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Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months. Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development. What is Known: ⢠There is increasing evidence of heterogeneity among the SMA newborns identified via NBS. ⢠The proposed nosology describes a clinically silent disease, an intermediate category ('paucisymptomatic') and 'symptomatic SMA'. What is New: ⢠The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay. ⢠The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.
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Tamizaje Neonatal , Examen Neurológico , Humanos , Tamizaje Neonatal/métodos , Recién Nacido , Femenino , Masculino , Examen Neurológico/métodos , Lactante , Estudios Prospectivos , Estudios de Seguimiento , Preescolar , Desarrollo Infantil/fisiologíaRESUMEN
Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic-dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.
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Cardiomiopatías , Dinaminas , Mutación , Humanos , Femenino , Dinaminas/genética , Cardiomiopatías/genética , Mutación/genética , Lactante , Resultado Fatal , Encefalopatías/genética , Encefalopatías/patología , GTP Fosfohidrolasas/genéticaRESUMEN
BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Niño , Lactante , Humanos , Recién Nacido , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Estudios de Seguimiento , Oligonucleótidos/uso terapéutico , Examen Neurológico , Atrofia Muscular Espinal/tratamiento farmacológicoRESUMEN
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new member of the Betacoronaviridae family, responsible for the recent pandemic outbreak of COVID-19. To start exploring the molecular events that follow host cell infection, we queried VirusCircBase and identified a circular RNA (circRNA) predicted to be synthesized by SARS-CoV-2, circ_3205, which we used to probe: (i) a training cohort comprised of two pools of cells from three nasopharyngeal swabs of SARS-CoV-2 infected (positive) or uninfected (negative, UCs) individuals; (ii) a validation cohort made up of 12 positive and 3 negative samples. The expression of circRNAs, miRNAs and miRNA targets was assayed through real-time PCR. CircRNA-miRNA interactions were predicted by TarpMiR, Analysis of Common Targets for circular RNAs (ACT), and STarMir tools. Enrichment of the biological processes and the list of predicted miRNA targets were retrieved from DIANA miRPath v3.0. Our results showed that the predicted SARS-CoV-2 circ_3205 was expressed only in positive samples and its amount positively correlated with that of SARS-CoV-2 Spike (S) mRNA and the viral load (r values = 0.80952 and 0.84867, Spearman's correlation test, respectively). Human (hsa) miR-298 was predicted to interact with circ_3205 by all three predictive tools. KCNMB4 and PRKCE were predicted as hsa-miR-298 targets. Interestingly, the function of both is correlated with blood coagulation and immune response. KCNMB4 and PRKCE mRNAs were upregulated in positive samples as compared to UCs (6 and 8.1-fold, p values = 0.049 and 0.02, Student's t test, respectively) and their expression positively correlated with that of circ_3205 (r values = 0.6 and 0.25, Spearman's correlation test, respectively). We propose that our results convincingly suggest that circ_3205 is a circRNA synthesized by SARS-CoV-2 upon host cell infection and that it may behave as a competitive endogenous RNA (ceRNA), sponging hsa-miR-298 and contributing to the upregulation of KCNMB4 and PRKCE mRNAs.
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COVID-19/genética , COVID-19/metabolismo , ARN Circular/genética , ARN Viral , SARS-CoV-2/genética , Biología Computacional , Regulación Viral de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Subunidades beta de los Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , MicroARNs/genética , MicroARNs/metabolismo , Nasofaringe/virología , Proteínas del Tejido Nervioso/genética , Mapeo de Interacción de Proteínas , Proteína Quinasa C-epsilon/genética , Reproducibilidad de los ResultadosRESUMEN
The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs. CONCLUSIONS: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients. WHAT IS KNOWN: ⢠The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease. ⢠The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period. WHAT IS NEW: ⢠Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening and may help to predict the individual therapeutic outcome of these patients. ⢠Iinfants with 2 SMN2 copies identified through the screening had a more variable neonatal examination compared to those with three or more copies, in agreement with similar findings in older infants.
