RESUMEN
Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
Asunto(s)
Neoplasias Cerebelosas/metabolismo , Mutación de Línea Germinal , Meduloblastoma/metabolismo , Factores de Elongación Transcripcional/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Niño , Femenino , Humanos , Masculino , Meduloblastoma/genética , Linaje , ARN de Transferencia/metabolismo , Factores de Elongación Transcripcional/genéticaRESUMEN
Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
Asunto(s)
Genómica , Meduloblastoma/genética , Meduloblastoma/patología , Análisis de la Célula Individual , Transcriptoma , Adolescente , Adulto , Animales , Linaje de la Célula , Cerebelo/metabolismo , Cerebelo/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Ácido Glutámico/metabolismo , Humanos , Lactante , Meduloblastoma/clasificación , Ratones , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
Astrocytes that reside in superficial (SL) and deep cortical layers have distinct molecular profiles and morphologies, which may underlie specific functions. Here, we demonstrate that the production of SL and deep layer (DL) astrocyte populations from neural progenitor cells in the mouse is temporally regulated. Lineage tracking following in utero and postnatal electroporation with PiggyBac (PB) EGFP and birth dating with EdU and FlashTag, showed that apical progenitors produce astrocytes during late embryogenesis (E16.5) that are biased to the SL, while postnatally labeled (P0) astrocytes are biased to the DL. In contrast, astrocytes born during the predominantly neurogenic window (E14.5) showed a random distribution in the SL and DL. Of interest, E13.5 astrocytes birth dated at E13.5 with EdU showed a lower layer bias, while FT labeling of apical progenitors showed no bias. Finally, examination of the morphologies of "biased" E16.5- and P0-labeled astrocytes demonstrated that E16.5-labeled astrocytes exhibit different morphologies in different layers, while P0-labeled astrocytes do not. Differences based on time of birth are also observed in the molecular profiles of E16.5 versus P0-labeled astrocytes. Altogether, these results suggest that the morphological, molecular, and positional diversity of cortical astrocytes is related to their time of birth from ventricular/subventricular zone progenitors.
Asunto(s)
Astrocitos , Corteza Cerebral , Células-Madre Neurales , Animales , Astrocitos/metabolismo , Astrocitos/citología , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Ratones , Ratones Transgénicos , Femenino , Animales Recién Nacidos , Regulación del Desarrollo de la Expresión Génica , Transcriptoma , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ventrículos Cerebrales/citología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation. AIM: To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy. METHODS: The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted. RESULTS: From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis. CONCLUSION: HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population.
RESUMEN
Optimal dosing of valganciclovir (VGCV) for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation recipients (SOTR) is controversial. Dosing calculated based on body surface area (BSA) and creatinine clearance is recommended but simplified body weight (BW) dosing is often prescribed. We conducted a retrospective 6-center study to compare safety and efficacy of these strategies in the first-year posttransplant There were 100 (24.2%) pediatric SOTR treated with BSA and 312 (75.7%) with BW dosing. CMV DNAemia was documented in 31.0% vs 23.4% (P = .1) at any time during the first year and breakthrough DNAemia in 16% vs 12.2% (P = .3) of pediatric SOTR receiving BSA vs BW dosing, respectively. However, neutropenia (50% vs 29.3%, P <.001), lymphopenia (51% vs 15.0%, P <.001), and acute kidney injury causing treatment modification (8.0% vs 1.8%, P <.001) were documented more frequently during prophylaxis in pediatric SOTR receiving BSA vs BW dosing. The adjusted odds ratio of VGCV-attributed toxicities comparing BSA and BW dosing was 2.3 (95% confidence interval [CI], 1.4-3.7] for neutropenia, 7.0 (95% CI, 3.9-12.4) for lymphopenia, and 4.6 (95% CI, 2.2-9.3) for premature discontinuation or dose reduction of VGCV, respectively. Results demonstrate that BW dosing is associated with significantly less toxicity without any increase in CMV DNAemia.
