Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

Congenital CMV infection in a Brazilian neonatal intensive care unit: high prevalence among twin newborns.

BACKGROUND: Cytomegalovirus (CMV) is one of the most important pathogens associated with congenital infection worldwide. Most congenital CMV-infected infants are asymptomatic at birth; however, some can develop delayed sequelae, especially hearing loss. METHODS: This study aimed to investigate the prevalence of congenital CMV infection in a neonatal intensive care unit in a low-income region of Brazil. The objectives extended to identifying associated factors, assessing the clinical status of infected newborns, and undertaking a two-year follow-up to discern potential long-term consequences in the affected infants. This cross-sectional prospective study enrolled newborns up to three weeks of life requiring intensive medical care. We employed a convenience sampling method to include 498 newborns and 477 mothers in the study. Categorical variables underwent analysis employing Fisher's exact test, whereas the examination of continuous variables involved the Mann‒Whitney test. RESULTS: CMV DNA was detected in saliva/urine samples from 6 newborns (1.21%), confirming congenital infection. We noted a significantly greater incidence (OR: 11.48; 95% CI: 2.519-52.33; p = 0.0094) of congenital infection among twins (7.14%) than among nontwins (0.66%). The twin patients exhibited discordant infection statuses, suggesting that only one of the babies tested positive for CMV. Most of the infected children were born to mothers who initiated sexual activity at a younger age (p = 0.0269). Only three out of the six newborns diagnosed with CMV infection underwent comprehensive clinical assessments and received continuous follow-up until they reached two years of age. Only one of the children had weight and height measurements below the norm for their age, coupled with developmental delays. CONCLUSIONS: The prevalence of congenital CMV infection among newborns admitted to the NICU was low and similar to that in the general population. However, we found a significantly greater incidence of congenital CMV infection in twins than in singletons. Interestingly, the twin-infected patients exhibited discordant infection statuses, suggesting that CMV was present in only one of the babies. We also found that most of the infected children were born to mothers who initiated sexual activity at a younger age. Diagnostic accessibility and comprehensive surveillance programs are imperative for effectively managing and preventing congenital CMV infections.

Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia.

Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.02). Further, in patients with CD3+ T cell counts between 51 and 300 cells/µL, there was a higher proliferative response with the PHA flow assay compared to the 3H-T assay (p < 0.0001), suggesting that the method of analysis influences the resolution and interpretation of PHA results. Importantly, we observed many SCID patients with profound T cell lymphopenia having normal T cell proliferation when assessed by flow cytometry. We recommend this test be considered only as supportive in the diagnosis of typical SCID.

Posttransplantation late complications increase over time for patients with SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) landmark study.

BACKGROUND: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children in the United States and Canada onto a retrospective multicenter natural history study of hematopoietic cell transplantation (HCT). OBJECTIVE: We investigated outcomes of HCT for severe combined immunodeficiency (SCID). METHODS: We evaluated the chronic and late effects (CLE) after HCT for SCID in 399 patients transplanted from 1982 to 2012 at 32 PIDTC centers. Eligibility criteria included survival to at least 2 years after HCT without need for subsequent cellular therapy. CLE were defined as either conditions present at any time before 2 years from HCT that remained unresolved (chronic), or new conditions that developed beyond 2 years after HCT (late). RESULTS: The cumulative incidence of CLE was 25% in those alive at 2 years, increasing to 41% at 15 years after HCT. CLE were most prevalent in the neurologic (9%), neurodevelopmental (8%), and dental (8%) categories. Chemotherapy-based conditioning was associated with decreased-height z score at 2 to 5 years after HCT (P < .001), and with endocrine (P < .001) and dental (P = .05) CLE. CD4 count of ≤500 cells/µL and/or continued need for immunoglobulin replacement therapy >2 years after transplantation were associated with lower-height z scores. Continued survival from 2 to 15 years after HCT was 90%. The presence of any CLE was associated with increased risk of late death (hazard ratio, 7.21; 95% confidence interval, 2.71-19.18; P < .001). CONCLUSION: Late morbidity after HCT for SCID was substantial, with an adverse impact on overall survival. This study provides evidence for development of survivorship guidelines based on disease characteristics and treatment exposure for patients after HCT for SCID.