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Atrofia Muscular Espinal , Tamizaje Neonatal , Anciano , Humanos , Lactante , Recién Nacido , Atrofia Muscular Espinal/diagnóstico , Tamizaje Neonatal/métodos , Examen Neurológico , Proyectos PilotoRESUMEN
The study aimed to evaluate oxytocin (Oxt) serum levels before and after sexual intercourse in women affected by anorgasmia. The sample was constituted of 15 anorgasmic women and 16 orgasmic women. The Female Sexual Function Index (FSFI, cutoff ≤26.55) and the Female Sexual Distress Scale (FSDS, cutoff ≥15) questionnaires were used to assess sexual function and sexual distress, respectively. Serum Oxt levels were measured before sexual intercourse (T0) and 5 min after coital sexual activity (T1). Anorgasmic women had an unpleasant sexual experience (FSFI total score, 20.1 ± 1.2;) and were stressed (FSDS score, 19.4 ± 1.3), whereas orgasmic women were fully satisfied with their sexual activity (FSFI total score 28.7 ± 1.3; FSDS score 11.5 ± 1.8). At T0, anorgasmic women had lower levels of Oxt than orgasmic women, 1.8 ± 0.2 pg/mL versus 2.1 ± 0.5 pg/mL, respectively, [95% CI: (-0.58, -0.01); p < .04]. At T1, Oxt levels did not change in anorgasmic women (1.8 ± 0.2 pg/mL versus 2 ± 0.4 pg/mL, p = .09). Finally, orgasmic women had higher levels of Oxt than anorgasmic women, 4.6 ± 0.7 pg/mL versus 2 ± 0.4 pg/mL, respectively [95% CI: (-3.02, -2.17); p < .001]. The repetitive processes to experience the sexual body sensations could represent a survival behavior of species by attachment to a partner.
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Coito/fisiología , Orgasmo/fisiología , Oxitocina/sangre , Disfunciones Sexuales Fisiológicas/sangre , Adulto , Femenino , Humanos , Satisfacción Personal , Prolactina/sangre , Estudios Prospectivos , Conducta Sexual/fisiología , Encuestas y CuestionariosRESUMEN
OBJECTIVE: The aim of this study was to assess early language acquisitions in treated individuals with spinal muscular atrophy (SMA) type 1 and in infants identified by newborn screening (NBS). METHODS: Parents of SMA individuals aged between 8 and 36 months were asked to fill in the MacArthur-Bates Communicative Development Inventory (MB-CDI) that assesses comprehension, gesture and expressive skills. A follow-up assessment was performed in 21 of the 36. RESULTS: The MB-CDI was completed by parents of 24 type 1 and 12 infants identified by NBS. Comprehension skills were preserved in 81% of the type 1 SMA and in 87% infants identified by NBS. Gesture abilities were <5th centile in 55% of the type 1 SMA and in none of those identified by NBS. Lexical expressions were <5th centile in more than 80% type 1 SMA and in 50% of infants identified by NBS. At follow-up, despite an increase in lexical expression skills, the scores remained below the fifth centile in 43% type 1 SMA and in 86% of infants identified by NBS. CONCLUSIONS: These results suggest that language and communication development may follow a similar pattern to that observed in motor function with the possibility to develop skills (eg, ability to say clear words) that are not usually present in untreated infants but with a level of performance that does not reach that of their typically developing peers.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Recién Nacido , Lactante , Humanos , Preescolar , Estudios de Cohortes , Atrofia Muscular Espinal/diagnóstico , Atrofias Musculares Espinales de la Infancia/diagnóstico , Desarrollo del Lenguaje , GestosRESUMEN
A viral etiology of sudden hearing loss has been hypothesized by many authors. HSV1 neurotropism and its involvement in sudden hearing loss has implicated HSV1 as one of the most accredited etiological agents. A non-invasive method such as the titration of HSV1-specific IgA was evaluated to determine the role of HSV1 as a possible cause sudden hearing loss. A prospective study was carried out by titration of serum IgA to HSV1 in 93 patients and in a control group of 50 healthy subjects and 35 subjects suffering from recent herpes labialis reactivation. Statistical analysis of the results disclosed that IgA titers to HSV1 higher than 1:80 are suggestive for the association of HSV1 infection and sudden hearing loss. Moreover, acyclovir therapy was effective in 81% of patients who showed high specific IgA titers. Overall, the titration of specific serum IgA to HSV1 can be a useful tool to determine the viral etiology of certain cases of sudden hearing loss. This method is simple to perform and minimally invasive. It can lead to a rapid presumptive diagnosis and to prompt specific therapy, reducing the need for corticosteroids.
