Predictors of azathioprine and mycophenolate mofetil response in patients with neuromyelitis optica spectrum disorder: A cohort study.

BACKGROUND: Relapse rates of 47 % have been reported in patients with neuromyelitis optica (NMOSD) using Azathioprine (AZA) and mycophenolate mofetil (MMF). Prediction of non-responders could help determine which patients are most likely to benefit from newer monoclonal antibody treatments from the outset. OBJECTIVES: To identify predictors of AZA and MMF treatment response in NMOSD. METHODS: Multicenter cohort study of NMOSD patients from Brazil and the United Kingdom, treated with AZA and MMF. An unsatisfactory response was defined as one severe or two non-severe attacks in a year. Cox regression was used to identify predictive factors of unsatisfactory response to AZA and MMF. RESULTS: 103 NMOSD patients, mean age 38 years, 83% female, and 65% of Black ethnic group were included. An unsatisfactory IS response was observed in 42% of patients over 2.5 years (IQR 1.0-8.8) years. A severe preceding attack was more common in non-responders (31.1% x 76.7%, p = <0.001). In multivariable analysis, severe attack (RR 3.13; 95 % CI 1.37-7.18, p = 0.007) or higher annualized relapse rate (RR 4.84; 95 % CI 2.01-11.65, p = < 0.001) predicted an unsatisfactory response. Interestingly, Black NMOSD patients had a lower risk of poor response (RR 0.39, 95 % CI 0.17-0.85, p = 0.019). CONCLUSION: Severe attack and a higher annualized relapse rate before AZA or MMF initiation were associated with an unsatisfactory IS response. In patients with these characteristics, treatment with higher-efficacy drugs should be considered from the outset.

Timing of MOG-IgG Testing Is Key to 2023 MOGAD Diagnostic Criteria.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a recently identified autoimmune demyelinating disorder of the CNS affecting both adults and children. Diagnostic criteria for MOGAD have recently been published. We aimed to validate the 2023 MOGAD diagnostic criteria in a real-world cohort of patients with atypical CNS inflammation. METHODS: All patients referred to the National neuromyelitis optica spectrum disorder (NMOSD) specialized service at The Walton Center NHS Foundation Trust between 2012 and 2023 with an atypical demyelinating syndrome were evaluated. We systematically applied the 2023 MOGAD diagnostic criteria and previous 2018 International Diagnostic Recommendations for MOG encephalomyelitis to our retrospective cohort. RESULTS: 474 patients were screened and 66 were excluded for lack of clinical information. Preexisting diagnoses within our cohort included the following: MOGAD, n = 127; AQP4-IgG NMOSD, n = 125; seronegative NMOSD, n = 33; multiple sclerosis (MS), n = 10; and other diagnoses, n = 113. Of patients with preexisting MOGAD, 97% (123/127) fulfilled the 2023 MOGAD diagnostic criteria. Three patients with a low-positive MOG-IgG did not meet supportive features though 2/3 had insufficient investigations. Alternative diagnoses could not be excluded in 1 patient with MS-MOGAD overlap. No patients with a non-MOGAD diagnosis were found to fulfill the 2023 diagnostic criteria. The sensitivity and specificity of the 2023 MOGAD diagnostic criteria were 97% and 100% with no false positives, improving on 2018 International Diagnostic Recommendations for MOG encephalomyelitis. Low-positive MOG-IgG results were more often associated with a longer time from disease onset to sampling (p < 0.001). In addition, in patients with a MOG-IgG1 test within 6 months of clinical onset, approximately 25% can become low positive by 6 months. Of patients with preexisting MOGAD, 9% (12/127) had insufficient investigations and examinations to fully evaluate additional supportive features. However, in those who were completely evaluated, supportive features were fulfilled in 97% (111/115). DISCUSSION: The 2023 MOGAD diagnostic criteria were highly sensitive and specific and closely align with historically established cases of MOGAD. However, because additional supportive features are stipulated for patients with a low-positive MOG-IgG result, missed diagnoses may occur due to delayed testing or insufficient investigations.

Development and characterization of a bacteriophage cocktail with high lytic efficacy against field-isolated Salmonella enterica.