Linear epitope mapping in the E and NS1 proteins of dengue and Zika viruses: Prospection of peptides for vaccines and diagnostics.

The arrival of the Zika virus (ZIKV) in dengue virus (DENV)-endemic areas has posed challenges for both differential diagnosis and vaccine development. Peptides have shown promise in addressing these issues. The aim of this study was to identify the linear epitope profile recognized by serum samples from dengue and Zika patients in the E and NS1 proteins of DENV and ZIKV. This cross-sectional study included individuals of all ages with laboratory-confirmed DENV and ZIKV infections, who were selected through convenience sampling. The serum samples from dengue and Zika patients detected epitopes evenly distributed across the viral proteins in a peptide microarray platform. However, several epitopes were located within "epitope hotspots", characterized by clusters of peptides recognized in more than 30% of the sub-arrays analyzed using individual or pooled serum samples. The serum samples from dengue and Zika patients showed a high level of cross-reactivity with peptides in the DENV and ZIKV proteins. Analysis using an additional peptide microarray platform, which contained peptides selected based on the results of the initial screening, revealed that two DENV and one ZIKV peptide, highly specific to their related viruses, were located within the epitope hotspots; however, they presented low detection rates (32.5, 35.0, and 28.6%, respectively). In addition, two DENV peptides detected at similarly high rates by both dengue and Zika patients were also found within the epitope hotspots. These hotspots contain several immunodominant epitopes that are recognized by a larger number of individuals when compared to 15-amino acid (aa) sequence peptides. Thus, epitope hotspots may have greater potential to serve as antigens in diagnostic tests and vaccine development than peptides composed of only 15 amino acids.

Performance evaluation of Biofire Film Array Respiratory Panel 2.1 for SARS-CoV-2 detection in a pediatric hospital setting.

The highly contagious nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), requires rapid diagnostic tests to prevent the virus from spreading within hospitals and communities. Reverse transcription followed by the polymerase chain reaction (RT-PCR) test is the gold standard for detecting SARS-CoV-2 infections but is time-consuming, labor-intensive, and restricted to centralized laboratories. There is a growing need to develop and implement point-of-care and rapid tests for SARS-CoV-2 detection to address these limitations. We aimed to evaluate the performance of BioFire Film Array Respiratory Panel 2.1 (BioFire FA-RP2.1) for SARS-CoV-2 detection in a pediatric hospital setting. The BioFire FA-RP2.1 test provides rapid results and can identify several viral and bacterial infections in a single test. This prospective, cross-sectional, diagnostic accuracy study enrolled participants ranging from 0 to 18 years of age, seeking medical consultation for any reason, who had been in contact with individuals confirmed to have COVID-19 or managed at the hospital for medical or surgical reasons. We employed a systematic sampling technique to ensure a representative sample. The study included 339 participants with a median age of 5 years. The BioFire FA-RP2.1 test detected SARS-CoV-2 in 18.6% of cases, while the reference RT-PCR test in 14% of cases. The BioFire FA-RP2.1 sensitivity and specificity for SARS CoV-2 detection were 98% and 94%, respectively. The positive probability coefficient (LR+) was 18. The agreement between the two tests was 0.80. In addition, the BioFire FA-RP2.1 test detected coinfection with two viruses in 7,6% of cases. The BioFire FA-RP2.1 is a reliable solution to meet pediatric healthcare needs and improve prognosis in the post-pandemic era thanks to its friendly interface and rapid testing process.

Retrospective Observational Assessment of the Impact of Cefepime Prophylaxis in Neutropenic Pediatric Patients With Acute Myelogenous Leukemia.