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Antivirales/uso terapéutico , Pérdida Auditiva Sensorineural/virología , Pérdida Auditiva Súbita/virología , Inmunoglobulina A/sangre , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Femenino , Técnica del Anticuerpo Fluorescente , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Súbita/diagnóstico , Pérdida Auditiva Súbita/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 1/patogenicidad , Humanos , Inmunoglobulina A/inmunología , Masculino , Adulto JovenRESUMEN
Isavuconazole is a new broad-spectrum triazole, with significant in vitro activity against yeasts. Isavuconazole in vitro susceptibility can be evaluated through broth microdilution as a reference method. Considering difficulties in equipping such methods in a laboratory routine, a commercial MIC Strip test has been designed. This study aims to implement data about isavuconazole in vitro activity and compare EUCAST broth microdilution and MIC Strip test in defining yeast isavuconazole susceptibility. The study involved 629 isolates from positive blood cultures (January 2017-December 2021). The identified species were C. albicans (283), C. glabrata (53), C. krusei (23), C. tropicalis (68), C. parapsilosis complex (151), C. guilliermondii (12), C. famata (6), S. cerevisiae (12), C. neoformans (5), S. capitata (12), and Rhodotorula species (4). All the isolates were tested with EUCAST microdilution and MIC Strip methods. The total essential agreement between these two methods was 99.3%. As a result, we can consider that both methods are useful in testing isavuconazole susceptibility. Proposed cut-off values (P-ECOFF) were calculated using ECOFFinder software. Further studies could lead to either definitive E-COFF or clinical breakpoints, which represent the most important categorization tool of the laboratory data, allowing a better insertion of an antimicrobial drug in clinical practice.
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The increasing pressure to include non ambulant Duchenne muscular dystrophy (DMD) boys in clinical trials has highlighted the need for outcome measures that could address the impact of upper limb function on activities of daily living. The aim of the present study was to establish the correlation between the recently developed Patient Reported Outcome Measure for the upper limb (PROM UL) and the observer rated functional scale Performance of Upper Limb (PUL 2.0) in a large cohort of DMD boys and young adults. As part of a larger natural history study, non ambulant DMD patients were assessed using PUL2.0 and PROM UL. One hundred and twenty-five concurrent PUL 2.0 and PROM UL evaluations from 60 non ambulant DMD boys were taken into consideration. The total PROM UL scores showed a strong correlation with both PUL 2.0 total scores and with PUL 2.0 entry item score. The strong correlation between the two tools confirms the clinical meaningfulness of the PUL2.0 and that the PROM UL can help to detect the gradient of progression of upper limb involvement.
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Actividades Cotidianas , Distrofia Muscular de Duchenne , Masculino , Adulto Joven , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Medición de Resultados Informados por el Paciente , Extremidad SuperiorRESUMEN
Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None.
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The recent development of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify clinical outcome measures for planned efficacy studies. Although several studies have reported the value of functional scales, timed tests, and measures of endurance aimed at ambulant individuals, less has been done to identify reliable measures of function in individuals who have lost ambulation. The aim of this paper is to provide a critical review of the existing literature on functional measures assessing upper extremity function in DMD. Four observer-rated, performance-based measures and four self-reported scales have been previously used in DMD. Each scale provides useful information but none reflects all the different levels of functional ability in activities of daily living observed in individuals with DMD at different ages.
