A scoping review exploring cure definitions and language for inherited hemoglobinopathies.

Purpose: Sickle cell disease and beta thalassemia are some of the first targets for potentially curative cell-based therapies. Currently, bone marrow transplants, stem cell transplants, and gene therapy are being researched and utilized for people living with these hemoglobinopathies. Although these therapies are often described as curative, there is not a clear definition of what cure means for these hemoglobinopathies. Methods: Five databases were searched for this scoping review. Two reviewers screened each article at the title/abstract and full text levels using Covidence. Articles were included if they were (1) about bone marrow transplants, stem cell transplants, or gene therapy; (2) conditions of focus were sickle cell disease or beta thalassemia; and (3) reported original data on clinical outcomes, psychosocial outcomes, or key stakeholder perspectives and opinions. Data were collected by 2 reviewers also using Covidence, and analyses were conducted in Excel and R. Results: We found that, although cure is widely and indiscriminately used, it is not often defined, and when cure is defined, there is no clear convergence or consensus on the definition. Furthermore, cure is often qualified and undefined euphemisms for cure are often used. We also report the major ways in which the success and complications of these treatment modalities are described. Conclusion: We frame the significance of our findings by discussing their scientific, ethical, and social implications and focus on the need for precise and clear terminology that centers lived experience and acknowledges the interplay between scientific and lay expertise and perceptions.

Views of adults living with sickle cell disease on the theoretical return of secondary genomic findings.

PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.

Examining resilience of individuals living with sickle cell disease in the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has impacted the physical and mental health of people worldwide including those living with genetic conditions. Sickle cell disease (SCD) is a hematologic chronic disease that causes multisystem damage and morbidity. Individuals living with SCD have had to continue managing their care for their chronic disease while following public health measures to protect against infection with COVID-19. Promoting resilience has been posited as being psychologically protective for those living with SCD. This study examines changes in resilience over time in a SCD population in the context of the COVID-19 pandemic. METHODS: Ninety-seven adults living with SCD completed two parent studies: (1) The INSIGHTS Study, a cross-sectional natural history study conducted from 2014-2019 and (2) The Living with SCD in COVID-19 Pandemic Study, an online survey conducted in 2020. Changes over time in resilience, perceived stress, emotional distress, and physical and mental health were analyzed in multivariable repeated measures model. RESULTS: Results showed that the psychological resilience of our study cohort had significantly decreased (0.19, p=0.01) over time. Resilience during the pandemic was associated with better mental health and physical health and lower perceived stress and emotional distress. In addition, results showed that marital status, education level, and employment were significantly associated with the psychological resilience of study participants. CONCLUSION: Resilience declined during the COVID-19 pandemic but was still associated with better physical and mental health outcomes. Future studies should investigate the relationship between resilience and sociodemographic factors.

An approach for improving the quality of country-level TB modelling.

Mathematical modelling is increasingly used to inform budgeting and strategic decision-making by national TB programmes. Despite the importance of these decisions, there is currently no mechanism to review and confirm the appropriateness of modelling analyses. We have developed a benchmarking, reporting, and review (BRR) approach and accompanying tools to allow constructive review of country-level TB modelling applications. This approach has been piloted in five modelling applications and the results of this study have been used to revise and finalise the approach. The BRR approach consists of 1) quantitative benchmarks against which model assumptions and results can be compared, 2) standardised reporting templates and review criteria, and 3) a multi-stage review process providing feedback to modellers during the application, as well as a summary evaluation after completion. During the pilot, use of the tools prompted important changes in the approaches taken to modelling. The pilot also identified issues beyond the scope of a review mechanism, such as a lack of empirical evidence and capacity constraints. This approach provides independent evaluation of the appropriateness of modelling decisions during the course of an application, allowing meaningful changes to be made before results are used to inform decision-making. The use of these tools can improve the quality and transparency of country-level TB modelling applications.

Cultivating diversity as an ethos with an anti-racism approach in the scientific enterprise.

