-Lynch C , Fraser H , Hofman K , Tempia S , McMorrow M , Ramkrishna W , Lambach P , Hutubessy R , Cohen C . Vaccine 2020 39 (2) 412-422 BACKGROUND: Seasonal influenza imposes a significant health and economic burden in South Africa, particularly in populations vulnerable to severe consequences of influenza. This study assesses the cost-effectiveness of South Africa's seasonal influenza vaccination strategy, which involves vaccinating vulnerable populations with trivalent inactivated influenza vaccine (TIV) during routine facility visits. Vulnerable populations included in our analysis are persons aged ≥ 65 years; pregnant women; persons living with HIV/AIDS (PLWHA), persons of any age with underlying medical conditions (UMC) and children aged 6-59 months. METHOD: We employed the World Health Organisation's (WHO) Cost Effectiveness Tool for Seasonal Influenza Vaccination (CETSIV), a decision tree model, to evaluate the 2018 seasonal influenza vaccination campaign from a public healthcare provider and societal perspective. CETSIV was populated with existing country-specific demographic, epidemiologic and coverage data to estimate incremental cost-effectiveness ratios (ICERs) by comparing costs and benefits of the influenza vaccination programme to no vaccination. RESULTS: The highest number of clinical events (influenza cases, outpatient visits, hospitalisation and deaths) were averted in PLWHA and persons with other UMCs. Using a cost-effectiveness threshold of US$ 3400 per quality-adjusted life year (QALY), our findings suggest that the vaccination programme is cost-effective for all vulnerable populations except for children aged 6-59 months. ICERs ranged from ~US$ 1 750 /QALY in PLWHA to ~US$ 7500/QALY in children. In probabilistic sensitivity analyses, the vaccination programme was cost-effective in pregnant women, PLWHA, persons with UMCs and persons aged ≥65 years in >80% of simulations. These findings were robust to changes in many model inputs but were most sensitive to uncertainty in estimates of influenza-associated illness burden. CONCLUSION: South Africa's seasonal influenza vaccination strategy of opportunistically targeting vulnerable populations during routine visits is cost-effective. A budget impact analysis will be useful for supporting future expansions of the programme. |
Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities.
Fraser K , Kodali V , Yanamala N , Birch ME , Cena L , Casuccio G , Bunker K , Lersch TL , Evans DE , Stefaniak A , Hammer MA , Kashon ML , Boots T , Eye T , Hubczak J , Friend SA , Dahm M , Schubauer-Berigan MK , Siegrist K , Lowry D , Bauer AK , Sargent LM , Erdely A . Part Fibre Toxicol 2020 17 (1) 62 BACKGROUND: Carbon nanotubes and nanofibers (CNT/F) have known toxicity but simultaneous comparative studies of the broad material class, especially those with a larger diameter, with computational analyses linking toxicity to their fundamental material characteristics was lacking. It was unclear if all CNT/F confer similar toxicity, in particular, genotoxicity. Nine CNT/F (MW #1-7 and CNF #1-2), commonly found in exposure assessment studies of U.S. facilities, were evaluated with reported diameters ranging from 6 to 150 nm. All materials were extensively characterized to include distributions of physical dimensions and prevalence of bundled agglomerates. Human bronchial epithelial cells were exposed to the nine CNT/F (0-24 μg/ml) to determine cell viability, inflammation, cellular oxidative stress, micronuclei formation, and DNA double-strand breakage. Computational modeling was used to understand various permutations of physicochemical characteristics and toxicity outcomes. RESULTS: Analyses of the CNT/F physicochemical characteristics illustrate that using detailed distributions of physical dimensions provided a more consistent grouping of CNT/F compared to using particle dimension means alone. In fact, analysis of binning of nominal tube physical dimensions alone produced a similar grouping as all characterization parameters together. All materials induced epithelial cell toxicity and micronuclei formation within the dose range tested. Cellular oxidative stress, DNA double strand breaks, and micronuclei formation consistently clustered together and with larger physical CNT/F dimensions and agglomerate characteristics but were distinct from inflammatory protein changes. Larger nominal tube diameters, greater lengths, and bundled agglomerate characteristics were associated with greater severity of effect. The portion of tubes with greater nominal length and larger diameters within a sample was not the majority in number, meaning a smaller percentage of tubes with these characteristics was sufficient to increase toxicity. Many of the traditional physicochemical characteristics including surface area, density, impurities, and dustiness did not cluster with the toxicity outcomes. CONCLUSION: Distributions of physical dimensions provided more consistent grouping of CNT/F with respect to toxicity outcomes compared to means only. All CNT/F induced some level of genotoxicity in human epithelial cells. The severity of toxicity was dependent on the sample containing a proportion of tubes with greater nominal lengths and diameters. |