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Actividades Cotidianas/clasificación , Evaluación de la Discapacidad , Trastornos de la Destreza Motora/diagnóstico , Distrofia Muscular de Duchenne/diagnóstico , Trastornos Psicomotores/diagnóstico , Niño , Humanos , Trastornos de la Destreza Motora/rehabilitación , Distrofia Muscular de Duchenne/rehabilitación , Evaluación de Resultado en la Atención de Salud , Trastornos Psicomotores/rehabilitación , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The SARS-CoV-2 virus has assumed considerable importance during the COVID-19 pandemic. Its mutation rate is high, involving the spike (S) gene and thus there has been a rapid spread of new variants. Herein, we describe a rapid, easy, adaptable, and affordable workflow to uniquely identify all currently known variants through as few analyses. Our method only requires two conventional PCRs of the S gene and two Sanger sequencing reactions, and possibly another PCR/sequencing assay on a N gene portion to identify the B.1.160 lineage. METHODS: We selected an S gene 1312 bp portion containing a set of SNPs useful for discriminating all variants. Mathematical, statistical, and bioinformatic analyses demonstrated that our choice allowed us to identify all variants even without looking for all related mutations, as some of them are shared by different variants (e.g., N501Y is found in the Alpha, Beta, and Gamma variants) whereas others, that are more informative, are unique (e.g., A57 distinctive to the Alpha variant). RESULTS: A "weight" could be assigned to each mutation that may be present in the selected portion of the S gene. The method's robustness was confirmed by analyzing 80 SARS-CoV-2-positive samples. CONCLUSIONS: Our workflow identified the variants without the need for whole-genome sequencing and with greater reliability than with commercial kits.
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Técnicas de Laboratorio Clínico/métodos , Polimorfismo de Nucleótido Simple , SARS-CoV-2/genética , COVID-19/virología , Biología Computacional , Proteínas de la Nucleocápside de Coronavirus/genética , Genotipo , Humanos , Mutación , Fosfoproteínas/genética , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , SARS-CoV-2/aislamiento & purificación , Análisis de Secuencia de ADN , Glicoproteína de la Espiga del Coronavirus/genética , Flujo de TrabajoRESUMEN
INTRODUCTION: The aim of the study was to longitudinally assess swallowing abilities in nusinersen-treated patients with type 1 spinal muscular atrophy. METHODS: Twenty infants with type 1 SMA (11 female and 9 male) treated with nusinersen between 3 weeks and 15 months of age, were assessed using the Oral and Swallowing Abilities Tool (OrSAT). The duration of the follow-up after treatment ranged between 12 months and 62 months. RESULTS: Twelve of the 20 infants had normal swallowing and there was no need for tube feeding at the time treatment started. Ten of the 12 had consistently normal swallowing with no need for tube feeding on follow-up. The other two required tube feeding but they regained the ability to eat some food by mouth.The remaining 8 infants already had tube feeding inserted at the time treatment started: 4 of them also had tracheostomy and they showed no changes on the OrSAT Scale. The other 4 who had tube feeding but no tracheostomy had partial functional improvement. CONCLUSION: Our results suggest that the degree of functional impairment at the time treatment is started can help to predict the progression of swallowing abilities. The use of a structured assessment also helped to detect partial improvements.
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The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.
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Atrofia Muscular Espinal , Estudios de Cohortes , Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/farmacología , Oligonucleótidos/uso terapéutico , Extremidad SuperiorRESUMEN
Treatment of myocarditis and pericarditis can differ on the basis of aetiology: systemic or auto-immune disease can be positively influenced by corticoid therapy, whereas this kind of treatment can worsen the course of virus-induced disease. Therefore, the aetiological diagnosis is extremely important. The synergistic use of minimally invasive serological, IgG, IgM, IgA, and neutralizing titres, and RNA detection was evaluated on representative patients out of 238 suffering from cardiopathies. The results obtained for each case can yield reliable guidelines that rapidly highlight the presence of a viral aetiology so that an endomyocardial biopsy can be performed thus eliminating incorrect therapies. Thus, not only is this technique rapid, minimally invasive providing the clinician with decisive data, but it is cost effective for the health system.
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Infecciones por Enterovirus/diagnóstico , Miocarditis/virología , Pericarditis/virología , Adulto , Línea Celular , Niño , Infecciones por Enterovirus/virología , Femenino , Técnica del Anticuerpo Fluorescente , Cardiopatías/virología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We describe the development of a new tool specifically designed to record oral abilities, swallowing and, more generally, feeding in young type 1 SMA patients, to be used during the first 24 months of life.The tool is composed by a checklist and a separate section summarizing the functional abilities into levels of feeding/swallowing impairment. The checklist includes 12 questions assessing aspects thought to be clinically meaningful for a type 1 SMA population and developmentally appropriate for infants during the first months of life. Each item is graded with a score of 0 or 1, depending on the child's ability to perform the activity. As some items are age-dependent, the number of items to be used, and therefore the maximum score, changes with increasing age. The levels of feeding/swallowing impairment include four levels that can be identified using easily identifiable clinical criteria.In an attempt to validate the tool in an untreated population we applied it to 24 type 1 SMA patients (age range: 2.3-24.1 months, mean: 10.8) in whom the same information collected by the new tool had been previously recorded using a less-structured format.When patients were classified in three groups according to the Dubowitz decimal classification, there was a significant difference both at baseline and at follow-up (pâ<â0.001). The items assessing fatigue during the nursing sessions were the most frequently impaired even in infants who did not have any other obvious clinical sign of swallowing difficulties.