The diversity of the U.S. population is currently not reflected in the genomic workforce and across the greater scientific enterprise. Although diversity and inclusion efforts have focused on increasing the number of individuals from underrepresented groups across scientific fields, structural racism remains. Thus, the cultivation and adoption of diversity as an ethos requires shifting our focus to being intentional about an institution's character, culture, and climate. One way for this ethos to be sustained is by facilitating an intentional anti-racism approach within the field. Adopting a new perspective on diversity utilizing an anti-racism approach will support genomics researchers as we build supportive, collaborative research environments. We seek to expand critical thought in the framing of diversity in the research enterprise and propose an anti-racism approach that informs deliberate actions required to address structural racism.

Improving the quality of modelling evidence used for tuberculosis policy evaluation.

Mathematical modelling is commonly used to evaluate policy options for tuberculosis (TB) control in high-burden countries. Although major policy and funding decisions are made based on these analyses, there is concern about the variability of results produced using modelled policy analyses. We discuss new guidance for country-level TB policy modelling. The guidance was developed by the TB Modelling and Analysis Consortium in collaboration with the World Health Organization Global TB Programme, with input from a range of TB stakeholders (funders, modelling groups, country TB programme staff and subject matter experts). The guidance describes principles for country-level TB modelling, as well as good practices for operationalising the principles. The principles cover technical concerns such as model design, parameterisation and validation, as well as approaches for incorporating modelling into country-led policy making and budgeting. For modellers, this guidance suggests approaches to improve the quality and relevance of modelling undertaken to support country-level planning. For non-modellers, this guidance describes considerations for engaging modelling technical assistance, contributing to a modelling exercise and reviewing the results of modelled analyses. If routinely adopted, this guidance should improve the reliability, transparency and usefulness of modelling for country-level TB policy making. However, this guidance will not address all challenges facing modelling, and ongoing work is needed to improve the empirical evidence base for TB policy evaluation and develop stronger mechanisms for validating models. Increasing country ownership of the modelling process remains a challenge, requiring sustained engagement and capacity building.

Global tuberculosis targets and milestones set for 2016-2035: definition and rationale.

BACKGROUND: Global tuberculosis (TB) targets were set as part of the World Health Organization's End TB Strategy (2016-2035) and the Sustainable Development Goals (2016-2030). OBJECTIVE: To define and explain the rationale for these targets. DESIGN: Scenarios for plausible reductions in TB deaths and cases were developed using empirical evidence from best-performing countries and modelling of the scale-up of under-used interventions and hypothetical TB vaccines. Results were discussed at consultations in 2012 and 2013. A final proposal was presented to the World Health Assembly in 2014 and unanimously endorsed by all Member States. RESULTS: The 2030 targets are a 90% reduction in TB deaths and 80% reduction in TB incidence compared with 2015 levels. The 2035 targets are for reductions of 95% and 90%, respectively. A third target-that no TB-affected households experience catastrophic costs due to the disease by 2020-was also agreed. CONCLUSION: The global TB targets and milestones set for the period 2016-2035 are ambitious. Achieving them requires concerted action on several fronts, but two things are fundamental: 1) progress towards universal health coverage to ensure that everyone with TB can access high-quality treatment; and 2) substantial investment in research and development for new tools to prevent TB disease among the approximately 1.7 billion people infected.

Policies and practices on the programmatic management of latent tuberculous infection: global survey.

SETTING: Global survey among low tuberculosis (TB) burden countries, which are primary target countries for the World Health Organization (WHO) guidelines on the programmatic management of latent tuberculous infection (LTBI). OBJECTIVE: To perform a baseline assessment of policies and practices for the programmatic management of LTBI. DESIGN: Online and paper-based pre-tested questionnaire filled out by national TB programme managers or their equivalents from 108 countries. RESULTS: Of 74 respondent countries, 75.7% (56/74) had a national policy on LTBI. The majority of the countries (67/74, 90.5%) provided LTBI testing and treatment for child contacts of TB cases, while almost two thirds (49/74, 66%) reported provision of LTBI testing and treatment to people living with the human immunodeficiency virus (PLHIV). Six countries (8.1%) did not report providing LTBI management to child contacts and PLHIV. Among countries that reported both the availability of policy and practice of testing and treatment of LTBI for at-risk populations, a system for recording and reporting data was available in 62% (33/53) for child contacts and in 53% (21/40) for PLHIV. CONCLUSION: Countries need to ensure that national LTBI policies and a standardised monitoring and evaluation system are in place to promote the programmatic management of LTBI.

