Immune response stability to the SARS-CoV-2 mRNA vaccine booster is influenced by differential splicing of HLA genes.

Many molecular mechanisms that lead to the host antibody response to COVID-19 vaccines remain largely unknown. In this study, we used serum antibody detection combined with whole blood RNA-based transcriptome analysis to investigate variability in vaccine response in healthy recipients of a booster (third) dose schedule of the mRNA BNT162b2 vaccine against COVID-19. The cohort was divided into two groups: (1) low-stable individuals, with antibody concentration anti-SARS-CoV IgG S1 below 0.4 percentile at 180 days after boosting vaccination; and (2) high-stable individuals, with antibody values greater than 0.6 percentile of the range in the same period (median 9525 [185-80,000] AU/mL). Differential gene expression, expressed single nucleotide variants and insertions/deletions, differential splicing events, and allelic imbalance were explored to broaden our understanding of the immune response sustenance. Our analysis revealed a differential expression of genes with immunological functions in individuals with low antibody titers, compared to those with higher antibody titers, underscoring the fundamental importance of the innate immune response for boosting immunity. Our findings also provide new insights into the determinants of the immune response variability to the SARS-CoV-2 mRNA vaccine booster, highlighting the significance of differential splicing regulatory mechanisms, mainly concerning HLA alleles, in delineating vaccine immunogenicity.

Pharmacogenomic implications of the differential distribution of CYP3A5 metabolic phenotypes among Latin American populations.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.

THE OPTIMUM LEVEL OF MELD TO MINIMIZE THE MORTALITY ON LIVER TRANSPLANTATION WAITING LIST, AND LIVER TRANSPLANTED PATIENT IN SÃO PAULO STATE, BRAZIL.

BACKGROUND: After validation in multiple types of liver disease patients, the MELD score was adopted as a standard by which liver transplant candidates with end-stage liver disease were prioritized for organ allocation in the United States since 2002, and in Brazil, since 2006. AIMS: To analyze the mortality profile of patients on the liver transplant waiting list correlated to MELD score at the moment of transplantation. METHODS: This study used the data from the Secretary of Health of the São Paulo State, Brazil, which listed 22,522 patients, from 2006 (when MELD score was introduced in Brazil) until June 2009. Patients with acute hepatic failure and tumors were included as well. We also considered the mortality of both non-transplanted and transplanted patients as a function of the MELD score at presentation. RESULTS: Our model showed that the best MELD score for patients on the liver transplant waiting list associated to better results after liver transplantation was 26. CONCLUSIONS: We found that the best score for applying to liver transplant waiting list in the State of São Paulo was 26. This is the score that minimizes the mortality in both non-transplanted and liver transplanted patients.

Theoretical models: necessary reflections. / Modelos teóricos: reflexões necessárias.

OBJECTIVE: To present theoretical-methodological reflections on the elaboration, types, and functions of theoretical models as well as their conceptual and analytic frameworks. METHODS: This is an essay, whose material collection was carried out in a non-systematic way, by electing studies exclusively based on the line of argument and reflection that the authors intend to submit to appreciation and public debate. RESULTS: We present reflections on the types and functions of theoretical models, theoretical foundations in research, and reflections on the importance of theoretical models for public health research and their relation with the process of elaboration, development, and reporting in scientific studies. In addition, we describe types of theoretical models referring to the conceptual and empirical levels and the important elaboration and description of their combination for scientific practice. CONCLUSION: With this article, our intention is to stimulate discussions and reflections on current methods that permeate scientific practice and encourage the use of Theoretical Models as a basis for scientific research in its elaboration, development, and reporting process.