Influenza economic burden among potential target risk groups for immunization in South Africa, 2013-2015
Tempia S , Moyes J , Cohen AL , Walaza S , McMorrow ML , Edoka I , Fraser H , Treurnicht FK , Hellferscee O , Wolter N , von Gottberg A , McAnerney JM , Dawood H , Variava E , Cohen C . Vaccine 2020 38 (45) 7007-7014 BACKGROUND: Data on influenza economic burden in risk groups for severe influenza are important to guide targeted influenza immunization, especially in resource-limited settings. However, this information is limited in low- and middle-income countries. METHODS: We estimated the cost (from a health system and societal perspective) and years of life lost (YLL) for influenza-associated illness in South Africa during 2013-2015 among (i) children aged 6-59 months, (ii) individuals aged 5-64 years with HIV, pulmonary tuberculosis (PTB) and selected underlying medical conditions (UMC), separately, (iii) pregnant women and (iv) individuals aged ≥65 years, using publicly available data and data collected through laboratory-confirmed influenza surveillance and costing studies. All costs were expressed in 2015 prices using the South Africa all-items Consumer Price Index. RESULTS: During 2013-2015, the mean annual cost of influenza-associated illness among the selected risk groups accounted for 52.1% ($140.9/$270.5 million) of the total influenza-associated illness cost (for the entire population of South Africa), 45.2% ($52.2/$115.5 million) of non-medically attended illness costs, 43.3% ($46.7/$107.9 million) of medically-attended mild illness costs and 89.3% ($42.0/$47.1 million) of medically-attended severe illness costs. The YLL among the selected risk groups accounted for 86.0% (262,069 /304,867 years) of the total YLL due to influenza-associated death. CONCLUSION: In South Africa, individuals in risk groups for severe influenza accounted for approximately half of the total influenza-associated illness cost but most of the cost of influenza-associated medically attended severe illness and YLL. This study provides the foundation for future studies on the cost-effectiveness of influenza immunization among risk groups. |
Tumorigenic response in lung tumor susceptible A/J mice after sub-chronic exposure to calcium chromate or iron (III) oxide
Zeidler-Erdely PC , Falcone LM , Antonini JM , Fraser K , Kashon ML , Battelli LA , Salmen R , Trainor T , Grose L , Friend S , Yang C , Erdely A . Toxicol Lett 2020 334 60-65 Iron oxides are Group 3 (not classifiable as to its carcinogenicity to humans) according to the International Agency for Research on Cancer (IARC). Occupational exposures during iron and steel founding and hematite underground mining as well as other iron predominant exposures such as welding are Group 1 (carcinogenic to humans). The objective of this study was to investigate the potential of iron as iron (III) oxide (Fe(2)O(3)) to initiate lung tumors in A/J mice, a lung tumor susceptible strain. Male A/J mice were exposed by oropharyngeal aspiration to suspensions of Fe(2)O(3) (1 mg) or calcium chromate (CaCrO(4); 100 µg; positive control) for 26 weeks (once per week). Shams were exposed to 50 µL phosphate buffered saline (PBS; vehicle). Mice were euthanized 70 weeks after the first exposure and lung nodules were enumerated. Both CaCrO(4) and Fe(2)O(3) significantly increased gross-observed lung tumor multiplicity in A/J mice (9.63 ± 0.55 and 3.35 ± 0.30, respectively) compared to sham (2.31 ± 0.19). Histopathological analysis showed that bronchiolo-alveolar adenomas (BAA) and carcinomas (BAC) were the primary lung tumor types in all groups and were increased in the exposed groups compared to sham. BAC were significantly increased (146 %) in the CaCrO(4) group and neared significance in the Fe(2)O(3) group (100 % increase; p = 0.085). BAA and other histopathological indices of toxicity followed the same pattern with exposed groups increased compared to sham control. In conclusion, evidence from this study, in combination with our previous studies, demonstrate that exposure to iron alone may be a potential risk factor for lung carcinogenesis. |
Influenza disease burden among potential target risk groups for immunization in South Africa, 2013-2015