BACKGROUND: The potential for cefepime prophylaxis to reduce bloodstream infections (BSIs) in pediatric patients with acute myelogenous leukemia (AML) has been incompletely characterized. METHODS: A retrospective quasi-experimental study of patients under 21 years of age admitted with AML from 2010 through 2018 at two affiliated pediatric tertiary-care hospitals before and after the adoption of routine cefepime prophylaxis for afebrile AML patients during profound neutropenia. RESULTS: The rate of BSIs per 1000 neutropenia days was significantly lower in the prophylaxis group than the baseline group (2.6 vs 15.5, incidence rate ratio [IRR] 0.17, 95% CI 0.09-0.32). Interrupted time-series analysis showed that a sharp reduction in BSIs coincided with the implementation of prophylaxis. Bacteremia with viridans group streptococci was frequent in the baseline group but not observed after adopting prophylaxis. Despite the increased use of cefepime, the rate of cefepime-nonsusceptible BSIs per 1000 neutropenia days decreased (1.6 vs 4.1, IRR 0.40, 95% CI 0.16-0.99). The median number of febrile neutropenia episodes per patient also decreased in the prophylaxis group, as did the proportion of patients admitted to the intensive care unit (ICU) (22/51 (43.1%) vs 26/38 (68.4%); risk difference -25.3%, 95% CI -44.4 to -2.8). A trend was observed toward an increased proportion of patients with Clostridioides difficile infection in the prophylaxis group (10/51 (19.6%) vs 3/38 (7.9%); risk difference 11.7%, 95% CI -3.4 to 29.0). CONCLUSIONS: Cefepime prophylaxis was associated with a significant reduction in BSIs, febrile neutropenia, and ICU admission among pediatric AML patients.

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

[Evaluation of the implementation of the Care Network for People with Disabilities in the Brazilian Unified National Health System: a multiple case study]. / Avaliação da implantação da Rede de Cuidados à Pessoa com Deficiência no Sistema Único de Saúde: um estudo de casos múltiplos.

The Care Network for People with Disabilities (RCPCD) was implemented in 2012 as a consequence of the actions of the Viver sem Limite (Living without Limits) plan and has been the research object of recent studies. However, no published studies address the degree of implementation of this network. This study aimed to evaluate the degree of implementation of the RCPCD in eight states in the five regions of Brazil. This multiple case study performed evaluative research of the degree of implementation of the RCPCD in the states of Amazonas, Bahia, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraíba, Rio Grande do Sul, and São Paulo. A logical model of the policy and a measurement matrix were developed. The degree of implementation of seven states was moderate, but Amazonas had an incipient degree of implementation. The evaluation of each stage of the process showed important differences, as the regional diagnosis and network adhesion stages presented moderate to advanced degrees of implementation in most states. In the service contracting stage, no state had an advanced degree of implementation, and the stage of follow-up and monitoring of the RCPCD was not even reached. The measurement matrix helps evaluate the degree of implementation of the RCPCD, and, by recognizing its results, the state steering groups and technical area recommend its use. Actions to improve this implementation, such as strengthening regionalization, establishing regional steering groups, ensuring contracting mechanisms, and defining criteria for certification of the care points, are necessary.

A Rede de Cuidados à Pessoa com Deficiência (RCPCD) foi implantada em 2012 como desdobramento das ações do Plano Viver sem Limite, sendo objeto de pesquisas recentes, entretanto, não foram encontrados estudos de avaliação do grau de implantação dessa rede. O objetivo deste artigo foi avaliar o grau de implantação da RCPCD em oito estados nas cinco regiões geográficas brasileiras. Realizou-se estudo de casos múltiplos mediante pesquisa avaliativa do grau de implantação da RCPCD nos estados/casos: Amazonas, Bahia, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraíba, Rio Grande do Sul e São Paulo. Para tanto, desenvolveu-se um modelo lógico da política e uma matriz de medidas. O grau de implantação de sete estados foi classificado como moderado, somente o Amazonas obteve grau de implantação incipiente. Foram identificadas diferenças importantes na avaliação de cada fase desse processo, as fases de diagnóstico regional e adesão à rede obtiveram grau de implantação de moderado a avançado na maioria dos estados. Na fase da contratualização dos serviços, nenhum estado alcançou o grau avançado de implantação e a fase de acompanhamento e monitoramento da RCPCD basicamente não ocorreu em todos os estados. A matriz de medidas permite avaliar o grau de implantação da RCPCD. Ainda, o reconhecimento dos resultados do grau de implantação pelos grupos condutores e áreas técnicas estaduais referendou o uso desse instrumento. Salienta-se a necessidade de ações para o aprimoramento dessa implantação, tais como: fortalecer a regionalização, instituir grupos condutores regionais, garantir mecanismos de contratualização e definir critérios para certificação dos pontos de atenção.