The effect of household poverty on tuberculosis.

pSETTING: Households in Malawi, Mongolia, Myanmar, the Philippines, Rwanda, Tanzania, Viet Nam and Zambia.OBJECTIVE To assess the relationship between household socio-economic level, both relative and absolute, and individual tuberculosis (TB) disease. DESIGN: We analysed national TB prevalence surveys from eight countries individually and in pooled multicountry models. Socio-economic level (SEL) was measured in terms of both relative household position and absolute wealth. The outcome of interest was whether or not an individual had TB disease. Logistic regression models were used to control for putative risk factors for TB disease such as age, sex and previous treatment history. RESULTS: Overall, a strong and consistent association between household SEL and individual TB disease was not found. Significant results were found in four individual country models, with the lowest socio-economic quintile being associated with higher TB risk in Mongolia, Myanmar, Tanzania and Viet Nam. CONCLUSIONS: TB prevalence surveys are designed to assess prevalence of disease and, due to the small numbers of cases usually detected, may not be the most efficient means of investigating TB risk factors. Different designs are needed, including measuring the SEL of individuals in nested case-control studies within TB prevalence surveys or among TB patients seeking treatment in health care facilities.

Sputum smear microscopy result: a predictor for drug-resistant tuberculosis?

Until countries establish capacity for continuous surveillance systems, representative surveys of tuberculosis (TB) patients continue to improve our understanding of the burden of drug-resistant TB and help ensure appropriate allocation of resources. Although the available data are limited, the current recommendation of restricting surveys to sputum smear-positive patients is justified, given the greatly simplified logistics and only limited evidence in specific settings of an association between drug resistance and sputum smear status. Nonetheless, the relationship between drug resistance and sputum smear microscopy results may vary according to the setting and population under study. With the increasing availability and use of molecular diagnostics and the drive for universal drug susceptibility testing under the World Health Organization's End TB Strategy, substantially more data on drug resistance in the whole TB patient population should become available in the near future.

The affordability for patients of a new universal MDR-TB coverage model in China.

BACKGROUND: China has piloted a new model of universal coverage for multidrug-resistant tuberculosis (MDR-TB), designed to rationalize hospital use of drugs and tests and move away from fee-for-service payment towards a standard package with financial protection against catastrophic health costs. OBJECTIVE: To evaluate the affordability to patients of this new model. DESIGN: This was an observational study of 243 MDR-TB cases eligible for enrolment on treatment under the project. We assessed the affordability of the project from the perspective of households, with a focus on catastrophic costs. RESULTS: Of the 243 eligible cases, 172 (71%) were enrolled on treatment; of the 71 cases not enrolled, 26 (37%) cited economic reasons. The 73 surveyed cases paid an average of RMB 5977 (US$920) out-of-pocket in search costs incurred outside the pilot model. Within the pilot, they paid another RMB 2094 (US$322) in medical fees and RMB 5230 (US$805) in direct non-medical costs. Despite 90% reimbursement of medical fees, 78% of households experienced catastrophic costs, including indirect costs. CONCLUSION: The objectives of the pilot model are aligned with health reform in China and universal health coverage globally. Enrollment would almost certainly be higher with 100% reimbursement of medical fees, but patient enablers will be required to truly eliminate catastrophic costs.

Sudden cardiac death in postmyocardial-infarction patients.

Patients who survive a myocardial infarction are at increased risk for sudden death, owing largely to ventricular arrhythmia. In this article, we will review the epidemiology of sudden cardiac death in postmyocardial-infarction patients, arrhythmia mechanisms and substrate leading to cardiac arrest, identifying possible risk factors for sudden cardiac death (SCD) in high risk population and apply risk stratification strategies for prevention of SCD. We will also review relevant major trials and evidence-based therapy currently used, in addition to the indications and role of implantable cardioverter-defibrillators in this population. We will end this review with a summary of the current guidelines recommendations and a look into the future of this domain.

Estimating tuberculosis burden and reporting in resource-limited countries: a capture-recapture study in Iraq.

