Publications by authors named "David Watkins"

392 Publications

Balancing health and financial protection in health benefit package design.

Health Econ 2021 Oct 8. Epub 2021 Oct 8.

Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Policymakers face difficult choices over which health interventions to publicly finance. We developed an approach to health benefits package design that accommodates explicit tradeoffs between improvements in health and provision of financial risk protection (FRP). We designed a mathematical optimization model to balance gains in health and FRP across candidate interventions when publicly financed. The optimal subset of interventions selected for inclusion was determined with bi-criterion integer programming conditional on a budget constraint. The optimal set of interventions to publicly finance in a health benefits package varied according to whether the objective for optimization was population health benefits or FRP. When both objectives were considered jointly, the resulting optimal essential benefits package depended on the weights placed on the two objectives. In the Sustainable Development Goals era, smart spending toward universal health coverage is essential. Mathematical optimization provides a quantitative framework for policymakers to design health policies and select interventions that jointly prioritize multiple objectives with explicit financial constraints.
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http://dx.doi.org/10.1002/hec.4434DOI Listing
October 2021

Methionine Synthase Deficiency: Variable Clinical Presentation And Benefit Of Early Diagnosis And Treatment.

J Inherit Metab Dis 2021 Oct 9. Epub 2021 Oct 9.

Section of Genetics and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and non-specific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present 5 patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of pre-symptomatic patients, cblG warrants inclusion in newborn screening. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jimd.12448DOI Listing
October 2021

Prioritizing Health-Sector Interventions for Noncommunicable Diseases and Injuries in Low- and Lower-Middle Income Countries: National NCDI Poverty Commissions.

Glob Health Sci Pract 2021 Sep 30;9(3):626-639. Epub 2021 Sep 30.

Partners In Health NCD Synergies, Boston, MA, USA.

Health sector priorities and interventions to prevent and manage noncommunicable diseases and injuries (NCDIs) in low- and lower-middle-income countries (LLMICs) have primarily adopted elements of the World Health Organization Global Action Plan for NCDs 2013-2020. However, there have been limited efforts in LLMICs to prioritize among conditions and health-sector interventions for NCDIs based on local epidemiology and contextually relevant risk factors or that incorporate the equitable distribution of health outcomes. The Commission on Reframing Noncommunicable Diseases and Injuries for the Poorest Billion supported national NCDI Poverty Commissions to define local NCDI epidemiology, determine an expanded set of priority NCDI conditions, and recommend cost-effective, equitable health-sector interventions. Fifteen national commissions and 1 state-level commission were established from 2016-2019. Six commissions completed the prioritization exercise and selected an average of 25 NCDI conditions; 15 conditions were selected by all commissions, including asthma, breast cancer, cervical cancer, diabetes mellitus type 1 and 2, epilepsy, hypertensive heart disease, intracerebral hemorrhage, ischemic heart disease, ischemic stroke, major depressive disorder, motor vehicle road injuries, rheumatic heart disease, sickle cell disorders, and subarachnoid hemorrhage. The commissions prioritized an average of 35 health-sector interventions based on cost-effectiveness, financial risk protection, and equity-enhancing rankings. The prioritized interventions were estimated to cost an additional US$4.70-US$13.70 per capita or approximately 9.7%-35.6% of current total health expenditure (0.6%-4.0% of current gross domestic product). Semistructured surveys and qualitative interviews of commission representatives demonstrated positive outcomes in several thematic areas, including understanding NCDIs of poverty, informing national planning and implementation of NCDI health-sector interventions, and improving governance and coordination for NCDIs. Overall, national NCDI Poverty Commissions provided a platform for evidence-based, locally driven determination of priorities within NCDIs.
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http://dx.doi.org/10.9745/GHSP-D-21-00035DOI Listing
September 2021

Incidence of acute rheumatic fever in northern and western Uganda: a prospective, population-based study.

Lancet Glob Health 2021 10 19;9(10):e1423-e1430. Epub 2021 Aug 19.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; The University of Cincinnati School of Medicine, Cincinnati, OH, USA. Electronic address:

Background: Acute rheumatic fever is infrequently diagnosed in sub-Saharan African countries despite the high prevalence of rheumatic heart disease. We aimed to determine the incidence of acute rheumatic fever in northern and western Uganda.

Methods: For our prospective epidemiological study, we established acute rheumatic fever clinics at two regional hospitals in the north (Lira district) and west (Mbarara district) of Uganda and instituted a comprehensive acute rheumatic fever health messaging campaign. Communities and health-care workers were encouraged to refer children aged 3-17 years, with suspected acute rheumatic fever, for a definitive diagnosis using the Jones Criteria. Children were referred if they presented with any of the following: (1) history of fever within the past 48 h in combination with any joint complaint, (2) suspicion of acute rheumatic carditis, or (3) suspicion of chorea. We excluded children with a confirmed alternative diagnosis. We estimated incidence rates among children aged 5-14 years and characterised clinical features of definite and possible acute rheumatic fever cases.