Asunto(s)
Infecciones por Citomegalovirus , Linfopenia , Neutropenia , Trasplante de Órganos , Niño , Humanos , Valganciclovir/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/prevención & control , Superficie Corporal , Estudios Retrospectivos , Citomegalovirus , Neutropenia/etiología , Neutropenia/tratamiento farmacológico , Trasplante de Órganos/efectos adversos , Peso Corporal , Ganciclovir/uso terapéuticoRESUMEN
Favipiravir (FAV) has become a promising antiviral agent for the treatment of COVID-19. Herein, a green, fast, high-sample-throughput, non-instrumental, and affordable analytical method is proposed based on surfactant-assisted dispersive liquid-liquid microextraction (SA-DLLME) combined with thin-layer chromatography-digital image colourimetry (TLC-DIC) for determining favipiravir in biological and pharmaceutical samples. Triton X-100 and dichloromethane (DCM) were used as the disperser and extraction solvents, respectively. The extract obtained after DLLME procedure was spotted on a TLC plate and allowed to develop with a mobile phase of chloroform:methanol (8:2, v/v). The developed plate was photographed using a smartphone under UV irradiation at 254 nm. The quantification of FAV was performed by analysing the digital images' spots with open-source ImageJ software. Multivariate optimisation using Plackett-Burman design (PBD) and central composite design (CCD) was performed for the screening and optimisation of significant factors. Under the optimised conditions, the method was found to be linear, ranging from 5 to 100 µg/spot, with a correlation coefficient (R2) ranging from 0.991 to 0.994. The limit of detection (LOD) and limit of quantification (LOQ) were in the ranges of 1.2-1.5 µg/spot and 3.96-4.29 µg/spot, respectively. The developed approach was successfully applied for the determination of FAV in biological (i.e., human urine and plasma) and pharmaceutical samples. The results obtained using the proposed methodology were compared to those obtained using HPLC-UV analysis and found to be in close agreement with one another. Additionally, the green character of the developed method with previously reported protocols was evaluated using the ComplexGAPI, AGREE, and Eco-Scale greenness assessment tools. The proposed method is green in nature and does not require any sophisticated high-end analytical instruments, and it can therefore be routinely applied for the analysis of FAV in various resource-limited laboratories during the COVID-19 pandemic.
Asunto(s)
COVID-19 , Microextracción en Fase Líquida , Surfactantes Pulmonares , Humanos , Tensoactivos , Colorimetría , Cromatografía en Capa Delgada , Microextracción en Fase Líquida/métodos , Teléfono Inteligente , Pandemias , Solventes , Cromatografía Líquida de Alta Presión , Lipoproteínas , Preparaciones Farmacéuticas , Límite de DetecciónRESUMEN
OBJECTIVE: To identify subgroups likely to benefit from monoclonal antibody and antiviral therapy by evaluating the relationship between comorbidities and hospitalization among US adolescents with symptomatic coronavirus disease 2019 (COVID-19). STUDY DESIGN: We analyzed the relationship between presence of comorbidities and need for hospitalization within 28 days of COVID-19 diagnosis for adolescents aged 12-17 years listed in the Pediatric COVID-19 US registry, a multicenter retrospective cohort of US pediatric patients with COVID-19. Comorbidities assessed included obesity, chronic kidney disease (CKD), diabetes, immunosuppressive disease or treatment, sickle cell disease (SCD), heart disease, neurologic disease/neurodevelopmental disorders, and pulmonary disease (excluding patients with mild asthma). We used multivariable logistic regression to determine race/ethnicity-adjusted associations between comorbidities and hospitalization. RESULTS: A total of 1877 patients met our inclusion criteria, of whom 284 (15%) were hospitalized within 28 days of their COVID-19 diagnosis. In a race/ethnicity-adjusted model, the following comorbidities were independently associated with increased odds of hospitalization: SCD (aOR, 6.9; 95% CI, 3.0-15.9), immunocompromising condition (aOR, 6.4; 95% CI, 3.8-10.8), obesity (aOR, 3.2; 95% CI, 2.1-4.9), diabetes (aOR, 3.0; 95% CI, 1.4-6.2), neurologic disease (aOR, 2.8; 95% CI, 1.8-4.3), and pulmonary disease (excluding mild asthma) (aOR, 1.9; 95% CI, 1.2-3.1). Heart disease and CKD were not independently associated with hospitalization. CONCLUSIONS: SCD, immunocompromising conditions, obesity, diabetes, neurologic disease, and pulmonary disease (excluding mild asthma) were associated with hospitalization for symptomatic COVID-19. Adolescents with acute COVID-19 and these comorbidities should be prioritized for consideration of therapy to avert hospitalization.
Asunto(s)
Asma , COVID-19 , Diabetes Mellitus , Cardiopatías , Insuficiencia Renal Crónica , Adolescente , Asma/epidemiología , Asma/terapia , COVID-19/epidemiología , COVID-19/terapia , Prueba de COVID-19 , Niño , Comorbilidad , Diabetes Mellitus/epidemiología , Hospitalización , Humanos , Obesidad/epidemiología , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
Iridoid glycosides are monoterpenoids synthesized in several plant species known to exhibit a diverse range of pharmacological activities. They are used as important bioactive ingredients in many commercially available drug formulations and as lead compounds in pharmaceutical research. The genus Picrorhiza comprises two medicinally important herbs endemic to the Himalayan region viz. Picrorhiza kurrooa Royle and Picrorhiza scrophulariiflora Hong. The medicinal properties of these two species are mainly due to iridoid glycosides present in their root, rhizome, and leaves. Unregulated harvesting from the wild, habitat specificity, narrow distribution range, small population size and lack of organized cultivation led to the enrolling of these species in the endangered category by the International Union for Conservation of Nature and Natural Resources (IUCN). Therefore, there is a need for immediate biotechnological and molecular interventions. Such intercessions will open up new vistas for large-scale propagation, development of genomic/transcriptomic resources for understanding the biosynthetic pathway, the possibility of genetic/metabolic manipulations, and possible commercialization of iridoid glycosides. The current review article elucidates the phytochemistry and pharmacological importance of iridoid glycosides from the genus Picrorhiza. In addition, the role of biotechnological approaches and opportunities offered by next-generation sequencing technologies in overcoming challenges associated with the genetic engineering of these species are also discussed.
RESUMEN
Invasive aspergillosis (IA) remains a common cause of mortality in pediatric immunocompromised populations. Much of our knowledge of IA stems from adult literature. We conducted a retrospective evaluation of cases of proven or probable IA, defined according to the 2019 EORTC/MSG criteria, in patients with underlying immunocompromising conditions at Boston Children's Hospital from January 1, 2007 to January 1, 2019. We estimated survival curves over 12 weeks using the Kaplan-Meier method for all-cause mortality, and we used univariate Cox proportional hazards modeling to evaluate for mortality risk factors. We identified 59 cases, 29% with proven and 71% with probable IA. Pulmonary IA was the most common presentation (78%). The median age at diagnosis was 11 years (range, 0.5-28). Hematopoietic cell transplantation (HCT) was the most frequent predisposing underlying condition (41%). Among affected patients, 44.8% were neutropenic and 59.3% were lymphopenic at diagnosis. The 12-week all-cause mortality rate was 25.4%; HCT recipients comprised the majority of deaths (9/15) with a hazard ratio of 2.47 [95% CI, 0.87-6.95]. No patients with congenital immunodeficiencies (n = 8) died within 12 weeks of IA diagnosis. Other risk factors that were significantly associated with mortality included mechanical ventilation at diagnosis, intensive care unit stay, and lymphopenia; treatment with an Aspergillus-active azole was associated with decreased mortality.In conclusion, our study found that in pediatric immunocompromised hosts, IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the HCT population. LAY ABSTRACT: This study explores the epidemiology, outcomes and predictors of mortality of invasive aspergillosis (IA) at a high-volume pediatric center for immunocompromised hosts. Much of our understanding of pediatric IA is extrapolated from the adult literature. Our study found that IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the hematopoietic cell transplantation study cohort.
Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Animales , Aspergilosis/diagnóstico , Aspergilosis/veterinaria , Aspergillus , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/veterinaria , Estudios RetrospectivosRESUMEN
In this study, a bacterial carbonic anhydrase (CA) was purified from Corynebacterium flavescens for the CO2 conversion into CaCO3. The synthesized CaCO3 can be utilized in the papermaking industry as filler material, construction material and in steel industry. Herein, the CA was purified by using a Sephadex G-100 column chromatography having 29.00 kDa molecular mass in SDS-PAGE analysis. The purified CA showed an optimal temperature of 35 °C and pH 7.5. In addition, a kinetic study of CA using p-NPA as substrate showed Vmax (166.66 µmoL/mL/min), Km (5.12 mM), and Kcat (80.56 sec-1) using Lineweaver Burk plot. The major inhibitors of CA activity were Na2+, K+, Mn2+, and Al3+, whereas Zn2+ and Fe2+ slightly enhanced it. The purified CA showed a good efficacy to convert the CO2 into CaCO3 with a total conversion rate of 65.05 mg CaCO3/mg of protein. In silico analysis suggested that the purified CA has conserved Zn2+ coordinating residues such as His 111, His 113, and His 130 in the active site center. Further analysis of the CO2 binding site showed conserved residues such as Val 132, Val 142, Leu 196, Thr 197, and Val 205. However, a substitution has been observed where Trp 208 of its closest structural homolog T. ammonificans CA is replaced with Arg 207 of C. flavescens. The presence of a hydrophilic mutation in the CO2 binding hydrophobic region is a further subject of investigation.
Asunto(s)
Anhidrasas Carbónicas , Carbonato de Calcio , Dióxido de Carbono/química , Anhidrasas Carbónicas/química , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/metabolismo , Electroforesis en Gel de Poliacrilamida , TemperaturaRESUMEN
Biocatalytic conversion of greenhouse gases such as carbon dioxide into commercial products is one of the promising key approaches to solve the problem of climate change. Microbial enzymes, including carbonic anhydrase, NAD-dependent formate dehydrogenase, ribulose bisphosphate carboxylase, and methane monooxygenase, have been exploited to convert atmospheric gases into industrial products. Carbonic anhydrases are Zn2+-dependent metalloenzymes that catalyze the reversible conversion of CO2 into bicarbonate. They are widespread in bacteria, algae, plants, and higher organisms. In higher organisms, they regulate the physiological pH and contribute to CO2 transport in the blood. In plants, algae, and photosynthetic bacteria carbonic anhydrases are involved in photosynthesis. Converting CO2 into bicarbonate by carbonic anhydrases can solidify gaseous CO2, thereby reducing global warming due to the burning of fossil fuels. This review discusses the three-dimensional structures of carbonic anhydrases, their physiological role in marine life, their catalytic mechanism, the types of inhibitors, and their medicine and industry applications.
Asunto(s)
Anhidrasas Carbónicas , Dióxido de Carbono , Anhidrasas Carbónicas/química , Fotosíntesis , Plantas/metabolismo , Ribulosa-Bifosfato Carboxilasa/química , Ribulosa-Bifosfato Carboxilasa/metabolismoRESUMEN
Immobilized enzyme-based catalytic constructs could greatly improve various industrial processes due to their extraordinary catalytic activity and reaction specificity. In recent decades, nano-enzymes, defined as enzyme immobilized on nanomaterials, gained popularity for the enzymes' improved stability, reusability, and ease of separation from the biocatalytic process. Thus, enzymes can be strategically incorporated into nanostructured materials to engineer nano-enzymes, such as nanoporous particles, nanofibers, nanoflowers, nanogels, nanomembranes, metal-organic frameworks, multi-walled or single-walled carbon nanotubes, and nanoparticles with tuned shape and size. Surface-area-to-volume ratio, pore-volume, chemical compositions, electrical charge or conductivity of nanomaterials, protein charge, hydrophobicity, and amino acid composition on protein surface play fundamental roles in the nano-enzyme preparation and catalytic properties. With proper understanding, the optimization of the above-mentioned factors will lead to favorable micro-environments for biocatalysts of industrial relevance. Thus, the application of nano-enzymes promise to further strengthen the advances in catalysis, biotransformation, biosensing, and biomarker discovery. Herein, this review article spotlights recent progress in nano-enzyme development and their possible implementation in different areas, including biomedicine, biosensors, bioremediation of industrial pollutants, biofuel production, textile, leather, detergent, food industries and antifouling.
Asunto(s)
Nanoestructuras , Nanotubos de Carbono , Biocatálisis , Estabilidad de Enzimas , Enzimas Inmovilizadas/química , Nanoestructuras/químicaRESUMEN
A continuous increase in the amount of greenhouse gases (GHGs) is causing serious threats to the environment and life on the earth, and CO2 is one of the major candidates. Reducing the excess CO2 by converting into industrial products could be beneficial for the environment and also boost up industrial growth. In particular, the conversion of CO2 into methanol is very beneficial as it is cheaper to produce from biomass, less inflammable, and advantageous to many industries. Application of various plants, algae, and microbial enzymes to recycle the CO2 and using these enzymes separately along with CO2-phillic materials and chemicals can be a sustainable solution to reduce the global carbon footprint. Materials such as MOFs, porphyrins, and nanomaterials are also used widely for CO2 absorption and conversion into methanol. Thus, a combination of enzymes and materials which convert the CO2 into methanol could energize the CO2 utilization. The CO2 to methanol conversion utilizes carbon better than the conventional syngas and the reaction yields fewer by-products. The methanol produced can further be utilized as a clean-burning fuel, in pharmaceuticals, automobiles and as a general solvent in various industries etc. This makes methanol an ideal fuel in comparison to the conventional petroleum-based ones and it is advantageous for a safer and cleaner environment. In this review article, various aspects of the circular economy with the present scenario of environmental crisis will also be considered for large-scale sustainable biorefinery of methanol production from atmospheric CO2.
Asunto(s)
Dióxido de Carbono , Metanol , Biomasa , Carbono , CatálisisRESUMEN
AIM: To analyze the impact of implant angulation and implant number on the dimensional accuracy of definitive casts. MATERIALS AND METHODS: Seven definitive casts with implant analogs placed in a triangular pattern were made from dental stone. The groups were as follows: group 1 (control group) all implant analogs perpendicular to the plane of the cast; the center implant analog (implant 2) being at 90° to the plane of the cast in all groups and implant analogs number 1 and 3 arranged in 5°, 10°, or 15° divergence from or convergence to the center implant (implant number 2). Three open-tray impressions of definitive casts were made in each group. Impressions were poured in type IV dental stone. Coordinates in the three planes were measured at the implant analog top surface and the base of the cast using a fine tip measuring stylus. The data were aligned and the angular differences between implant analog vectors from definitive and duplicate casts were calculated in degrees. RESULTS: The impact of implant number on the dimensional accuracy of definitive casts was significant whereas for implant angulation it was nonsignificant. The correlation of angulation and the number of the implant did not show an interpretable pattern. The precision of duplicate casts (compared to definitive casts) is not affected by the combined interaction of implant number and implant angulation. CONCLUSION: The close proximity of implant angulation toward a right-angled direction results in higher precision of implant. In the impression, there is direct picking from the impression copings which decreases the discrepancies in implant angulation on impression and master cast. The interaction of implant angulation and the number shows a noninterpretable pattern. CLINICAL SIGNIFICANCE: Dimensionally accurate implant impressions can be made by using an open tray technique for three implants angled up to 15°.
Asunto(s)
Implantes Dentales , Técnica de Impresión Dental , Materiales de Impresión Dental , Modelos DentalesRESUMEN
Metagenomic next-generation sequencing (mNGS) of plasma cell-free DNA (cfDNA) is commercially available, but its role in the workup of infectious diseases is unclear. To understand the clinical utility of plasma mNGS, we retrospectively reviewed patients tested at a pediatric institution over 2 years to evaluate the clinical relevance of the organism(s) identified and the impact on antimicrobial management. We also investigated the effect of pretest antimicrobials and interpretation of molecules of microbial cfDNA per microliter (MPM) of plasma. Twenty-nine of 59 (49%) mNGS tests detected organism(s), and 28/51 (55%) organisms detected were clinically relevant. The median MPM of clinically relevant organisms was 1,533, versus 221 for irrelevant organisms (P = 0.01). mNGS test positive and negative percent agreements were 53% and 79%, respectively, and 50% of negative mNGS tests were true negatives. Fourteen percent of tests impacted clinical management by changing antimicrobial therapy. Immunocompromised status was the only patient characteristic that trended toward a significant clinical impact (P = 0.056). No patients with culture-negative endocarditis had organisms identified by mNGS. There were no significant differences in antimicrobial duration retest between tests with clinically relevant organism(s) and those that returned negative, nor were the MPMs different between pretreated and untreated organisms, suggesting that 10 days of antimicrobial therapy as observed in this cohort did not sterilize testing; however, no pretreated organisms identified resulted in a new diagnosis impacting clinical management. Plasma mNGS demonstrated higher utility for immunocompromised patients, but given the detection of many clinically irrelevant organisms (45%), cautious interpretation and infectious diseases consultation are prudent.
Asunto(s)
Hospitales Pediátricos , Metagenómica , Niño , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
PURPOSE OF REVIEW: Immunocompromised children are a largely under-vaccinated population and are vulnerable to acquiring vaccine-preventable infections (VPIs). A variety of factors contribute to poor vaccine coverage including: severity of underlying illness, sporadic contact with primary care physicians, and lack of awareness among specialty providers regarding vaccination status. In this review, we report recent data regarding incidence of VPIs, new approaches to vaccine use, rates of vaccine coverage, and strategies to optimize vaccine administration in immunocompromised populations. RECENT FINDINGS: Pediatric transplant recipients and patients with autoimmune disorders receiving novel biological therapies, represent growing immunocompromised patient populations. VPIs continue to be a concern for such patients. Underlying disease severity may limit efforts to immunize pediatric patients early in their disease process, prior to immunosuppression. Inactive vaccines are safe and immunogenic after the introduction of immunosuppression, but live vaccines are typically contraindicated. Emerging data support the safety and effectiveness of live vaccines in certain immunocompromised individuals. Care providers must remain vigilant in maintaining patients' vaccination status based on current vaccination guidelines, and create a multidisciplinary approach to optimizing vaccination. SUMMARY: Immunocompromised children remain under-vaccinated and vulnerable to VPIs. Optimizing vaccines should be a priority for every provider caring for this population.
Asunto(s)
Control de Enfermedades Transmisibles/métodos , Enfermedades Transmisibles/terapia , Promoción de la Salud , Huésped Inmunocomprometido/inmunología , Vacunación/estadística & datos numéricos , Vacunas/uso terapéutico , Niño , Control de Enfermedades Transmisibles/estadística & datos numéricos , Enfermedades Transmisibles/transmisión , Promoción de la Salud/estadística & datos numéricos , Humanos , Incidencia , Guías de Práctica Clínica como Asunto , Vacunación/tendencias , Cobertura de Vacunación/estadística & datos numéricosRESUMEN
A 20-year-old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination. Lumbar puncture was initially non-diagnostic and a broad infectious workup was unrevealing. Three months after presentation, a repeat LP detected JC virus for which tests had not earlier been conducted. He continued to deteriorate despite withdrawal of prior immunosuppression and addition of mirtazapine, maraviroc, and steroids. He died of progressive neurologic decompensation 5 months after his initial presentation. This case highlights progressive multifocal leukoencephalopathy (PML) as a rare complication after solid organ transplantation and acute sensorineural hearing loss as an unusual first presenting symptom of PML. JC virus should be considered in the differential diagnosis of acute sensorineural hearing loss in any immunocompromised patient.
Asunto(s)
Pérdida Auditiva Sensorineural/etiología , Intestinos/trasplante , Leucoencefalopatía Multifocal Progresiva/etiología , Trasplante de Órganos/efectos adversos , Resultado Fatal , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/virología , Humanos , Virus JC , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Leucoencefalopatía Multifocal Progresiva/virología , Imagen por Resonancia Magnética , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/diagnóstico , Adulto JovenRESUMEN
In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.
Asunto(s)
Neoplasias Cerebelosas/clasificación , Meduloblastoma/clasificación , Adolescente , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Niño , Preescolar , Metilación de ADN , ADN de Neoplasias/genética , Femenino , Perfilación de la Expresión Génica , Genes myc , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Meduloblastoma/genética , Meduloblastoma/mortalidad , Meduloblastoma/patología , TranscriptomaRESUMEN
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Human T-cell lymphotrophic virus 1 (HTLV)-1 in the pre- and post-transplant period. HTLV-1 is an oncogenic human retrovirus rare in North America but endemic in the Caribbean and parts of Africa, South America, Asia, and Oceania. While most infected persons do not develop disease, <5% will develop adult T-cell leukemia/lymphoma or neurological disease. No proven antiviral treatment for established HTLV-1 infection is available. The effect of immunosuppression on the development of HTLV-1-associated disease in asymptomatically infected recipients is not well characterized, and HTLV-1-infected individuals should be counseled that immunosuppression may increase the risk of developing HTLV-1-associated disease and they should be monitored post-transplant for HTLV-1-associated disease. Currently approved screening assays do not distinguish between HTLV-1 and HTLV-2, and routine screening of deceased donors without risk factors in low seroprevalence areas is likely to result in significant organ wastage and is not recommended. Targeted screening of donors with risk factors for HTLV-1 infection and of living donors (as time is available to perform confirmatory tests) is reasonable.
Asunto(s)
Antivirales/uso terapéutico , Selección de Donante/normas , Infecciones por HTLV-I/diagnóstico , Infecciones por HTLV-I/tratamiento farmacológico , Trasplante de Órganos/efectos adversos , Guías de Práctica Clínica como Asunto/normas , Donantes de Tejidos/provisión & distribución , Infecciones por HTLV-I/etiología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Sociedades Médicas , Receptores de TrasplantesRESUMEN
End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.