BACKGROUND: The global target for tuberculosis (TB) control set by the Millennium Development Goals is a decrease in TB incidence by 2015. Direct measurement of country-level TB incidence using population-based methods is impractical, emphasising the need for well-performing surveillance systems and, where these are not available, accurate quantification of incidence and under-reporting of TB. OBJECTIVE: To estimate TB incidence and TB under-reporting in Iraq in 2011. METHODS: Prospective longitudinal surveillance was established among all eligible public and private non-National TB Programme (NTP) providers in a random sample of eight of the 18 Iraqi governorates from May to July 2011. Record linkage with the NTP and three-source capture-recapture analysis of data were then conducted using log-linear modelling. RESULTS: A total of 1985 TB cases were identified after record linkage. The NTP registered 1677 patients (observed completeness 84%). The estimated total number of TB cases was 2460 (95%CI 2381-2553), with identified TB cases representing 81% (95%CI 69-89) after adjusting for sampling design. The estimated ratio of notified to incident cases was 69% (95%CI 58-76). CONCLUSIONS: We estimate 14 500 TB cases in Iraq in 2011, of which 31% (95%CI 24-42) were unreported. TB surveillance needs to be strengthened to reduce under-reporting.

Tabletop scenarios for realism in bioterrorism and threat preparedness.

Five realistic tabletop scenarios were designed to facilitate threat preparedness training of Medical, Public Health, Nursing, Emergency Services, Mental Health, Allied Health, and Pharmacy personnel. Training scenarios were (1) student contaminates lettuce (Act) in a state university with Shigella sonnei (Agent), (2) dismissed athlete contaminates ice (Act) at the basketball tournament with Escherichia coli (Agent), (3) workers fail to report abandoned backpacks (Act) at a state fair that contain smallpox virus (Agent), (4) terrorists expose county residents (Act) to Pneumonic plague bacterium (Agent), and (5) infected birds expose field-trip participants (Act) to Avian influenza virus (Agent). Evaluation of the tabletops yielded positive ratings of educational outcomes in these domains: well-structured, organized, plausible, realistic, engaging, on-target, useful, and multidisciplinary. Attendees with previous blended-learning courses on bioterrorism and threat preparedness enhanced performance in the tabletop exercises. Evaluative data indicated a new level of competence and self-confidence about being part of a coordinated, local-level, interdisciplinary response.

A cost-benefit analysis of scaling up tuberculosis control in India.

OBJECTIVES: To measure the economic costs and benefits of scaling up tuberculosis (TB) control under the Revised National Tuberculosis Control Programme (RNTCP) in India. DESIGN: Modelling based on country-level programme and epidemiological data from 1997 to 2006. RESULTS: The scale-up of TB control in India has resulted in a total health benefit of 29.2 million disability-adjusted life years (DALYs), including 1.3 million deaths averted. In 2006, the burden of TB measured in terms of DALYs lost would have been 1.8 times higher in the absence of the programme. The total gain in economic well-being from TB control is estimated at US$88.1 billion over the 1997-2006 10-year period. Total public expenditure on TB control over this period amounted to US$768 million, with the RNTCP accounting for US$299 million and other health sector costs accounting for US$469 million. The cost of TB control averaged just US$26 per DALY gained over 1997-2006 and generated a return of US$115 per dollar spent. CONCLUSIONS: The scale-up of TB control has been a very cost-effective strategy for improving the health status of India's population, while the return on investment has been exceptional from a societal perspective.

Heavy metal distribution and bioaccumulation in Chihuahuan Desert Rough Harvester ant (Pogonomyrmex rugosus) populations.

Heavy metal contamination can negatively impact arid ecosystems; however a thorough examination of bioaccumulation patterns has not been completed. We analyzed the distribution of As, Cd, Cu, Pb and Zn in soils, seeds and ant (Pogonomyrmex rugosus) populations of the Chihuahuan Desert near El Paso, TX, USA. Concentrations of As, Cd, Cu, and Pb in soils, seeds and ants declined as a function of distance from a now inactive Cu and Pb smelter and all five metals bioaccumulated in the granivorous ants. The average bioaccumulation factors for the metals from seeds to ants ranged from 1.04x (As) to 8.12x (Cd). The findings show bioaccumulation trends in linked trophic levels in an arid ecosystem and further investigation should focus on the impacts of heavy metal contamination at the community level.

A major QTL for acute ethanol sensitivity in the alcohol tolerant and non-tolerant selected rat lines.