Findings: Data were collected between Jan 17, 2018, and Dec 30, 2018, in Lira district and between June 5, 2019, and Feb 28, 2020, in Mbarara district. Of 1075 children referred for evaluation, 410 (38%) met the inclusion criteria; of these, 90 (22%) had definite acute rheumatic fever, 82 (20·0%) had possible acute rheumatic fever, and 24 (6%) had rheumatic heart disease without evidence of acute rheumatic fever. Additionally, 108 (26%) children had confirmed alternative diagnoses and 106 (26%) had an unknown alternative diagnosis. We estimated the incidence of definite acute rheumatic fever among children aged 5-14 years as 25 cases (95% CI 13·7-30·3) per 100 000 person-years in Lira district (north) and 13 cases (7·1-21·0) per 100 000 person-years in Mbarara district (west).

Interpretation: To the best of our knowledge, this is the first population-based study to estimate the incidence of acute rheumatic fever in sub-Saharan Africa. Given the known rheumatic heart disease burden, it is likely that only a proportion of children with acute rheumatic fever were diagnosed. These data dispel the long-held hypothesis that the condition does not exist in sub-Saharan Africa and compel investment in improving prevention, recognition, and diagnosis of acute rheumatic fever.

Funding: American Heart Association Children's Strategically Focused Research Network Grant, THRiVE-2, General Electric, and Cincinnati Children's Heart Institute Research Core.
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http://dx.doi.org/10.1016/S2214-109X(21)00288-6DOI Listing
October 2021

Household Economic Consequences of Rheumatic Heart Disease in Uganda.

Front Cardiovasc Med 2021 30;8:636280. Epub 2021 Jul 30.

Department of Community-Based Rehabilitation Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Rheumatic heart disease (RHD) has declined dramatically in wealthier countries in the past three decades, but it remains endemic in many lower-resourced regions and can have significant costs to households. The objective of this study was to quantify the economic burden of RHD among Ugandans affected by RHD. This was a cross-sectional cost-of-illness study that randomly sampled 87 participants and their households from the Uganda National RHD registry between December 2018 and February 2020. Using a standardized survey instrument, we asked participants and household members about outpatient and inpatient RHD costs and financial coping mechanisms incurred over the past 12 months. We used descriptive statistics to analyze levels and distributions of costs and the frequency of coping strategies. Multivariate Poisson regression models were used to assess relationships between socioeconomic characteristics and utilization of financial coping mechanisms. Most participants were young or women, demonstrating a wide variation in socioeconomic status. Outpatient and inpatient costs were primarily driven by transportation, medications, and laboratory tests, with overall RHD direct and indirect costs of $78 per person-year. Between 20 and 35 percent of households experienced catastrophic healthcare expenditure, with participants in the Northern and Western Regions 5-10 times more likely to experience such hardship and utilize financial coping mechanisms than counterparts in the Central Region, a wealthier area. Increases in total RHD costs were positively correlated with increasing use of coping behaviors. Ugandan households affected by RHD, particularly in lower-income areas, incur out-of-pocket costs that are very high relative to income, exacerbating the poverty trap. Universal health coverage policy reforms in Uganda should include mechanisms to reduce or eliminate out-of-pocket expenditures for RHD and other chronic diseases.
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http://dx.doi.org/10.3389/fcvm.2021.636280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363312PMC
July 2021

Health system costs of rheumatic heart disease care in South Africa.

BMC Public Health 2021 07 3;21(1):1303. Epub 2021 Jul 3.

Health Economics Unit, Faculty of Health Sciences, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.

Background: Rheumatic Heart Disease (RHD) is a disease of poverty that is neglected in developing countries, including South Africa. Lack of adequate evidence regarding the cost of RHD care has hindered national and international actions to prevent RHD related deaths. The objective of this study was to estimate the cost of RHD-related health services in a tertiary hospital in the Western Cape, South Africa.

Methods: The primary data on service utilisation were collected from a randomly selected sample of 100 patient medical records from the Global Rheumatic Heart Disease Registry (the REMEDY study) - a registry of individuals living with RHD. Patient-level clinical data, including, prices and quantities of medications and laboratory tests, were collected from the main tertiary hospital providing RHD care. All annual costs from a health system perspective were estimated in 2017 (base year) in South African Rand (ZAR) using a combination of ingredients and step-down costing approaches and later converted to United States dollars (USD). Step-down costing was used to estimate provider time costs and all other facility costs such as overheads. A 3% discount rate was also employed in order to allow depreciation and opportunity cost. We aggregated data to estimate the total annual costs and the average annual per-patient cost of RHD and conducted a one-way sensitivity analysis.

Results: The estimated total cost of RHD care at the tertiary hospital was USD 2 million (in 2017 USD) for the year 2017, with surgery costs accounting for 65%. Per-patient, average annual costs were USD 3900. For the subset of costs estimated using the ingredients approach, outpatient medications, and consumables related to cardiac catheterisation and heart valve surgery were the main cost drivers.

Conclusions: RHD-related healthcare consumes significant tertiary hospital resources in South Africa, with annual per-patient costs higher than many other non-communicable and infectious diseases. This analysis supports the scaling up of primary and secondary prevention programmes at primary health centers in order to reduce future tertiary care costs. The study could also inform resource allocation efforts and provide cost estimates for future studies of intervention cost-effectiveness.
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http://dx.doi.org/10.1186/s12889-021-11314-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254987PMC
July 2021

Shifting landscapes of human MTHFR missense-variant effects.