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Trastornos de Deglución/diagnóstico , Atrofias Musculares Espinales de la Infancia/complicaciones , Actividades Cotidianas , Deglución , Trastornos de Deglución/complicaciones , Fatiga/diagnóstico , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Encuestas y CuestionariosRESUMEN
OBJECTIVE: The aim of this paper was to report the 2-year follow-up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. METHODS: Sixty-eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE-2) at the time they started treatment and 12 and 24 months after that. RESULTS: For both CHOP and HINE-2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24-month scores for the whole group. When age subgroups (<210 days, <2 years, 2-4 years, 5-11 years, 12-18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE-2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not. INTERPRETATION: Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.
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Oligonucleótidos/farmacología , Evaluación de Resultado en la Atención de Salud , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Atrofias Musculares Espinales de la Infancia/fisiopatología , Adolescente , Niño , Preescolar , Estudios de Seguimiento , Humanos , Lactante , Índice de Severidad de la Enfermedad , Atrofias Musculares Espinales de la Infancia/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has posed a serious threat to global health. As no specific therapeutics are yet available to control disease evolution, more in-depth understanding of the pathogenic mechanisms induced by SARS-CoV-2 will help to characterize new targets for the management of COVID-19. The present study identified a specific set of biological pathways altered in primary human lung epithelium upon SARS-CoV-2 infection, and a comparison with SARS-CoV from the 2003 pandemic was studied. The transcriptomic profiles were also exploited as possible novel therapeutic targets, and anti-signature perturbation analysis predicted potential drugs to control disease progression. Among them, Mitogen-activated protein kinase kinase (MEK), serine-threonine kinase (AKT), mammalian target of rapamycin (mTOR) and I kappa B Kinase (IKK) inhibitors emerged as candidate drugs. Finally, sex-specific differences that may underlie the higher COVID-19 mortality in men are proposed.
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Infecciones por Coronavirus/genética , Infecciones por Coronavirus/mortalidad , Neumonía Viral/genética , Neumonía Viral/mortalidad , Factores Sexuales , Betacoronavirus , COVID-19 , Células Cultivadas , Infecciones por Coronavirus/patología , Descubrimiento de Drogas , Células Epiteliales/virología , Femenino , Humanos , Pulmón/citología , Masculino , Pandemias , Neumonía Viral/patología , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave , Serina-Treonina Quinasas TOR , TranscriptomaRESUMEN
Reverse transcriptionquantitative polymerase chain reaction (RTqPCR) is the gold standard method for the diagnosis of COVID19 infection. Due to preanalytical and technical limitations, samples with low viral load are often misdiagnosed as falsenegative samples. Therefore, it is important to evaluate other strategies able to overcome the limits of RTqPCR. Blinded swab samples from two individuals diagnosed positive and negative for COVID19 were analyzed by droplet digital PCR (ddPCR) and RTqPCR in order to assess the sensitivity of both methods. Intercalation chemistries and a World Health Organization (WHO)/Center for Disease Control and Prevention (CDC)approved probe for the SARSCoV2 N gene were used. SYBRGreen RTqPCR is not able to diagnose as positive samples with low viral load, while, TaqMan Probe RTqPCR gave positive signals at very late Ct values. On the contrary, ddPCR showed higher sensitivity rate compared to RTqPCR and both EvaGreen and probe ddPCR were able to recognize the sample with low viral load as positive even at 10fold diluted concentration. In conclusion, ddPCR shows higher sensitivity and specificity compared to RTqPCR for the diagnosis of COVID19 infection in falsenegative samples with low viral load. Therefore, ddPCR is strongly recommended in clinical practice for the diagnosis of COVID19 and the followup of positive patients until complete remission.