The Alcohol Tolerant and Alcohol Non-Tolerant rats (AT, ANT) were selectively bred for ethanol-induced ataxia as measured on the inclined plane. Here we report on a quantitative trait locus (QTL) study in an F(2) intercross population derived from inbred AT and ANT (IAT, IANT) and a follow-up study of congenics that were bred to examine one of the mapped QTLs. Over 1200 F(2) offspring were tested for inclined plane sensitivity, acute tolerance on the inclined plane, duration of the loss of righting reflex (LORR) and blood ethanol at regain of the righting reflex (BECRR). F(2) rats that were in the upper and lower 20% for inclined plane sensitivity were genotyped with 78 SSLP markers. Significant QTLs for inclined plane sensitivity were mapped on chromosomes 8 and 20; suggestive QTLs were mapped on chromosomes 1, 2 and 3. Highly significant QTLs for LORR duration (LOD = 12.4) and BECRR (LOD = 5.7) were mapped to the same locus on chromosome 1. Breeding and testing of reciprocal congenic lines confirmed the chromosome 1 LORR/BECRR QTL. A series of recombinant congenic sub-lines were bred to fine-map this QTL. Current results have narrowed the QTL to an interval of between 5 and 20 Mb. We expect to be able to narrow the interval to less than 5 Mb with additional genotyping and continued breeding of recombinant sub-congenic lines.

Economic evaluation of public-private mix for tuberculosis care and control, India. Part I. Socio-economic profile and costs among tuberculosis patients.

SETTING: Bangalore City, India. OBJECTIVES: To assess the socio-economic profile, health-seeking behaviour and costs related to tuberculosis (TB) diagnosis and treatment among patients treated under the Revised National TB Control Programme (RNTCP). DESIGN: All 1106 new TB patients registered for treatment under the RNTCP in the second quarter of 2005 participated. Interviews at the beginning and at the end of treatment were conducted. A convenience sample of 32 patients treated outside the RNTCP also participated. RESULTS: Among the TB patients, respectively 50% and 39% were from low and middle standard of living (SL) households, and 77% were from households with a per capita income of less than US$1 per day. The first health contact was with a private practitioner in the case of >70% of patients. Mean patient delay was low, at 21 days, but the mean health system delay was 52 days. The average cost incurred by patients before treatment in the RNTCP was US$145, and during treatment it was US$21. Costs as a proportion of annual household income per capita were 53% for people from low SL households and 41% for those from other households. Costs during treatment faced by patients treated outside the RNTCP averaged US$127. CONCLUSION: Patients treated under the RNTCP through a public-private mix approach were predominantly poor. Many of them experienced considerable health expenditures before starting treatment. Additional efforts are required to reduce the delays and the number of health care providers consulted, and to ensure that patients are shifted to subsidised treatment within the RNTCP.

Economic evaluation of public-private mix for tuberculosis care and control, India. Part II. Cost and cost-effectiveness.

SETTING: Bangalore City, India. OBJECTIVES: To assess the cost and cost-effectiveness of public-private mix (PPM) for tuberculosis (TB) care and control when implemented on a large scale. DESIGN: DOTS implementation under the Revised National TB Control Programme (RNTCP) began in 1999, PPM was introduced in mid-2001 and a second phase of intensified PPM began in 2003. Data on the costs and effects of TB treatment from 1999 to 2005 were collected and used to compare the two distinct phases of PPM with a scenario of no PPM. Costs were assessed in 2005 $US for public and private providers, patients and patient attendants. Sources of data included expenditure records, medical records, interviews with staff and patient surveys. Effectiveness was measured as the number of cases successfully treated. RESULTS: When PPM was implemented, total provider costs increased in proportion to the number of successfully treated TB cases. The average cost per patient treated from the provider perspective when PPM was implemented was stable, at US$69, in the intensified phase compared with US$71 pre-PPM. PPM resulted in the shift of an estimated 7200 patients from non-DOTS to DOTS treatment over 5 years. PPM implementation substantially reduced costs to patients, such that the average societal cost per patient successfully treated fell from US$154 to US$132 in the 4 years following the initiation of PPM. CONCLUSION: Implementation of PPM on a large scale in an urban setting can be cost-effective, and considerably reduces the financial burden of TB for patients.