La Red de Atención a Personas con Discapacidad (RCPCD) se implementó en 2012 en el Sistema Único de Salud como resultado de las acciones del Plan Vivir sin Límite, y es objeto de una investigación reciente; sin embargo, no hay estudios de evaluación del grado de implementación de esta red. El objetivo de este estudio fue evaluar el grado de implementación de la RCPCD en ocho estados de las cinco regiones geográficas brasileñas. Se realizó un estudio de caso múltiple mediante una investigación evaluativa sobre el grado de implementación de la RCPCD en los estados/casos: Amazonas, Bahia, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraíba, Rio Grande do Sul y São Paulo. Para ello, se elaboraron un modelo lógico de la política y una matriz de medidas. El grado de implementación de siete estados se clasificó como moderado, solamente Amazonas obtuvo un grado de implementación incipiente. Se identificaron diferencias importantes en la evaluación de cada fase de este proceso, las fases de diagnóstico regional y adhesión a la red lograron un grado de implementación de moderado a avanzado en la mayoría de los estados. En la fase de contratación de los servicios, ningún estado alcanzó el nivel avanzado de implementación, y la fase de seguimiento y monitoreo de la RCPCD básicamente no se realizó en todos los estados. La matriz de medidas permite evaluar el grado de implementación de la RCPCD, y el reconocimiento de los resultados del grado de implementación por parte de los grupos de dirección y el área técnica de los estados avaló su uso. Son necesarias más acciones para mejorar esta implementación, tales como: fortalecer la regionalización, establecer grupos de dirección regional, garantizar mecanismos de contratación y definir criterios para la certificación de puntos de atención.

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions.

BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Microplastics and hydrocarbons in soils: Quantification as an anthropic carbon source.

The literature on the presence of microplastics (MPs) and their potential impact on terrestrial ecosystems is still scarce. Interestingly, soil MPs are detected as organic carbon (SOC) using traditional quantification methods (e.g., loss on ignition [LOI]), although its dynamics in the environment will be different. The objective of this study was to quantify the carbon (C) contribution of MPs to the SOC in superficial soil samples from a coastal urban wetland (Avellaneda, Buenos Aires, Argentina) with the features of a humid subtropical forest and compare with hydrocarbon contribution. Soil samples were split for analysis of moisture content; texture (sieve and pipet method); organic matter as a LOI (8 h at 450 °C); total hydrocarbons (THCs; gravimetry of solvent extractable matter); n-alkanes (solvent extraction and gas chromatography-flame ionization detection analysis); and extraction of MPs (floatation in NaClaq , filtration, H2 O2 digestion, and visual sorting under a stereomicroscope). The superficial soil was a sandy clay loam with a large organic matter content (19%-30%). The THC averaged 2.5 ± 1.9 g kg and the marked predominance of odd-numbered carbon n-alkanes maximizing at C29 and C31 show the contribution of the terrestrial plant waxes. The average number of MPs was 587 ± 277 items kg of dry soil, predominantly fibers. Taking account of the C content, THCs and MPs add to the soil 1.23 ± 1.10 ton C ha and 0.10-0.97 ton C ha, respectively. Therefore, in this system with humid forest characteristics, the MPs represent between 0.12% and 1.25% of soil estimated carbon, in a magnitude similar to the C contribution of THCs (0.6%-4.2%). This preliminary study shows the relevance of discriminating MPs from other carbon sources and presents a description of their impact on soils to advance future research or tools for decision-makers. Integr Environ Assess Manag 2023;19:698-705. © 2022 SETAC.