OBJETIVO: Apresentar reflexões teórico-metodológicas sobre elaboraçõo, tipos e funções dos modelos teóricos, bem como suas estruturas conceituais e de análise. MÉTODOS: Trata-se de um ensaio cujo processo de coleta do material foi realizado de forma não sistemática, eleito exclusivamente e baseado na linha de argumentaçõo e reflexão que os autores pretendem submeter à apreciaçõo e ao debate público. RESULTADOS: Este trabalho apresenta reflexões sobre tipos e funções dos modelos teóricos, fundamentaçõo teórica nas pesquisas e reflexões sobre a importância dos modelos teóricos para as pesquisas em saúde pública e sua relaçõo com o processo de elaboraçõo, desenvolvimento e relato nos estudos científicos. Além disso, são descritos tipos de modelos teóricos referentes aos planos conceitual e empírico, e a importante elaboraçõo e descriçõo da junçõo de ambos para o fazer científico. CONCLUSÃO: Espera-se que este artigo levante discussões e reflexões sobre os métodos atuais que permeiam o fazer científico e fomentem a utilizaçõo dos modelos teóricos como base das pesquisas científicas em seu processo de elaboraçõo, desenvolvimento e relato.

The effectiveness of COVID-19 vaccines against severe cases and deaths in Brazil from 2021 to 2022: a registry-based study.

Background: Brazil started the COVID-19 mass vaccination in January 2021 with CoronaVac and ChAdOx1, followed by BNT162b2 and Ad26.COV2.S vaccines. By the end of 2021, more than 317 million vaccine doses were administered in the adult population. This study aimed at estimating the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases and deaths in Brazil during the first year of vaccination. Methods: A cohort dataset of over 158 million vaccination and severe cases records linked from official national registries was analyzed via a mixed-effects Poisson model, adjusted for age, state of residence, time after immunization, and calendar time to estimate the absolute vaccine effectiveness of the primary series of vaccination and the relative effectiveness of the booster. The method permitted analysis of effectiveness against hospitalizations and deaths, including in the periods of variant dominance. Findings: Vaccine effectiveness against severe cases and deaths remained over 25% and 50%, respectively, after 19 weeks from primary vaccination of BNT162b2, ChAdOx1, or CoronaVac vaccines. The boosters conferred greater protection than the primary series of vaccination, with heterologous boosters providing marginally greater protection than homologous. The effectiveness against hospitalization during the Omicron dominance in the 60+ years old population started at 61.7% (95% CI, 26.1-86.2) for ChAdOx1, 95.6% (95% CI, 82.4-99.9) for CoronaVac, and 72.3% (95% CI, 51.4-87.4) for the BNT162b2 vaccine. Interpretation: This study provides real-world evidence of the effectiveness of COVID-19 vaccination in Brazil, including during the Omicron wave, demonstrating protection even after waning effectiveness. Comparisons of the effectiveness among different vaccines require caution due to potential bias effects related to age groups, periods in the pandemic, and eventual behavioural changes. Funding: Fundação Oswaldo Cruz (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Pan American Health Organization (PAHO), Departamento de Ciência e Tecnologia da Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde do Ministério da Saúde do Brasil (DECIT/SCTIE/MS).

Estimated COVID-19 severe cases and deaths averted in the first year of the vaccination campaign in Brazil: A retrospective observational study.

Background: A nationwide Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination campaign was initiated in Brazil in January 2021 with CoronaVac (Sinovac Biotech) and ChAdOx1 nCoV-19 (AstraZeneca) followed by BNT162b2 mRNA (Pfizer-BioNTech) and Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines. Here we provide estimates of the number of severe cases and deaths due to coronavirus disease (COVID-19) averted during the first year of the mass vaccination campaign in Brazil. Methods: Data on COVID-19 vaccination and COVID-19-related illness and death were obtained from the Brazilian Ministry of Health and used to estimate the direct effects of the vaccination campaign on the number of severe cases and deaths due to COVID-19 occurring between January 17, 2021 and January 31, 2022. To this end, we compared the daily age-specific rates between the unvaccinated population and the "at least partly vaccinated" population (received at least one dose of a two-dose vaccine), as well as other two vaccination subgroups, "fully vaccinated" (completed the one- or two-dose vaccine schedule), and "boosted-vaccinated" (fully vaccinated and recipients of booster dose) populations. Findings: We estimated that 74% (n = 875,846; 95% confidence interval, CI 843,383-915,709) of total expected cases of severe COVID-19 and 82% (n = 303,129; 95% CI 284,019-321,681) of total expected deaths due to COVID-19 were averted in the first year of the national vaccination campaign. The averted burden was heterogeneous between age groups and higher in the more populous states. However, outcome rate differences between vaccinated and unvaccinated groups were higher in the less populated states. Interpretation: The first year of the COVID-19 vaccination program in Brazil saved the lives of at least 303,129 adults. The results highlight the need for future vaccination campaigns, including those required in the current pandemic, to rapidly achieve high uptake, particularly among the elderly and residents of the least populous regions. Funding: Ministry of Health (Brazil).