Am J Hum Genet 2021 07;108(7):1283-1300

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada. Electronic address:

Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322931PMC
July 2021

Achieving global mortality reduction targets and universal health coverage: The impact of COVID-19.

PLoS Med 2021 06 24;18(6):e1003675. Epub 2021 Jun 24.

Center for Policy Impact in Global Health, Duke Global Health Institute, Duke University, Durham, North Carolina, United States of America.

Wenhui Mao and coauthors discuss possible implications of the COVID-19 pandemic for health aspirations in low- and middle-income countries.
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http://dx.doi.org/10.1371/journal.pmed.1003675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270396PMC
June 2021

Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.

Nat Ecol Evol 2021 07 20;5(7):1024-1032. Epub 2021 May 20.

Translational Oncogenomics Laboratory, The Institute of Cancer Research, London, UK.

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRCs), but acquired resistance invariably evolves. It is unknown which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis (a transient cetuximab-induced increase in mutation generation) contributes in patients. Here, we investigate these questions in exome sequencing data from 42 baseline and progression biopsies from cetuximab-treated CRCs. Mutation loads did not increase from baseline to progression, and evidence for a contribution of adaptive mutagenesis was limited. However, the chemotherapy-induced mutational signature SBS17b was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are enriched at acquired resistance. Detectable SBS17b activity before treatment predicted shorter progression-free survival and the evolution of these specific mutations during subsequent cetuximab treatment. This result suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor.
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http://dx.doi.org/10.1038/s41559-021-01470-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611134PMC
July 2021

A global compact to counter vaccine nationalism.

Lancet 2021 05 14;397(10289):2046-2047. Epub 2021 May 14.

Nuffield Department of Medicine, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1016/S0140-6736(21)01105-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121530PMC
May 2021

An investment case for the prevention and management of rheumatic heart disease in the African Union 2021-30: a modelling study.

Lancet Glob Health 2021 07 10;9(7):e957-e966. Epub 2021 May 10.

Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA; Program in Global Noncommunicable Disease and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA; Partners In Health, Boston, MA, USA. Electronic address:

Background: Despite declines in deaths from rheumatic heart disease (RHD) in Africa over the past 30 years, it remains a major cause of cardiovascular morbidity and mortality on the continent. We present an investment case for interventions to prevent and manage RHD in the African Union (AU).

Methods: We created a cohort state-transition model to estimate key outcomes in the disease process, including cases of pharyngitis from group A streptococcus, episodes of acute rheumatic fever (ARF), cases of RHD, heart failure, and deaths. With this model, we estimated the impact of scaling up interventions using estimates of effect sizes from published studies. We estimated the cost to scale up coverage of interventions and summarised the benefits by monetising health gains estimated in the model using a full income approach. Costs and benefits were compared using the benefit-cost ratio and the net benefits with discounted costs and benefits.

Findings: Operationally achievable levels of scale-up of interventions along the disease spectrum, including primary prevention, secondary prevention, platforms for management of heart failure, and heart valve surgery could avert 74 000 (UI 50 000-104 000) deaths from RHD and ARF from 2021 to 2030 in the AU, reaching a 30·7% (21·6-39·0) reduction in the age-standardised death rate from RHD in 2030, compared with no increase in coverage of interventions. The estimated benefit-cost ratio for plausible scale-up of secondary prevention and secondary and tertiary care interventions was 4·7 (2·9-6·3) with a net benefit of $2·8 billion (1·6-3·9; 2019 US$) through 2030. The estimated benefit-cost ratio for primary prevention scale-up was low to 2030 (0·2, <0·1-0·4), increasing with delayed benefits accrued to 2090. The benefit-cost dynamics of primary prevention were sensitive to the costs of different delivery approaches, uncertain epidemiological parameters regarding group A streptococcal pharyngitis and ARF, assumptions about long-term demographic and economic trends, and discounting.

Interpretation: Increased coverage of interventions to control and manage RHD could accelerate progress towards eradication in AU member states. Gaps in local epidemiological data and particular components of the disease process create uncertainty around the level of benefits. In the short term, costs of secondary prevention and secondary and tertiary care for RHD are lower than for primary prevention, and benefits accrue earlier.

Funding: World Heart Federation, Leona M and Harry B Helmsley Charitable Trust, and American Heart Association.
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http://dx.doi.org/10.1016/S2214-109X(21)00199-6DOI Listing
July 2021

Recombinant Herpesvirus Vectors: Durable Immune Responses and Durable Protection against Simian Immunodeficiency Virus SIVmac239 Acquisition.

J Virol 2021 06 24;95(14):e0033021. Epub 2021 Jun 24.

Department of Immunology and Microbiology, Scripps Research, Jupiter, Florida, USA.

A prophylactic vaccine that confers durable protection against human immunodeficiency virus (HIV) would provide a valuable tool to prevent new HIV/AIDS cases. As herpesviruses establish lifelong infections that remain largely subclinical, the use of persistent herpesvirus vectors to deliver HIV antigens may facilitate the induction of long-term anti-HIV immunity. We previously developed recombinant (r) forms of the gamma-herpesvirus rhesus monkey rhadinovirus (rRRV) expressing a replication-incompetent, near-full-length simian immunodeficiency virus (SIVnfl) genome. We recently showed that 8/16 rhesus macaques (RMs) vaccinated with a rDNA/rRRV-SIVnfl regimen were significantly protected against intrarectal (i.r.) challenge with SIVmac239. Here we investigated the longevity of this vaccine-mediated protection. Despite receiving no additional booster immunizations, the protected rDNA/rRRV-SIVnfl vaccinees maintained detectable cellular and humoral anti-SIV immune responses for more than 1.5 years after the rRRV boost. To assess if these responses were still protective, the rDNA/rRRV-SIVnfl vaccinees were subjected to a second round of marginal-dose i.r. SIVmac239 challenges, with eight SIV-naive RMs serving as concurrent controls. After three SIV exposures, 8/8 control animals became infected, compared to 3/8 vaccinees. This difference in SIV acquisition was statistically significant (0.0035). The three vaccinated monkeys that became infected exhibited significantly lower viral loads than those in unvaccinated controls. Collectively, these data illustrate the ability of rDNA/rRRV-SIVnfl vaccination to provide long-term immunity against stringent mucosal challenges with SIVmac239. Future work is needed to identify the critical components of this vaccine-mediated protection and the extent to which it can tolerate sequence mismatches in the challenge virus. We report on the long-term follow-up of a group of rhesus macaques (RMs) that received an AIDS vaccine regimen and were subsequently protected against rectal acquisition of simian immunodeficiency virus (SIV) infection. The vaccination regimen employed included a live recombinant herpesvirus vector that establishes persistent infection in RMs. Consistent with the recurrent SIV antigen expression afforded by this herpesvirus vector, vaccinees maintained detectable SIV-specific immune responses for more than 1.5 years after the last vaccination. Importantly, these vaccinated RMs were significantly protected against a second round of rectal SIV exposures performed 1 year after the first SIV challenge phase. These results are relevant for HIV vaccine development because they show the potential of herpesvirus-based vectors to maintain functional antiretroviral immunity without the need for repeated boosting.
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http://dx.doi.org/10.1128/JVI.00330-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223948PMC
June 2021

Non-neutralizing Antibodies May Contribute to Suppression of SIVmac239 Viremia in Indian Rhesus Macaques.

Front Immunol 2021 16;12:657424. Epub 2021 Mar 16.

Department of Pathology, George Washington University, Washington, DC, United States.

The antiviral properties of broadly neutralizing antibodies against HIV are well-documented but no vaccine is currently able to elicit protective titers of these responses in primates. While current vaccine modalities can readily induce non-neutralizing antibodies against simian immunodeficiency virus (SIV) and HIV, the ability of these responses to restrict lentivirus transmission and replication remains controversial. Here, we investigated the antiviral properties of non-neutralizing antibodies in a group of Indian rhesus macaques (RMs) that were vaccinated with , , and , as part of a previous study conducted by our group. These animals manifested rapid and durable control of viral replication to below detection limits shortly after SIVmac239 infection. Although these animals had no serological neutralizing activity against SIVmac239 prior to infection, their pre-challenge titers of Env-binding antibodies correlated with control of viral replication. To assess the contribution of anti-Env humoral immune responses to virologic control in two of these animals, we transiently depleted their circulating antibodies via extracorporeal plasma immunoadsorption and inhibition of IgG recycling through antibody-mediated blockade of the neonatal Fc receptor. These procedures reduced Ig serum concentrations by up to 80% and temporarily induced SIVmac239 replication in these animals. Next, we transferred purified total Ig from the rapid controllers into six vaccinated RMs one day before intrarectal challenge with SIVmac239. Although recipients of the hyperimmune anti-SIV Ig fraction were not protected from infection, their peak and chronic phase viral loads were significantly lower than those in concurrent unvaccinated control animals. Together, our results suggest that non-neutralizing Abs may play a role in the suppression of SIVmac239 viremia.
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http://dx.doi.org/10.3389/fimmu.2021.657424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008062PMC
September 2021

Examining the Ugandan health system's readiness to deliver rheumatic heart disease-related services.

PLoS Negl Trop Dis 2021 02 16;15(2):e0009164. Epub 2021 Feb 16.

Department of Global Health, University of Washington, Seattle, Washington, United States of America.

Background: In 2018, the World Health Assembly mandated Member States to take action on rheumatic heart disease (RHD), which persists in countries with weak health systems. We conducted an assessment of the current state of RHD-related healthcare in Uganda.

Methodology/principal Findings: This was a mixed-methods, deductive simultaneous design study conducted in four districts of Uganda. Using census sampling, we surveyed health facilities in each district using an RHD survey instrument that was modeled after the WHO SARA tool. We interviewed health workers with experience managing RHD, purposively sampling to ensure a range of qualification and geographic variation. Our final sample included 402 facilities and 36 health workers. We found major gaps in knowledge of clinical guidelines and availability of diagnostic tests. Antibiotics used in RHD prevention were widely available, but cardiovascular medications were scarce. Higher levels of service readiness were found among facilities in the western region (Mbarara district) and private facilities. Level III health centers were the most prepared for delivering secondary prevention. Health worker interviews revealed that limited awareness of RHD at the district level, lack of diagnostic tests and case management registries, and absence of clearly articulated RHD policies and budget prioritization were the main barriers to providing RHD-related healthcare.

Conclusions/significance: Uganda's readiness to implement the World Health Assembly RHD Resolution is low. The forthcoming national RHD strategy must focus on decentralizing RHD diagnosis and prevention to the district level, emphasizing specialized training of the primary healthcare workforce and strengthening supply chains of diagnostics and essential medicines.
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http://dx.doi.org/10.1371/journal.pntd.0009164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909659PMC
February 2021

Methionine dependence in tumor cells: The potential role of cobalamin and MMACHC.

Mol Genet Metab 2021 03 13;132(3):155-161. Epub 2021 Jan 13.

Department of Human Genetics, McGill University and Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; Division of Medical Biochemistry, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.

Methionine dependence of tumor cell lines, the inability to grow in tissue culture media lacking methionine but supplemented with homocysteine, has been known for decades, but an understanding of the mechanism underlying this phenomenon remains incomplete. Methionine dependence of certain glioma and melanoma cell lines has been linked to alterations in the metabolism of cobalamin (vitamin B). In the MeWo LC1 melanoma line, complementation analysis demonstrated that the genetic defect affected the same locus mutated in the cblC inborn error of cobalamin metabolism; hypermethylation of the MMACHC promoter was subsequently demonstrated. Analysis of data in the Cancer Cell Line Encyclopedia showed increased MMACHC methylation levels in melanoma lines compared to other types of cancer. RNA sequencing data from isolated tumors, tabulated at the cBioPortal for Cancer Genomics website, showed decreased MMACHC expression compared to other tumors; and methylation data tabulated at the TGGA Wanderer website demonstrated increased MMACHC methylation. These data suggest that disruptions in cobalamin metabolism might play a more general role in methionine dependence, and potentially in the pathogenesis of melanoma cell lines and primary tumors.
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http://dx.doi.org/10.1016/j.ymgme.2021.01.006DOI Listing
March 2021

The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing.

J Clin Med 2021 Jan 9;10(2). Epub 2021 Jan 9.

The Royal Marsden Hospital NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK.

1.

Background: The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal cancer. Given the widespread use of formalin-fixed paraffin-embedded (FFPE) samples in the study of this disease, it would be beneficial, especially for the purposes of biomarker evaluation, to assess the concordance between comprehensive exome-wide sequencing data from archival FFPE samples originating from a prospective clinical study and those derived from fresh-frozen material. 2.

Methods: We analysed whole-exome sequencing data to define the mutational concordance of 16 matched fresh-frozen and FFPE gastro-oesophageal tumours ( = 32) from a prospective clinical study. We assessed DNA integrity prior to sequencing and then identified coding mutations in genes that have previously been implicated in other cancers. In addition, we calculated the mutant-allele heterogeneity (MATH) for these samples. 3.

Results: Although there was increased degradation of DNA in FFPE samples compared with frozen samples, sequencing data from only two FFPE samples failed to reach an adequate mapping quality threshold. Using a filtering threshold of mutant read counts of at least ten and a minimum of 5% variant allele frequency (VAF) we found that there was a high median mutational concordance of 97% (range 80.1-98.68%) between fresh-frozen and FFPE gastro-oesophageal tumour-derived exomes. However, the majority of FFPE tumours had higher mutant-allele heterogeneity (MATH) scores when compared with corresponding frozen tumours ( < 0.001), suggesting that FFPE-based exome sequencing is likely to over-represent tumour heterogeneity in FFPE samples compared to fresh-frozen samples. Furthermore, we identified coding mutations in 120 cancer-related genes, including those associated with chromatin remodelling and Wnt/β-catenin and Receptor Tyrosine Kinase signalling. 4.

Conclusions: These data suggest that comprehensive genomic data can be generated from exome sequencing of selected DNA samples extracted from archival FFPE gastro-oesophageal tumour tissues within the context of prospective clinical trials.
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http://dx.doi.org/10.3390/jcm10020215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826535PMC
January 2021

Proactive prevention: Act now to disrupt the impending non-communicable disease crisis in low-burden populations.

PLoS One 2020 1;15(12):e0243004. Epub 2020 Dec 1.

Department of Population Health, New York University Grossman School of Medicine, New York, NY, United States of America.

Non-communicable disease (NCD) prevention efforts have traditionally targeted high-risk and high-burden populations. We propose an alteration in prevention efforts to also include emphasis and focus on low-risk populations, predominantly younger individuals and low-prevalence populations. We refer to this approach as "proactive prevention." This emphasis is based on the priority to put in place policies, programs, and infrastructure that can disrupt the epidemiological transition to develop NCDs among these groups, thereby averting future NCD crises. Proactive prevention strategies can be classified, and their implementation prioritized, based on a 2-dimensional assessment: impact and feasibility. Thus, potential interventions can be categorized into a 2-by-2 matrix: high impact/high feasibility, high impact/low feasibility, low impact/high feasibility, and low impact/low feasibility. We propose that high impact/high feasibility interventions are ready to be implemented (act), while high impact/low feasibility interventions require efforts to foster buy-in first. Low impact/high feasibility interventions need to be changed to improve their impact while low impact/low feasibility might be best re-designed in the context of limited resources. Using this framework, policy makers, public health experts, and other stakeholders can more effectively prioritize and leverage limited resources in an effort to slow or prevent the evolving global NCD crisis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243004PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707577PMC
January 2021

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Gut 2021 Sep 16;70(9):1632-1641. Epub 2020 Nov 16.

Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK.

Objective: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).

Design: CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.

Results: amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from -amplified aGEA.

Conclusion: CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
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http://dx.doi.org/10.1136/gutjnl-2020-322658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355876PMC
September 2021

Integrating the Prevention and Control of Rheumatic Heart Disease into Country Health Systems: A Systematic Review and Meta-Analysis.

Glob Heart 2020 09 14;15(1):62. Epub 2020 Sep 14.

Department of Medicine, University of Cape Town, ZA.

Background: National and international political commitments have been made recently on rheumatic heart disease (RHD), a preventable heart condition that is endemic in low-resource countries. To inform best practice and identify evidence gaps, we assessed the effectiveness of RHD prevention and control programmes and the extent and nature of their integration into local health systems.

Methods: We conducted a systematic review and meta-analysis using a previously published protocol that included electronic and manual searches for studies published between January 1990 and July 2019 reporting on prevention and control programmes for populations at risk for streptococcal pharyngitis, rheumatic fever, and/or RHD. We analysed programme integration according to a previously published framework and programme effectiveness using a results-chain framework. We meta-analysed secondary prophylaxis adherence using random-effects models. Study quality was assessed using peer-reviewed checklists (CASP and PRISM). PROSPERO registration: CRD42017076307.

Findings: Five observational studies met with the inclusion criteria. Studies were similar in extent and nature of integration into health systems; no programme was completely integrated or non-integrated. A single study reported on programme impact. Secondary prophylaxis adherence improved among partially integrated RHD programmes (RR, 1.18 [95% CI, 1.03 to 1.36], 3 studies, n = 618). Risk of bias was low in two studies, and indeterminable in the remaining three studies.

Interpretation: There is evidence that partially integrated RHD programmes are beneficial for a range of intermediate health outcomes. This review provides a starting point for the design and implementation of future RHD programmes by outlining current best practice for integration and identifying key gaps in knowledge.

Funding: National Research Foundation of South Africa.
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http://dx.doi.org/10.5334/gh.874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500229PMC
September 2020

Cardiovascular health and COVID-19: time to reinvent our systems and rethink our research priorities.

Authors:
David A Watkins

Heart 2020 12 3;106(24):1870-1872. Epub 2020 Nov 3.

Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA

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http://dx.doi.org/10.1136/heartjnl-2020-318323DOI Listing
December 2020

The American Heart Association's Call to Action for Reducing the Global Burden of Rheumatic Heart Disease: A Policy Statement From the American Heart Association.

Circulation 2020 11 19;142(20):e358-e368. Epub 2020 Oct 19.

Rheumatic heart disease (RHD) affects ≈40 million people and claims nearly 300 000 lives each year. The historic passing of a World Health Assembly resolution on RHD in 2018 now mandates a coordinated global response. The American Heart Association is committed to serving as a global champion and leader in RHD care and prevention. Here, we pledge support in 5 key areas: (1) professional healthcare worker education and training, (2) technical support for the implementation of evidence-based strategies for rheumatic fever/RHD prevention, (3) access to essential medications and technologies, (4) research, and (5) advocacy to increase global awareness, resources, and capacity for RHD control. In bolstering the efforts of the American Heart Association to combat RHD, we hope to inspire others to collaborate, communicate, and contribute.
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http://dx.doi.org/10.1161/CIR.0000000000000922DOI Listing
November 2020

Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome.

J Virol 2020 11 23;94(24). Epub 2020 Nov 23.

Department of Pathology, University of Miami, Miami, Florida, USA.

Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8 T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8 T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.
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http://dx.doi.org/10.1128/JVI.00979-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925177PMC
November 2020

Protecting essential health services in low-income and middle-income countries and humanitarian settings while responding to the COVID-19 pandemic.

BMJ Glob Health 2020 10;5(10)

Department of Global Public Health and Primary care, University of Bergen Faculty of Medicine and Dentistry, Bergen, Norway.

In health outcomes terms, the poorest countries stand to lose the most from these disruptions. In this paper, we make the case for a rational approach to public sector health spending and decision making during and in the early recovery phase of the COVID-19 pandemic. Based on ethics and equity principles, it is crucial to ensure that patients not infected by COVID-19 continue to get access to healthcare and that the services they need continue to be resourced. We present a list of 120 essential non-COVID-19 health interventions that were adapted from the model health benefit packages developed by the Disease Control Priorities project.
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http://dx.doi.org/10.1136/bmjgh-2020-003675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542611PMC
October 2020

Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data.

Front Oncol 2020 4;10:1634. Epub 2020 Sep 4.

Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.

Background: Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses.

Patients And Methods: All consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In the next step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and PROSPECT-R) were assessed for the DNA yield from biopsies assessed for complex genomic analysis.

Results: A total of 522 plugged core biopsies were performed in 457 patients [men, 52%; median age, 63 years (range, 17-93)]. Histological diagnosis was achieved in 501 of 522 (96%) performed biopsies. Age, gender, modality, metastatic site, and seniority of the interventionist were not found to be significant factors associated with odds of failure on a logistic regression. Seventeen (3.3%) were admitted due to biopsy-related complications; nine, three, two, one, one, and one were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, hematuria, and deranged liver functions, respectively; two patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular hematoma requiring conservative treatment. One patient (0.2%) developed grade III hemorrhage following biopsy of a gastric gastrointestinal stromal tumor (GIST). Overall molecular analysis was successful in 89% (197/222 biopsies). Prospective validation in 62 biopsies gave success rates of 92.06 and 79.03% for DNA extraction of >1 μm and tmour content of >20%, respectively.

Conclusion: The probability of diagnostic success for complex molecular analysis is increased with plugged large coaxial needle biopsy technique, which also minimizes complications and reduces hospital stay. High-yield DNA acquisition allows genomic molecular characterization for personalized medicine.
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http://dx.doi.org/10.3389/fonc.2020.01634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500492PMC
September 2020

An Automated Fluorescence-Based Method to Isolate Bone Marrow-Derived Plasma Cells from Rhesus Macaques Using SIVmac239 SOSIP.664.

Mol Ther Methods Clin Dev 2020 Sep 5;18:781-790. Epub 2020 Aug 5.

Department of Pathology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.

Simian immunodeficiency virus (SIV) infection of Indian rhesus macaques (RMs) is one of the best-characterized animal models for human immunodeficiency virus (HIV) infection. Monoclonal antibodies (mAbs) have shown promise for prevention and treatment of HIV infection. However, it has been difficult to isolate mAbs that potently neutralize the highly pathogenic SIVmac239 strain. This has been largely due to the low frequency of circulating B cells encoding neutralizing Abs. Here we describe a novel technique to isolate mAbs directly from bone marrow-derived, Ab-secreting plasma cells. We employed an automated micromanipulator to isolate single SIVmac239 SOSIP.664-specific plasma cells from the bone marrow of a SIVmac239-infected RM with serum neutralization titers against SIVmac239. After picking plasma cells, we obtained 44 paired Ab sequences. Ten of these mAbs were SIV specific. Although none of these mAbs neutralized SIVmac239, three mAbs completely neutralized the related SIVmac316 strain. The majority of these mAbs bound to primary rhesus CD4+ T cells infected with SIVmac239 and induced Ab-dependent cellular cytotoxicity. This method is a first step in successful isolation of antigen-specific bone marrow-derived plasma cells from RMs.
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http://dx.doi.org/10.1016/j.omtm.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476808PMC
September 2020

Rhesus Cytomegalovirus-Specific CD8 Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection.

Front Immunol 2020 12;11:1960. Epub 2020 Aug 12.

Department of Pathology, George Washington University School of Medicine, Washington, DC, United States.

CD8 cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, -restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of and RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28 CCR7) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy.
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http://dx.doi.org/10.3389/fimmu.2020.01960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457070PMC
April 2021

Economic consequences of rheumatic heart disease: A scoping review.

Int J Cardiol 2021 01 10;323:235-241. Epub 2020 Sep 10.

Department of Medicine, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA. Electronic address:

Background: Rheumatic heart disease (RHD) remains endemic in less-resourced regions and countries and results in high medical and non-medical costs to households, health systems, and society. This scoping review maps out the available evidence on the economic impact of RHD and its antecedents and suggests future research priorities.

Method: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. We identified articles through systematic electronic database search supplemented by expert knowledge of unpublished literature. Studies were included if they collected empirical RHD-related costing data as a primary or secondary objective and if the data were collected from 2000 onward. Main quantitative findings by intervention, costing perspective, and location were charted, and a standardized quality assessment tool was used to appraise included studies.

Results: The index search identified 2519 electronic records and two grey-literature graduate theses. Six full texts were included in the review. Primary prevention costs were modest, while secondary and especially tertiary prevention were more costly. Most estimates were of health sector costs and for tertiary interventions. Only two studies described RHD-related costs in non-high-income countries. Most studies were of adequate methodological quality.

Conclusion: Research into the costs of RHD has mostly been done in wealthy countries. Costs from the household perspective, which are particularly important in countries with limited public healthcare finance, are lacking. To inform advocacy and guide implementation of the 2018 World Health Assembly resolution on RHD, high-quality, local cost estimates will be needed from a range of representative, RHD-endemic countries.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.020DOI Listing
January 2021

Active Case Finding for Rheumatic Fever in an Endemic Country.

J Am Heart Assoc 2020 08 29;9(15):e016053. Epub 2020 Jul 29.

Cincinnati Children's Hospital Medical Center Cincinnati OH.