Avaliação da implantação da Rede de Cuidados à Pessoa com Deficiência no Sistema Único de Saúde: um estudo de casos múltiplos / Evaluation of the implementation of the Care Network for People with Disabilities in the Brazilian Unified National Health System: a multiple case study / Evaluación de la implementación de la Red de Atención a Personas con Discapacidad en el Sistema Único de Salud: un estudio de caso múltiple

Resumo: A Rede de Cuidados à Pessoa com Deficiência (RCPCD) foi implantada em 2012 como desdobramento das ações do Plano Viver sem Limite, sendo objeto de pesquisas recentes, entretanto, não foram encontrados estudos de avaliação do grau de implantação dessa rede. O objetivo deste artigo foi avaliar o grau de implantação da RCPCD em oito estados nas cinco regiões geográficas brasileiras. Realizou-se estudo de casos múltiplos mediante pesquisa avaliativa do grau de implantação da RCPCD nos estados/casos: Amazonas, Bahia, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraíba, Rio Grande do Sul e São Paulo. Para tanto, desenvolveu-se um modelo lógico da política e uma matriz de medidas. O grau de implantação de sete estados foi classificado como moderado, somente o Amazonas obteve grau de implantação incipiente. Foram identificadas diferenças importantes na avaliação de cada fase desse processo, as fases de diagnóstico regional e adesão à rede obtiveram grau de implantação de moderado a avançado na maioria dos estados. Na fase da contratualização dos serviços, nenhum estado alcançou o grau avançado de implantação e a fase de acompanhamento e monitoramento da RCPCD basicamente não ocorreu em todos os estados. A matriz de medidas permite avaliar o grau de implantação da RCPCD. Ainda, o reconhecimento dos resultados do grau de implantação pelos grupos condutores e áreas técnicas estaduais referendou o uso desse instrumento. Salienta-se a necessidade de ações para o aprimoramento dessa implantação, tais como: fortalecer a regionalização, instituir grupos condutores regionais, garantir mecanismos de contratualização e definir critérios para certificação dos pontos de atenção.

Abstract: The Care Network for People with Disabilities (RCPCD) was implemented in 2012 as a consequence of the actions of the Viver sem Limite (Living without Limits) plan and has been the research object of recent studies. However, no published studies address the degree of implementation of this network. This study aimed to evaluate the degree of implementation of the RCPCD in eight states in the five regions of Brazil. This multiple case study performed evaluative research of the degree of implementation of the RCPCD in the states of Amazonas, Bahia, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraíba, Rio Grande do Sul, and São Paulo. A logical model of the policy and a measurement matrix were developed. The degree of implementation of seven states was moderate, but Amazonas had an incipient degree of implementation. The evaluation of each stage of the process showed important differences, as the regional diagnosis and network adhesion stages presented moderate to advanced degrees of implementation in most states. In the service contracting stage, no state had an advanced degree of implementation, and the stage of follow-up and monitoring of the RCPCD was not even reached. The measurement matrix helps evaluate the degree of implementation of the RCPCD, and, by recognizing its results, the state steering groups and technical area recommend its use. Actions to improve this implementation, such as strengthening regionalization, establishing regional steering groups, ensuring contracting mechanisms, and defining criteria for certification of the care points, are necessary.

Resumen: La Red de Atención a Personas con Discapacidad (RCPCD) se implementó en 2012 en el Sistema Único de Salud como resultado de las acciones del Plan Vivir sin Límite, y es objeto de una investigación reciente; sin embargo, no hay estudios de evaluación del grado de implementación de esta red. El objetivo de este estudio fue evaluar el grado de implementación de la RCPCD en ocho estados de las cinco regiones geográficas brasileñas. Se realizó un estudio de caso múltiple mediante una investigación evaluativa sobre el grado de implementación de la RCPCD en los estados/casos: Amazonas, Bahia, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraíba, Rio Grande do Sul y São Paulo. Para ello, se elaboraron un modelo lógico de la política y una matriz de medidas. El grado de implementación de siete estados se clasificó como moderado, solamente Amazonas obtuvo un grado de implementación incipiente. Se identificaron diferencias importantes en la evaluación de cada fase de este proceso, las fases de diagnóstico regional y adhesión a la red lograron un grado de implementación de moderado a avanzado en la mayoría de los estados. En la fase de contratación de los servicios, ningún estado alcanzó el nivel avanzado de implementación, y la fase de seguimiento y monitoreo de la RCPCD básicamente no se realizó en todos los estados. La matriz de medidas permite evaluar el grado de implementación de la RCPCD, y el reconocimiento de los resultados del grado de implementación por parte de los grupos de dirección y el área técnica de los estados avaló su uso. Son necesarias más acciones para mejorar esta implementación, tales como: fortalecer la regionalización, establecer grupos de dirección regional, garantizar mecanismos de contratación y definir criterios para la certificación de puntos de atención.