Modelos teóricos: reflexões necessárias / Theoretical models: necessary reflections

RESUMO Objetivo: Apresentar reflexões teórico-metodológicas sobre elaboraçõo, tipos e funções dos modelos teóricos, bem como suas estruturas conceituais e de análise. Métodos: Trata-se de um ensaio cujo processo de coleta do material foi realizado de forma não sistemática, eleito exclusivamente e baseado na linha de argumentaçõo e reflexão que os autores pretendem submeter à apreciaçõo e ao debate público. Resultados: Este trabalho apresenta reflexões sobre tipos e funções dos modelos teóricos, fundamentaçõo teórica nas pesquisas e reflexões sobre a importância dos modelos teóricos para as pesquisas em saúde pública e sua relaçõo com o processo de elaboraçõo, desenvolvimento e relato nos estudos científicos. Além disso, são descritos tipos de modelos teóricos referentes aos planos conceitual e empírico, e a importante elaboraçõo e descriçõo da junçõo de ambos para o fazer científico. Conclusão: Espera-se que este artigo levante discussões e reflexões sobre os métodos atuais que permeiam o fazer científico e fomentem a utilizaçõo dos modelos teóricos como base das pesquisas científicas em seu processo de elaboraçõo, desenvolvimento e relato.

ABSTRACT Objective: To present theoretical-methodological reflections on the elaboration, types, and functions of theoretical models as well as their conceptual and analytic frameworks. Methods: This is an essay, whose material collection was carried out in a non-systematic way, by electing studies exclusively based on the line of argument and reflection that the authors intend to submit to appreciation and public debate. Results: We present reflections on the types and functions of theoretical models, theoretical foundations in research, and reflections on the importance of theoretical models for public health research and their relation with the process of elaboration, development, and reporting in scientific studies. In addition, we describe types of theoretical models referring to the conceptual and empirical levels and the important elaboration and description of their combination for scientific practice. Conclusion: With this article, our intention is to stimulate discussions and reflections on current methods that permeate scientific practice and encourage the use of Theoretical Models as a basis for scientific research in its elaboration, development, and reporting process.

The optimum level of meld to minimize the mortality on liver transplantation waiting list, and liver transplanted patient in são paulo state, brazil / Melhor nível do meld para minimizar a mortalidade em lista de transplante de fígado no estado de são paulo, brasil

ABSTRACT BACKGROUND: After validation in multiple types of liver disease patients, the MELD score was adopted as a standard by which liver transplant candidates with end-stage liver disease were prioritized for organ allocation in the United States since 2002, and in Brazil, since 2006. AIMS: To analyze the mortality profile of patients on the liver transplant waiting list correlated to MELD score at the moment of transplantation. METHODS: This study used the data from the Secretary of Health of the São Paulo State, Brazil, which listed 22,522 patients, from 2006 (when MELD score was introduced in Brazil) until June 2009. Patients with acute hepatic failure and tumors were included as well. We also considered the mortality of both non-transplanted and transplanted patients as a function of the MELD score at presentation. RESULTS: Our model showed that the best MELD score for patients on the liver transplant waiting list associated to better results after liver transplantation was 26. CONCLUSIONS: We found that the best score for applying to liver transplant waiting list in the State of São Paulo was 26. This is the score that minimizes the mortality in both non-transplanted and liver transplanted patients.