Salmonella spp. is a prevalent pathogen that causes great public health concern worldwide. Bacteriophage-based cocktails have arisen as an alternative to antibiotics to inhibit the growth of Salmonella. However, the bactericidal effect of bacteriophage cocktails in vivo largely differs from their observed effect in vitro. This is partly because in vitro developments of cocktails do not always consider the bacterial diversity nor the environmental conditions where bacteriophages will have to replicate. Here, we isolated and sequenced 47 bacteriophages that showed variable degrees of lytic activity against 258 Salmonella isolates from a commercial broiler company in Brazil. Three of these bacteriophages were characterized and selected to assemble a cocktail. In vitro quantitative assays determined the cocktail to be highly effective against multiple serovars of Salmonella, including Minnesota and Heidelberg. Remarkably, the in vitro lytic activity of the cocktail was retained or improved in conditions that more closely resembled the chicken gut, such as anaerobiosis, 42°C, and Salmonella mono-strain biofilms. Analysis of bacterial cross-resistance between the 3 bacteriophages composing the cocktail revealed limited or no generation of cross-resistance. Our results highlight the relevance of an optimized flux of work to develop bacteriophage cocktails against Salmonella with high lytic efficacy and strong potential to be applied in vivo in commercial broiler farms.

Implementation of FAIR principles in the IPCC: the WGI AR6 Atlas repository.

The Sixth Assessment Report (AR6) of the Intergovernmental Panel on Climate Change (IPCC) has adopted the FAIR Guiding Principles. We present the Atlas chapter of Working Group I (WGI) as a test case. We describe the application of the FAIR principles in the Atlas, the challenges faced during its implementation, and those that remain for the future. We introduce the open source repository resulting from this process, including coding (e.g., annotated Jupyter notebooks), data provenance, and some aggregated datasets used in some figures in the Atlas chapter and its interactive companion (the Interactive Atlas), open to scrutiny by the scientific community and the general public. We describe the informal pilot review conducted on this repository to gather recommendations that led to significant improvements. Finally, a working example illustrates the re-use of the repository resources to produce customized regional information, extending the Interactive Atlas products and running the code interactively in a web browser using Jupyter notebooks.

[Spontaneous coronary artery dissection in a heart transplant patient. Report of one case]. / Disección coronaria espontánea en paciente trasplantada de corazón.

Spontaneous coronary artery dissection is an uncommon cause of acute coronary syndrome that predominantly affects women without cardiovascular risk factors. In transplant patients, spontaneous coronary artery dissection is an extremely rare condition, having been described in only three patients, in whom vascular damage secondary to the use of anticalcineurinics is postulated as a probable mechanism. We report a spontaneous coronary dissection in a female who received a heart transplant at 34 years of age. The diagnosis was made in a follow-up coronary angiography three years after transplantation, supplemented with optical coherence tomography. A percutaneous coronary revascularization of the involved artery was performed, with good immediate results and at one year of follow-up.

Disección coronaria espontánea en paciente trasplantada de corazón / Spontaneous coronary artery dissection in a heart transplant patient: report of one case

Spontaneous coronary artery dissection is an uncommon cause of acute coronary syndrome that predominantly affects women without cardiovascular risk factors. In transplant patients, spontaneous coronary artery dissection is an extremely rare condition, having been described in only three patients, in whom vascular damage secondary to the use of anticalcineurinics is postulated as a probable mechanism. We report a spontaneous coronary dissection in a female who received a heart transplant at 34 years of age. The diagnosis was made in a follow-up coronary angiography three years after transplantation, supplemented with optical coherence tomography. A percutaneous coronary revascularization of the involved artery was performed, with good immediate results and at one year of follow-up.

Dabigatran and warfarin in nonvalvular atrial fibrillation or atrial flutter in outpatient clinic practice in Brazil.

OBJECTIVES: To compare warfarin and dabigatran for thromboembolic event prevention in patients with nonvalvular atrial fibrillation or atrial flutter. METHODS: This was a retrospective cohort of participants with nonvalvular atrial fibrillation or atrial flutter using either warfarin or dabigatran in a reference center in Brazil. RESULTS: There were 112 patients (mean age 65.5 years), with 55.3% using warfarin. The median duration of follow-up was 1.9 years for warfarin and 1.6 years for dabigatran (p = 0.167). Warfarin patients had a higher median of medical appointments per year (8.3 [6.8-10.4] vs 3.1 [2.3-4.2], p < 0.001) and the frequency of minor bleeding was more than four times higher (17.7% vs 4.0%, p = 0.035). Among patients with prior stroke, those using warfarin had 2.6 times more medical appointments for person-years of follow-up (8.5 vs 3.3). There was no major bleeding or embolic event during follow-up period. CONCLUSION: The dabigatran group had a lower frequency of minor bleeding and number of medical appointments than the warfarin group, without more embolic events or major bleeding.

Dabigatran and warfarin in nonvalvular atrial fibrillation or atrial flutter in outpatient clinic practice in Brazil / Dabigatrana e varfarina em pacientes com fibrilação atrial não valvar ou flutter em ambulatório especializado no Brasil

ABSTRACT Objectives: To compare warfarin and dabigatran for thromboembolic event prevention in patients with nonvalvular atrial fibrillation or atrial flutter. Methods: This was a retrospective cohort of participants with nonvalvular atrial fibrillation or atrial flutter using either warfarin or dabigatran in a reference center in Brazil. Results: There were 112 patients (mean age 65.5 years), with 55.3% using warfarin. The median duration of follow-up was 1.9 years for warfarin and 1.6 years for dabigatran (p = 0.167). Warfarin patients had a higher median of medical appointments per year (8.3 [6.8-10.4] vs 3.1 [2.3-4.2], p < 0.001) and the frequency of minor bleeding was more than four times higher (17.7% vs 4.0%, p = 0.035). Among patients with prior stroke, those using warfarin had 2.6 times more medical appointments for person-years of follow-up (8.5 vs 3.3). There was no major bleeding or embolic event during follow-up period. Conclusion: The dabigatran group had a lower frequency of minor bleeding and number of medical appointments than the warfarin group, without more embolic events or major bleeding.

RESUMO Objetivos: Comparar varfarina e dabigatrana para prevenção de eventos tromboembólicos em pacientes com fibrilação atrial não valvar ou flutter (FA). Métodos: Coorte retrospectiva de pacientes com FA em uso de varfarina ou dabigatrana em serviço especializado no Brasil. Resultados: Foram avaliados 112 pacientes (média idade 65,5), com 55,3% no grupo varfarina. A mediana do tempo de seguimento foi de 1,9 anos para o grupo varfarina e 1,6 para dabigatrana (p = 0,167). No grupo varfarina houve maior mediana de consultas médicas (CM) por ano (8,3[6,8-10,4] vs. 3,1[2,3-4,2], p < 0,001), com frequência de sangramento menor quatro vezes maior (17,7% vs. 4,0%, p = 0,035). Nos pacientes com acidente vascular cerebral isquêmico prévio, o grupo varfarina teve 2,6 vezes mais CM por pessoas-ano de seguimento (8,5 vs. 3,3). Não houve sangramento maior ou eventos embólicos no período de seguimento. Conclusão: Pacientes em uso de dabigatrana tiveram menor número de sangramento menor e CM que aqueles em uso de varfarina, sem aumentar eventos embólicos ou sangramentos maiores.

Anticoagulation in patients with cardiac manifestations of Chagas disease and cardioembolic ischemic stroke.

To describe anticoagulation characteristics in patients with cardiac complications from Chagas disease and compare participants with and without cardioembolic ischemic stroke (CIS). A retrospective cohort of patients with Chagas disease, using anticoagulation, conducted from January 2011 to December 2014. Forty-two patients with Chagas disease who were using anticoagulation were studied (age 62.9±12.4 years), 59.5% female and 47.6% with previous CIS, 78.6% with non-valvular atrial fibrillation and 69.7% with dilated cardiomyopathy. Warfarin was used in 78.6% of patients and dabigatran (at different times) in 38%. In the warfarin group, those with CIS had more medical appointments per person-years of follow-up (11.7 vs 7.9), a higher proportion of international normalized ratios within the therapeutic range (57% vs 42% medical appointments, p = 0.025) and an eight times higher frequency of minor bleeding (0.64 vs 0.07 medical appointments). Patients with Chagas disease and previous CIS had better control of INR with a higher frequency of minor bleeding.