Engineering Gold Shelled Nanomagnets for Pre-Setting the Operating Temperature for Magnetic Hyperthermia.

This study investigated the fabrication of spherical gold shelled maghemite nanoparticles for use in magnetic hyperthermia (MHT) assays. A maghemite core (14 ± 3 nm) was used to fabricate two samples with different gold thicknesses, which presented gold (g)/maghemite (m) content ratios of 0.0376 and 0.0752. The samples were tested in MHT assays (temperature versus time) with varying frequencies (100-650 kHz) and field amplitudes (9-25 mT). The asymptotic temperatures (T∞) of the aqueous suspensions (40 mg Fe/mL) were found to be in the range of 59-77 °C (naked maghemite), 44-58 °C (g/m=0.0376) and 33-51 °C (g/m=0.0752). The MHT data revealed that T∞ could be successful controlled using the gold thickness and cover the range for cell apoptosis, thereby providing a new strategy for the safe use of MHT in practice. The highest SAR (specific absorption rate) value was achieved (75 kW/kg) using the thinner gold shell layer (334 kHz, 17 mT) and was roughly twenty times bigger than the best SAR value that has been reported for similar structures. Moreover, the time that was required to achieve T∞ could be modeled by changing the thermal conductivity of the shell layer and/or the shape/size of the structure. The MHT assays were pioneeringly modeled using a derived equation that was analytically identical to the Box-Lucas method (which was reported as phenomenological).

Screening of febrile patients with suspected malaria from the Brazilian Amazon for virus infection.

Arthropod-borne viruses (arboviruses) are a significant public health threat, especially in tropical and subtropical regions. More than 150 arboviruses can cause febrile illness following infection in humans. The Brazilian Amazon region has the highest number of arboviruses detected worldwide. In addition to arboviruses, malaria, caused by Plasmodium vivax, is endemic in the Amazon. Patients with malaria and arboviral disease frequently show similar clinical presentation and laboratory findings, making the diagnosis of the cause of the infection challenging. The aim of this study was to evaluate the potential for viral infections in patients with suspected malaria but without Plasmodium infection in the Brazilian Amazon. We recruited 200 subjects with suspected malaria in Manaus, Brazil. First, we tested for arboviruses in serum samples from 124 of the 200 participants using an arbovirus DNA microarray platform, which did not detect any virus. Then, we mixed the serum samples of the other 76 participants in 10 pools and subjected them to next-generation sequencing. Analysis of the sequencing data revealed the presence of only one arbovirus (Zika virus) in one sample pool. This analysis also detected the presence of primate erythroparvovirus 1 and pegivirus C. These results suggest that arboviruses are not the most frequent viral infections in patients with suspected malaria but without Plasmodium infection in the metropolitan region of Manaus. Implementation of specific viral surveillance tests will help in the early detection of viruses with epidemic potential.

Comparison of hematopoietic cell transplant conditioning regimens for hemophagocytic lymphohistiocytosis disorders.

BACKGROUND: Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality. OBJECTIVE: The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders. METHODS: We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models. RESULTS: Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001). CONCLUSIONS: Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

Volumetric Modulated Arc Therapy Enabled Total Body Irradiation (VMAT-TBI): Six-year Clinical Experience and Treatment Outcomes.

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage >90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were <100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities.