Κυριακή 20 Νοεμβρίου 2022

Inverted repeats in the monkeypox virus genome are hot spots for mutation

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Abstract

The current monkeypox virus (MPXV) strain differs from the strain arising in 2018 by 50+ single nucleotide polymorphisms (SNPs) and is mutating much faster than expected. The cytidine deaminase apolipoprotein B mRNA editing enzyme, catalytic subunit B (APOBEC3) was hypothesised to be driving this increased mutation. APOBEC has recently been identified to preferentially mutate cruciform DNA secondary structures formed by inverted repeats (IRs). IRs were recently identified as hot spots for mutation in SARS-CoV-2, and we aimed to identify whether IRs were also hot spots for mutation within MPXV genomes. We found that MPXV genomes were replete with IR sequences. Of the 50+ SNPs identified in the 2022 outbreak strain, 63.9% of these were found to have arisen within IR regions in the 2018 reference strain (MT903344.1). Notably, IR sequences found in the 2018 reference strain were significantly lost over time, with an average of 32.5% of these sequences being cons erved in the 2022 MPXV genomes. This evidence was highly indicative that mutations were arising within IRs. This data provides further support to the hypothesis that APOBEC may be driving MPXV mutation and highlights the necessity for greater surveillance of IRs of MPXV genomes to detect new mutations.

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Παρασκευή 18 Νοεμβρίου 2022

Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation

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Abstract

Background

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies.

Procedure

We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose—busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor t herapies.

Results

With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II–IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025).

Conclusions

Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

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Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration

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Abstract

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

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The Effect of Hyperosmolar Water-Soluble Contrast for the Management of Adhesive Small Bowel Obstruction: A Systematic Review and Meta-Analysis

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imageObjective: To better understand the efficacy of water-soluble contrast (WSC) in the treatment of adhesive small bowel obstruction (SBO). Background: Guidelines recommend using WSC to treat adhesive SBO nonoperatively by acting as a cathartic agent. The evidence supporting this practice is mixed. Methods: A systematic review and meta-analysis of published articles describing the effect of WSC compared with control treatments was performed for the period of January 1, 1990 to November 1, 2021. Study quality was assessed using the Cochrane risk-of-bias and the Newcastle-Ottawa tools. The therapeutic effect of WSC was assessed by operative rates and hospital length of stay (HLOS) in nonsurgical patients. Results: The initial search yielded 4879 articles, of which, 28 were selected for full text review. We identified 11 eligible randomized controlled trials (RCTs) which included 817 patients and 9 observational studies of 3944 patients. HLOS in nonsurgical patients decreased by 1.95 days (95% confidence interval: 0.56–3.3) in the RCTs and could not be assessed in the observational studies. WSC did not significantly affect operative rates in the RCTs (19.8% vs. 21.4%) but did reduce rates in the observational studies (11% vs. 16%, risk ratio: 0.56, 95% confidence interval: 0.39–0.82). Conclusion: WSC studies may reduce HLOS for patients who have SBO and do not require surgery. However, the current literature is heterogenous with considerable design limitations. High-quality RCTs are needed using standardized protocols to determine the full benefit of WSC for the management of SBO.
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Πέμπτη 17 Νοεμβρίου 2022

Qué es el bocio amiloide y otras causas inusuales

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¿Qué es el bocio y cuál es su relevancia?

El bocio es el aumento de tamaño de la glándula tiroides, detectable a simple vista, por palpación o por pruebas de imagen. Cuando es visible en forma de bulto en la cara anterior del cuello, una característica del mismo es que el bulto sube y baja al tragar.

La relevancia del bocio es, en primer lugar, llamar la atención hacia el tiroides, su posible disfunción y las causas que lo originan. En segundo lugar, el aumento de tamaño per se puede ser un problema si provoca compresión de las estructuras vecinas (dificultad al tragar si comprime el esófago (disfagia), dificultad al respirar si comprime la tráquea (disnea), alteración de la voz si comprime el nervio recurrente que inerva las cuerdas vocales (disfonía).

Cuando el bocio ocasiona síntomas compresivos, es necesario tratarlos y habitualmente el tratamiento es quirúrgico.

¿Qué puede provocar bocio?

Las causas más frecuentes de bocio son las que se acompañan de disfunción del tiroides (hipo o hipertiroidismo) y aquellas en que el organismo aumenta el tamaño del tiroides para prevenirla (por ejemplo, en caso de falta de yodo o de autoinmunidad tiroidea). A nivel mundial, la deficiencia de yodo es la causa más frecuente.

Otras posibles causas son los nódulos tiroideos (quistes o tumores) y las infecciones e inflamaciones de la glándula. Cuando el bocio incluye nódulos se denomina bocio nodular.

Otro grupo de posibles causas son las infiltrativas/por depósito, muy infrecuentes pero diversas (sustancia amiloide, sarcoidosis, lipomatosis). La sustancia amiloide es un material formado por componentes proteicos que se pliegan anormalmente de una manera determinada. Se puede producir por acúmulo de sustancia amiloide de origen genético (amiloidosis primaria), por consecuencia de una infección o inflamación en el organismo de larga duración (por ejemplo, broquiectasias o artritis reumatoide, amiloidosis secundaria) o en ocasiones acompañando a un tumor. El bocio amiloide puede acompañarse de crecimiento rápido del tiroides y hay que sospechar la posibilidad de este diagnóstico cuando un bocio de crecimiento rápido se presenta en un paciente que tiene una enfermedad que lo puede originar.

La sustancia amiloide se puede apreciar por análisis microscópico del material de punción-aspiración con aguja fina, pero el diagnóstico definitivo de bocio amiloide se realiza tras cirugía y examen anatomopatológico. La cirugía supone también el tratamiento.

  • El bocio amiloide es el aumento de tamaño de la glándula tiroidea por acumulación de sustancia amiloide (fragmentos de proteína plegados de manera característica).
  • Se da por causas genéticas (amiloidosis primaria) o como consecuencia de infecciones o enfermedades inflamatorias de larga duración (amiloidosis secundaria).
  • Puede originar crecimiento rápido del tiroides y la cirugía proporciona confirmación diagnóstica y tratamiento.

Si te ha gustado este artículo, quizá te interese leer:

La entrada Qué es el bocio amiloide y otras causas inusuales se publicó primero en Cuida tu tiroides.

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Post‐operative survival in head & neck cancer patients with elevated troponins

alexandrossfakianakis shared this article with you from Inoreader

Abstract

Objective

The strenuous demands of head and neck cancer surgery (HNS) place patients at increased risk of myocardial injury. Troponin positivity (TP) post-operatively is a predictor of increased complications and mortality. The present study is the first to investigate the effects of TP on potential delays in adjuvant treatment and disease-specific survival.

Methods

All patients undergoing HNS from 2014 to 2016 had troponins measured at a single academic center. Relevant patient data was extracted on retrospective chart review.

Results

Of 166 patients, 26 (15.6%) developed TP post-operatively. There was no significant difference between cohorts for baseline characteristics except for age. Overall and disease-specific survival for TP patients were respectively 45.9% and 57.4% at 3 years. There was no significant difference between cohorts for overall & disease-specific survival, and time to adjuvant therapy.

Conclusion

No significant association was found between TP and overall & disease-specific survival, and time to adjuvant therapy.

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Oncologic Outcomes After Clinically Node-Negative Salvage Laryngectomy

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This cohort study investigates the association of elective nec k dissection vs observation with oncologic outcomes among patients who received clinically node-negative salvage total laryngectomy.
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