Anticoagulation in patients with cardiac manifestations of Chagas disease and cardioembolic ischemic stroke / Anticoagulação nas manifestações cardíacas da doença de Chagas e acidente vascular cerebral isquêmico cardioembólico

ABSTRACT Objectives To describe anticoagulation characteristics in patients with cardiac complications from Chagas disease and compare participants with and without cardioembolic ischemic stroke (CIS). Methods A retrospective cohort of patients with Chagas disease, using anticoagulation, conducted from January 2011 to December 2014. Results Forty-two patients with Chagas disease who were using anticoagulation were studied (age 62.9±12.4 years), 59.5% female and 47.6% with previous CIS, 78.6% with non-valvular atrial fibrillation and 69.7% with dilated cardiomyopathy. Warfarin was used in 78.6% of patients and dabigatran (at different times) in 38%. In the warfarin group, those with CIS had more medical appointments per person-years of follow-up (11.7 vs 7.9), a higher proportion of international normalized ratios within the therapeutic range (57% vs 42% medical appointments, p = 0.025) and an eight times higher frequency of minor bleeding (0.64 vs 0.07 medical appointments). Conclusion Patients with Chagas disease and previous CIS had better control of INR with a higher frequency of minor bleeding.

RESUMO Objetivos descrever as características da anticoagulação em pacientes com manifestações cardíacas da doença de Chagas (MCDC) e comparar os participantes com sem acidente vascular cerebral isquêmico cardioembólico (AVCIC). Resultados 42 pacientes com MCDC em anticoagulação foram estudados (62,9 ± 12,4 anos), 59,5% do sexo feminino e 47,6% com AVCIC prévio, 78,6% portadores de fibrilação atrial não valvar e 69,7% com cardiomiopatia dilatada. Varfarina foi utilizada em 78,6% dos pacientes e dabigatrana em 38% (em momentos diferentes). No grupo da varfarina, aqueles com AVCIC tiveram mais consultas médicas por pessoas-ano de seguimento (11,7 vs 7,9), maior taxa de RNI na faixa terapêutica (57% vs 42% consultas médicas, p = 0,025) e uma frequência oito vezes maior de sangramento menor (0,64 vs. 0,07 consultas médicas). Conclusão pacientes com MCDC e AVCIC prévio têm melhor controle de RNI com maior frequência de sangramento menor.

Pain prevalence, characteristics and associated factors in human T-cell lymphotropic virus type 1 infected patients: a systematic review of the literature

ABSTRACT Objective: To describe the pain in patients infected with human T-cell lymphotropic virus type 1, clinically and epidemiologically. Methods: This systematic review was based on The PRISMA Statement. Four reviewers searched PUBMED, SciELO, LILACS and BIREME for data from observational studies and clinical trials (n ≥ 30) regarding pain prevalence, characteristics, and associated factors in patients with human T-cell lymphotropic virus type 1. No limits on publication date or language were established. Studies that did not have pain as an outcome measure or not involving human T-cell lymphotropic virus type 1 infected patients were excluded. Results: A total of 3013 articles (including duplicates) were found of which seven met the predetermined criteria. The most common pain region was the lower back (53.0%). Non-neuropathic type (ranging from 52.6% to 86.8%) was more frequent in human T-cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis participants, and neuropathic pain was more common in human T-cell lymphotropic virus type 1 carriers (53.1%). The pain was mostly reported as moderate or severe. One study showed that chronic pain was negatively associated with quality of life. Discussion: Pain is a common complaint in human T-cell lymphotropic virus type 1 infected patients, with lower back pain as the most frequent site. Pain can either be nociceptive, neuropathic, or both, is frequently severe, and negatively affects quality of life. Only studies of two countries were included in this review, limiting the external validity of the conclusions. The heterogeneity of variables prevented us from implementing a meta-analysis. Further research should better characterize the pain and explore its impact on quality of life, especially using longitudinal study design.

Pain prevalence, characteristics and associated factors in human T-cell lymphotropic virus type 1 infected patients: a systematic review of the literature.

OBJECTIVE: To describe the pain in patients infected with human T-cell lymphotropic virus type 1, clinically and epidemiologically. METHODS: This systematic review was based on The PRISMA Statement. Four reviewers searched PUBMED, SciELO, LILACS and BIREME for data from observational studies and clinical trials (n≥30) regarding pain prevalence, characteristics, and associated factors in patients with human T-cell lymphotropic virus type 1. No limits on publication date or language were established. Studies that did not have pain as an outcome measure or not involving human T-cell lymphotropic virus type 1 infected patients were excluded. RESULTS: A total of 3013 articles (including duplicates) were found of which seven met the predetermined criteria. The most common pain region was the lower back (53.0%). Non-neuropathic type (ranging from 52.6% to 86.8%) was more frequent in human T-cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis participants, and neuropathic pain was more common in human T-cell lymphotropic virus type 1 carriers (53.1%). The pain was mostly reported as moderate or severe. One study showed that chronic pain was negatively associated with quality of life. DISCUSSION: Pain is a common complaint in human T-cell lymphotropic virus type 1 infected patients, with lower back pain as the most frequent site. Pain can either be nociceptive, neuropathic, or both, is frequently severe, and negatively affects quality of life. Only studies of two countries were included in this review, limiting the external validity of the conclusions. The heterogeneity of variables prevented us from implementing a meta-analysis. Further research should better characterize the pain and explore its impact on quality of life, especially using longitudinal study design.

Meis1 coordinates a network of genes implicated in eye development and microphthalmia.

Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1(-/-) embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations.

Analysis of the DNA-binding profile and function of TALE homeoproteins reveals their specialization and specific interactions with Hox genes/proteins.

The interactions of Meis, Prep, and Pbx1 TALE homeoproteins with Hox proteins are essential for development and disease. Although Meis and Prep behave similarly in vitro, their in vivo activities remain largely unexplored. We show that Prep and Meis interact with largely independent sets of genomic sites and select different DNA-binding sequences, Prep associating mostly with promoters and housekeeping genes and Meis with promoter-remote regions and developmental genes. Hox target sequences associate strongly with Meis but not with Prep binding sites, while Pbx1 cooperates with both Prep and Meis. Accordingly, Meis1 shows strong genetic interaction with Pbx1 but not with Prep1. Meis1 and Prep1 nonetheless coregulate a subset of genes, predominantly through opposing effects. Notably, the TALE homeoprotein binding profile subdivides Hox clusters into two domains differentially regulated by Meis1 and Prep1. During evolution, Meis and Prep thus specialized their interactions but maintained significant regulatory coordination.

The KPG index--a novel 3D classification system for maxillary canine impactions.

INTRODUCTION: Advancements in Cone Beam Computed Tomography (CBCT) have improved localization of impacted canines. The KPG index is the first 3-D classification system for classifying the position of canines based on their distance from the norm (1). The aim of this study was to determine if this index provides an estimate of the time necessary to treat an impacted canine using closed eruption. MATERIALS AND METHODS: CBCT scans of 28 impacted canines at The University of Texas School of Dentistry at Houston Department of Orthodontics were classified using the KPG index. The scores and categories were compared to the time from surgical exposure to proper positioning. RESULTS: Four canines were classified as "Easy," 11 as "Moderate," 9 as "Difficult," and 4 as "Extremely Difficult." Average treatment times associated in months were: "Easy"--11.23, "Moderate"--11.36, "Difficult"--12.76, and "Extremely Difficult"--13.23. CONCLUSIONS: The KPG index currently cannot be confirmed as an accurate means of estimating treatment time for an impacted canine. Further verification studies should include larger sample sizes and compare differing mechanics. However, there are limitations to 2-D imaging; therefore, the 3-D CBCT images and the KPG index, with further validation, will become increasingly valuable to orthodontists.