RESUMO RACIONAL: Desde 2002, após validação em múltiplos tipos de hepatopatias, o escore MELD foi adotado como padrão pelo qual os candidatos a transplante de fígado com doença hepática terminal têm sido priorizados para alocação de órgãos nos Estados Unidos, e em 2006 no Brasil. OBJETIVOS: Analisar a mortalidade de pacientes em lista de espera para transplante de fígado correlacionando com o MELD, no momento do transplante. MÉTODOS: Foram utilizados os dados da Secretaria de Saúde do Estado de São Paulo, Brasil, onde foram listados 22.522 pacientes, desde 2006 (quando o escore MELD foi introduzido no Brasil) até junho de 2009. Foram incluídos pacientes com falência hepática e tumores. A mortalidade de pacientes não transplantados e transplantados também foi considerada em função do escore MELD. RESULTADOS: Nosso modelo mostrou que o melhor valor do MELD, em pacientes em lista de espera para transplante e com melhores resultados, foi de 26. Este valor minimiza mortalidade em pacientes não transplantados bem comem pacientes na lista de espera para transplante de fígado. CONCLUSÕES: O escore MELD ótimo para entrar na lista de espera para transplante de fígado, no estado de São Paulo, é em torno de 26. Esse é o valor que minimiza a mortalidade tanto dos pacientes não transplantados em lista de espera, quanto dos submetidos à transplante de fígado.

Time-dependent vaccine efficacy estimation quantified by a mathematical model

In this paper we calculate the variation of the estimated vaccine efficacy (VE) due to the time-dependent force of infection resulting from the difference between the moment the Clinical Trial (CT) begins and the peak in the outbreak intensity. Using a simple mathematical model we tested the hypothesis that the time difference between the moment the CT begins and the peak in the outbreak intensity determines substantially different values for VE. We exemplify the method with the case of the VE efficacy estimation for one of the vaccines against the new coronavirus SARS-CoV-2.

Theoretical report: reflections and considerations for authors, reviewers, and editors.

Epidemiological studies focused on public health have currently shown significant limitations regarding in-depth theoretical reports, overvaluing methodological aspects. The lack of theoretical explanation affects both the quality and reproducibility of studies. This study therefore reflected on the importance of in-depth theoretical reports considering the theoretical foundation used by researchers in the main sections of the manuscript (title, abstract, introduction, methodology, results, discussion, and conclusion) based on a review of the scientific literature on the subject. We believe that this article can help understand the importance and the development of in-depth theoretical reports in scientific articles, contributing to assessments, interpretations, and criticisms of reviewers and editors regarding the explanation and reporting of theoretical foundation in manuscripts submitted to scientific journals.

Theoretical report: reflections and considerations for authors, reviewers, and editors / Relato teórico: reflexões e considerações para autores, revisores e editores

ABSTRACT Epidemiological studies focused on public health have currently shown significant limitations regarding in-depth theoretical reports, overvaluing methodological aspects. The lack of theoretical explanation affects both the quality and reproducibility of studies. This study therefore reflected on the importance of in-depth theoretical reports considering the theoretical foundation used by researchers in the main sections of the manuscript (title, abstract, introduction, methodology, results, discussion, and conclusion) based on a review of the scientific literature on the subject. We believe that this article can help understand the importance and the development of in-depth theoretical reports in scientific articles, contributing to assessments, interpretations, and criticisms of reviewers and editors regarding the explanation and reporting of theoretical foundation in manuscripts submitted to scientific journals.

RESUMO Atualmente, os estudos epidemiológicos voltados à saúde pública têm apresentado limitações importantes quanto ao relato teórico em profundidade, frente a uma supervalorização de aspectos metodológicos. A falta de explicitação teórica nas publicações, afeta não apenas a qualidade do estudo, como também sua reprodutibilidade. Nesse sentido, apoiados em uma revisão da literatura científica acerca do tema, apresentamos neste ensaio reflexões sobre a importância do relato teórico aprofundado, relacionado à fundamentação teórica adotada por pesquisadores nas principais seções do manuscrito (título, resumo, introdução, metodologia, resultados, discussão e conclusão). Acreditamos que este artigo pode favorecer a compreensão sobre a importância e desenvolvimento de relatos teóricos aprofundados em artigos científicos e contribuir para avaliações, interpretações e críticas dos revisores e editores em relação à importância da explicitação e do relato da fundamentação teórica nos manuscritos submetidos aos periódicos científicos.

Vulnerable populations and tuberculosis treatment outcomes in Brazil. / Populações vulneráveis e o desfecho dos casos de tuberculose no Brasil.

This article aims to assess the association between being a prisoner or homeless and treatment failure in cases of tuberculosis diagnosed in Brazil in 2015. We examined cases of tuberculosis in prisoners and the homeless in Brazil in 2015 reported to the national notifiable diseases information system using descriptive analysis and logistic regression. There were 82,056 cases of tuberculosis in 2015. Of these, 7,462 (10.3%) were prisoners and 2,782 (3.9%) were homeless. The rate of treatment success in prisoners was 78.6%, while the rate of failure in the homeless was 63.2%. Being a prisoner was a protective factor against treatment failure (adjusted odds ratio 0.68, 95%CI 0.63-0.73), while being homeless was a risk factor for treatment failure (adjusted odds ratio 2.38, 95%CI 2.17-2.61). Treatment success and failure rates differed between prisoners and the homeless. Our findings reinforce the need for public health policies tailored to the specific needs of these groups implemented in conjunction with social services and public security agencies in order to have a significant impact on TB incidence.

O objetivo deste artigo é avaliar a associação entre estar privado de liberdade ou em situação de rua e o insucesso no desfecho dos casos de tuberculose diagnosticados no Brasil em 2015. Foram estudados casos de tuberculose na população privada de liberdade e em situação de rua do Brasil em 2015, por análise descritiva e regressão logística baseado no Sistema de Informação de Agravos de Notificação. Em 2015 notificou-se 82.056 casos de tuberculose, destes 7.462 (10,3%) estavam privados de liberdade e 2.782 (3,9%) em situação de rua. A proporção de sucesso no desfecho dos casos na população privada de liberdade foi de 78,6%, enquanto na população em situação de rua, a proporção de insucesso foi 63,2%. Estar privado de liberdade mostrou-se protetor para o insucesso no desfecho dos casos (Razão de Chances ajustada 0,68, IC95% 0,63-0,73), enquanto estar em situação de rua mostrou-se um fator de risco para o insucesso (Razão de Chances ajustada 2,38, IC95% 2,17-2,61). O desfecho dos casos de tuberculose se diferencia entre as populações privada de liberdade e em situação de rua, fazendo-se necessário a implantação de políticas públicas de saúde que considerem suas especificidades e seja articulada com órgãos sociais e segurança a fim de que impacte nos indicadores da doença.

Populações vulneráveis e o desfecho dos casos de tuberculose no Brasil / Vulnerable populations and tuberculosis treatment outcomes in Brazil

Resumo O objetivo deste artigo é avaliar a associação entre estar privado de liberdade ou em situação de rua e o insucesso no desfecho dos casos de tuberculose diagnosticados no Brasil em 2015. Foram estudados casos de tuberculose na população privada de liberdade e em situação de rua do Brasil em 2015, por análise descritiva e regressão logística baseado no Sistema de Informação de Agravos de Notificação. Em 2015 notificou-se 82.056 casos de tuberculose, destes 7.462 (10,3%) estavam privados de liberdade e 2.782 (3,9%) em situação de rua. A proporção de sucesso no desfecho dos casos na população privada de liberdade foi de 78,6%, enquanto na população em situação de rua, a proporção de insucesso foi 63,2%. Estar privado de liberdade mostrou-se protetor para o insucesso no desfecho dos casos (Razão de Chances ajustada 0,68, IC95% 0,63-0,73), enquanto estar em situação de rua mostrou-se um fator de risco para o insucesso (Razão de Chances ajustada 2,38, IC95% 2,17-2,61). O desfecho dos casos de tuberculose se diferencia entre as populações privada de liberdade e em situação de rua, fazendo-se necessário a implantação de políticas públicas de saúde que considerem suas especificidades e seja articulada com órgãos sociais e segurança a fim de que impacte nos indicadores da doença.