Tempia S , Walaza S , Moyes J , McMorrow ML , Cohen AL , Edoka I , Fraser H , Treurnicht FK , Hellferscee O , Wolter N , von Gottberg A , McAnerney JM , Dawood H , Variava E , Cohen C . Vaccine 2020 38 (27) 4288-4297 BACKGROUND: Data on influenza burden in risk groups for severe influenza are important to guide targeted influenza immunization, especially in resource limited settings. However, this information is limited overall and in particular in low- and middle-income countries. We sought to assess the mean annual national burden of medically and non-medically attended influenza-associated mild, severe-non-fatal and fatal illness among potential target groups for influenza immunization in South Africa during 2013-2015. METHODS: We used published mean national annual estimates of mild, severe-non-fatal, and fatal influenza-associated illness in South Africa during 2013-2015 and estimated the number of such illnesses occurring among the following risk groups: (i) children aged 6-59 months; (ii) individuals aged 5-64 years with HIV, and/or pulmonary tuberculosis (PTB), and/or selected underlying medical conditions (UMC); (iii) pregnant women; and (iv) individuals aged >/=65 years. We also estimated the number of individuals among the same risk groups in the population. RESULTS: During 2013-2015, individuals in the selected risk groups accounted for 45.3% (24,569,328/54,086,144) of the population and 43.5% (4,614,763/10,598,138), 86.8% (111,245/128,173) and 94.5% (10,903/11,536) of the mean annual estimated number of influenza-associated mild, severe-non-fatal and fatal illness episodes, respectively. The rates of influenza-associated illness were highest in children aged 6-59 months (23,983 per 100,000 population) for mild illness, in pregnant women (930 per 100,000 population) for severe-non-fatal illness and in individuals aged >/=65 years (138 per 100,000 population) for fatal illness. CONCLUSION: Influenza immunization of the selected risk groups has the potential to prevent a substantial number of influenza-associated severe illness. Nonetheless, because of the high number of individuals at risk, South Africa, due to financial resources constrains, may need to further prioritize interventions among risk populations. Cost-burden and cost-effectiveness estimates may assist with further prioritization. |
Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis
Lim AG , Walker JG , Mafirakureva N , Khalid GG , Qureshi H , Mahmood H , Trickey A , Fraser H , Aslam K , Falq G , Fortas C , Zahid H , Naveed A , Auat R , Saeed Q , Davies CF , Mukandavire C , Glass N , Maman D , Martin NK , Hickman M , May MT , Hamid S , Loarec A , Averhoff F , Vickerman P . Lancet Glob Health 2020 8 (3) e440-e450 BACKGROUND: The WHO elimination strategy for hepatitis C virus advocates scaling up screening and treatment to reduce global hepatitis C incidence by 80% by 2030, but little is known about how this reduction could be achieved and the costs of doing so. We aimed to evaluate the effects and cost of different strategies to scale up screening and treatment of hepatitis C in Pakistan and determine what is required to meet WHO elimination targets for incidence. METHODS: We adapted a previous model of hepatitis C virus transmission, treatment, and disease progression for Pakistan, calibrating using available data to incorporate a detailed cascade of care for hepatitis C with cost data on diagnostics and hepatitis C treatment. We modelled the effect on various outcomes and costs of alternative scenarios for scaling up screening and hepatitis C treatment in 2018-30. We calibrated the model to country-level demographic data for 1960-2015 (including population growth) and to hepatitis C seroprevalence data from a national survey in 2007-08, surveys among people who inject drugs (PWID), and hepatitis C seroprevalence trends among blood donors. The cascade of care in our model begins with diagnosis of hepatitis C infection through antibody screening and RNA confirmation. Diagnosed individuals are then referred to care and started on treatment, which can result in a sustained virological response (effective cure). We report the median and 95% uncertainty interval (UI) from 1151 modelled runs. FINDINGS: One-time screening of 90% of the 2018 population by 2030, with 80% referral to treatment, was projected to lead to 13.8 million (95% UI 13.4-14.1) individuals being screened and 350 000 (315 000-385 000) treatments started annually, decreasing hepatitis C incidence by 26.5% (22.5-30.7) over 2018-30. Prioritised screening of high prevalence groups (PWID and adults aged >/=30 years) and rescreening (annually for PWID, otherwise every 10 years) are likely to increase the number screened and treated by 46.8% and decrease incidence by 50.8% (95% UI 46.1-55.0). Decreasing hepatitis C incidence by 80% is estimated to require a doubling of the primary screening rate, increasing referral to 90%, rescreening the general population every 5 years, and re-engaging those lost to follow-up every 5 years. This approach could cost US$8.1 billion, reducing to $3.9 billion with lowest costs for diagnostic tests and drugs, including health-care savings, and implementing a simplified treatment algorithm. INTERPRETATION: Pakistan will need to invest about 9.0% of its yearly health expenditure to enable sufficient scale up in screening and treatment to achieve the WHO hepatitis C elimination target of an 80% reduction in incidence by 2030. FUNDING: UNITAID. |
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