Background Despite the high burden of rheumatic heart disease in sub-Saharan Africa, diagnosis with acute rheumatic fever (ARF) is exceedingly rare. Here, we report the results of the first prospective epidemiologic survey to diagnose and characterize ARF at the community level in Africa. Methods and Results A cross-sectional study was conducted in Lira, Uganda, to inform the design of a broader epidemiologic survey. Key messages were distributed in the community, and children aged 3 to 17 years were included if they had either (1) fever and joint pain, (2) suspicion of carditis, or (3) suspicion of chorea, with ARF diagnoses made by the 2015 Jones Criteria. Over 6 months, 201 children met criteria for participation, with a median age of 11 years (interquartile range, 6.5) and 103 (51%) female. At final diagnosis, 51 children (25%) had definite ARF, 11 (6%) had possible ARF, 2 (1%) had rheumatic heart disease without evidence of ARF, 78 (39%) had a known alternative diagnosis (10 influenza, 62 malaria, 2 sickle cell crises, 2 typhoid fever, 2 congenital heart disease), and 59 (30%) had an unknown alternative diagnosis. Conclusions ARF persists within rheumatic heart disease-endemic communities in Africa, despite the low rates reported in the literature. Early data collection has enabled refinement of our study design to best capture the incidence of ARF and to answer important questions on community sensitization, healthcare worker and teacher education, and simplified diagnostics for low-resource areas. This study also generated data to support further exploration of the relationship between malaria and ARF diagnosis in rheumatic heart disease/malaria-endemic countries.
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http://dx.doi.org/10.1161/JAHA.120.016053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792248PMC
August 2020

Immunophenotyping of Rhesus CMV-Specific CD8 T-Cell Populations.

Cytometry A 2021 03 4;99(3):278-288. Epub 2020 Aug 4.

Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.

A vaccine to ameliorate cytomegalovirus (CMV)-related pathogenicity in transplantation patients is considered a top priority. A therapeutic vaccine must include components that elicit both neutralizing antibodies, and highly effective CD8 T-cell responses. The most important translational model of vaccine development is the captive-bred rhesus macaque (Macaca mulatta) of Indian origin. There is a dearth of information on rhesus cytomegalovirus (rhCMV)-specific CD8 T cells due to the absence of well-defined CD8 T-cell epitopes presented by classical MHC-I molecules. In the current study, we defined two CD8 T-cell epitopes restricted by high-frequency Mamu alleles: the Mamu-A1*002:01 restricted VY9 (VTTLGMALY aa291-299) epitope of protein IE-1, and the Mamu-A1*008:01 restricted NP8 (NPTDRPIP aa96-103) epitope of protein phosphoprotein 65-2. We developed tetramers and determined the level, phenotype, and functional capability of the two epitope-specific T-cell populations in circulation and various tissues. We demonstrated the value of these tetramers for in situ tetramer staining. Here, we first provided critical reagents and established a flow cytometric staining strategy to study rhCMV-specific T-cell responses in up to 40% of captive-bred rhesus macaques. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.
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http://dx.doi.org/10.1002/cyto.a.24197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855655PMC
March 2021

The FOCCUS study: a prospective evaluation of the frequency, severity and treatable causes of gastrointestinal symptoms during and after chemotherapy.

Support Care Cancer 2021 Mar 16;29(3):1443-1453. Epub 2020 Jul 16.

Royal Marsden Clinical Trials Unit Royal Marsden NHS Foundation Trust, Sutton, UK.

Background: The underlying mechanisms of chemotherapy-induced gastrointestinal (GI) symptoms are poorly researched. This study characterised the nature, frequency, severity and treatable causes for GI symptoms prospectively in patients undergoing chemotherapy for GI malignancy.

Methods: Patients receiving chemotherapy for a GI malignancy were assessed pre-chemotherapy, then monthly for 1 year using the Gastrointestinal Symptom Rating Scale, a validated patient-reported outcome measure. Patients with new, troublesome GI symptoms were offered investigations to diagnose the cause(s). Their oncologist was alerted when investigations were abnormal.

Results: A total of 241 patients, 60% male, median age 63 years (range 30-88), were enrolled; 122 patients were withdrawn, 93%, because of progressive disease or death. During the study, > 20% patients reported chronic faecal incontinence and > 10% reported moderate or severe problems with taste, dysphagia, belching, heartburn, early satiety, appetite, nausea, abdominal cramps, peri-rectal pain, rectal flatulence, borborygmi, urgency of defecation or tenesmus. Thirty percent reported continuing passage of hard stools and 30% on-going diarrhoea. Moderate or severe fatigue affected 40% participants at its peak and persisted in 15% at 1 year. Toxicity dictated change in chemotherapy for 13-29% patients/month. Common Terminology Criteria for Adverse Events underestimated gastrointestinal morbidity. Pre-chemotherapy screening identified previously undiagnosed pathology: exocrine pancreatic insufficiency (9%), vitamin B deficiency (12%) and thyroid dysfunction (20%). Patients often refused investigations to diagnose their chemotherapy-induced symptoms; however, for every three investigations performed, one treatable cause was diagnosed: particularly small intestinal bacterial overgrowth (54%), bile acid malabsorption (43%), previously not described after chemotherapy, and unsuspected urinary tract infection (17%).

Conclusions: Patients undergoing chemotherapy for GI malignancy commonly have difficult GI symptoms requiring active management which does not occur routinely. The underlying causes for these symptoms are often treatable or curable. Randomised trials are urgently needed to show whether timely investigation and treatment of symptoms improve quality of life and survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT02121626.
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http://dx.doi.org/10.1007/s00520-020-05610-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843552PMC
March 2021
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