Abstract This article aims to assess the association between being a prisoner or homeless and treatment failure in cases of tuberculosis diagnosed in Brazil in 2015. We examined cases of tuberculosis in prisoners and the homeless in Brazil in 2015 reported to the national notifiable diseases information system using descriptive analysis and logistic regression. There were 82,056 cases of tuberculosis in 2015. Of these, 7,462 (10.3%) were prisoners and 2,782 (3.9%) were homeless. The rate of treatment success in prisoners was 78.6%, while the rate of failure in the homeless was 63.2%. Being a prisoner was a protective factor against treatment failure (adjusted odds ratio 0.68, 95%CI 0.63-0.73), while being homeless was a risk factor for treatment failure (adjusted odds ratio 2.38, 95%CI 2.17-2.61). Treatment success and failure rates differed between prisoners and the homeless. Our findings reinforce the need for public health policies tailored to the specific needs of these groups implemented in conjunction with social services and public security agencies in order to have a significant impact on TB incidence.

Optimized delay of the second COVID-19 vaccine dose reduces ICU admissions.

Slower than anticipated, COVID-19 vaccine production and distribution have impaired efforts to curtail the current pandemic. The standard administration schedule for most COVID-19 vaccines currently approved is two doses administered 3 to 4 wk apart. To increase the number of individuals with partial protection, some governments are considering delaying the second vaccine dose. However, the delay duration must take into account crucial factors, such as the degree of protection conferred by a single dose, the anticipated vaccine supply pipeline, and the potential emergence of more virulent COVID-19 variants. To help guide decision-making, we propose here an optimization model based on extended susceptible, exposed, infectious, and removed (SEIR) dynamics that determines the optimal delay duration between the first and second COVID-19 vaccine doses. The model assumes lenient social distancing and uses intensive care unit (ICU) admission as a key metric while selecting the optimal duration between doses vs. the standard 4-wk delay. While epistemic uncertainties apply to the interpretation of simulation outputs, we found that the delay is dependent on the vaccine mechanism of action and first-dose efficacy. For infection-blocking vaccines with first-dose efficacy ≥50%, the model predicts that the second dose can be delayed by ≥8 wk (half of the maximal delay), whereas for symptom-alleviating vaccines, the same delay is recommended only if the first-dose efficacy is ≥70%. Our model predicts that a 12-wk second-dose delay of an infection-blocking vaccine with a first-dose efficacy ≥70% could reduce ICU admissions by 400 people per million over 200 d.

Backdrop to the development of Brazil's national COVID-19 immunization plan. / Contexto de elaboração do Plano de Imunização contra COVID-19 no Brasil.

The process of developing Brazil's COVID-19 immunization plan began belatedly and involved a number of experts, including a technical group responsible for defining priority groups for vaccination. This process was permeated by contradictions between the government and researchers. Finally, on 20 January 2021, the government published an updated version of the plan, which remains limited in scope.

O processo de elaboração do Plano de Imunização contra Covid-19 no Brasil se iniciou tardiamente e contou com a participação de especialistas incluindo o grupo técnico responsável pela definição de grupos prioritários para a vacinação. Este processo foi permeado de indefinições entre o Governo Federal e pesquisadores e, finalmente, no dia 20 de janeiro de 2021 foi divulgada a versão atualizada do Plano ainda incipiente no que tange a sua abrangência.

Contexto de elaboração do Plano de Imunização contra COVID-19 no Brasil / Backdrop to the development of Brazil's national COVID-19 immunization plan

Resumo O processo de elaboração do Plano de Imunização contra Covid-19 no Brasil se iniciou tardiamente e contou com a participação de especialistas incluindo o grupo técnico responsável pela definição de grupos prioritários para a vacinação. Este processo foi permeado de indefinições entre o Governo Federal e pesquisadores e, finalmente, no dia 20 de janeiro de 2021 foi divulgada a versão atualizada do Plano ainda incipiente no que tange a sua abrangência.

Abstract The process of developing Brazil's COVID-19 immunization plan began belatedly and involved a number of experts, including a technical group responsible for defining priority groups for vaccination. This process was permeated by contradictions between the government and researchers. Finally, on 20 January 2021, the government published an updated version of the plan, which remains limited in scope.