Gene Therapy for ß-Hemoglobinopathies: From Discovery to Clinical Trials.

Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the 20th and 21st centuries. Extensive characterization of the globin gene locus, accompanied by pioneering work on the utilization of viruses as human gene delivery tools in human hematopoietic stem and progenitor cells (HPSCs), has led to transformative and successful therapies via autologous hematopoietic stem-cell transplant with gene therapy (HSCT-GT). Due to the advanced understanding of the ß-globin gene cluster, the first diseases considered for autologous HSCT-GT were two prevalent ß-hemoglobinopathies: sickle cell disease and ß-thalassemia, both affecting functional ß-globin chains and leading to substantial morbidity. Both conditions are suitable for allogeneic HSCT; however, this therapy comes with serious risks and is most effective using an HLA-matched family donor (which is not available for most patients) to obtain optimal therapeutic and safe benefits. Transplants from unrelated or haplo-identical donors carry higher risks, although they are progressively improving. Conversely, HSCT-GT utilizes the patient's own HSPCs, broadening access to more patients. Several gene therapy clinical trials have been reported to have achieved significant disease improvement, and more are underway. Based on the safety and the therapeutic success of autologous HSCT-GT, the U.S. Food and Drug Administration (FDA) in 2022 approved an HSCT-GT for ß-thalassemia (Zynteglo™). This review illuminates the ß-globin gene research journey, adversities faced, and achievements reached; it highlights important molecular and genetic findings of the ß-globin locus, describes the predominant globin vectors, and concludes by describing promising results from clinical trials for both sickle cell disease and ß-thalassemia.

Spanish nurses' experiences with personal protective equipment and perceptions of risk of contagion from COVID-19: A qualitative rapid appraisal.

AIMS AND OBJETIVES: Explore nurses' experiences and perception of risk regarding the use of personal protective equipment during the first wave of the pandemic in Spain. BACKGROUND: The contribution of our study is to use qualitative methods to understand nurses' experiences and perceptions of the risk of the contagion linked to the shortage of PPE during the first wave of the pandemic, whose explosive start strained health systems around the globe. DESIGN: Qualitative descriptive design according to the Rapid Research Evaluation and Appraisal model. METHODS: Semi-structured videoconference interviews were conducted to explore the experiences of 29 nurses including staff nurses, nursing supervisors and nursing directors from hospital and community services of the Spanish health system. Interviews lasted 30-45 min and were conducted in May 2020. We carried out a thematic analysis using Dedoose. The COREQ checklist was used to report findings. RESULTS: We identified the following themes and subthemes: 1. Experiences with personal protective equipment: scarcity, inequality, reutilization, self-protection, delegation of responsibility, and gap between protocols and reality; 2. Perception of the risk of contagion: lack of credibility, lack of trust, lack of support, and meeting subjective needs. CONCLUSIONS: The scarcity of personal protective equipment and inequality in its distribution led nurses to take initiatives to feel more protected. Mid-ranking supervisors were caught between the responsibility of monitoring and rationing personal protective equipment and providing the necessary protection to nurses. The disjuncture between protocols and the available supply of personal protective equipment caused confusion. Lack of credibility, lack of trust and lack of support from management influenced participants' perception of the risk of contagion. Mid-ranking supervisors were often responsible for trying to alleviate fear among nursing staff. RELEVANCE TO CLINICAL PRACTICE: Understanding the factors involved in risk perception can be helpful to decision-makers who help protect nurses in clinical practice. These results can help administrators and policymakers because they point to the need for nurses to feel that their departments and centers look after their safety at work. Transparent communication and emotional support may contribute to their well-being in the face of risk.

Front-line nurses' responses to organisational changes during the COVID-19 in Spain: A qualitative rapid appraisal.

AIMS: To identify the organisational changes faced by front-line nurses working with COVID-19 patients during the first wave and describe how they responded to these changes. BACKGROUND: The COVID-19 pandemic has altered the provision of care and the management of health care around the world. Evolving information about SARS-CoV-2 meant that health care facilities had to be reorganised continually, causing stress and anxiety for nurses. METHODS: Qualitative study based on Rapid Research Evaluation and Appraisal (RREAL). The research took place in hospital and community health settings of the Spanish national health system with a purposive sampling of 23 front-line nurses. Semi-structured interviews were conducted between May and June 2020. The duration was 30-45 min per interview. We used the Dedoose® data analysis software to perform a thematic analysis. RESULTS: Nurses responded to organisational changes using the following strategies: improvisation, adaptation and learning. CONCLUSION: Our rapid approach allowed us to record how nurses responded to changing organisation, information that is easily lost in a disaster such as the COVID-19. IMPLICATIONS FOR NURSING MANAGEMENT: Knowing about their strategies can help planning for future health disasters, including subsequent waves of the COVID-19.

Opinión de los pacientes tras un programa de ejercicio físico domiciliario / Patient opinion after a home physical exercise program

Introducción: Las personas con enfermedad renal deben recibir una atención integral que incluya programas de ejercicio físico adaptado a sus necesidades. Objetivo: Evaluar la satisfacción de los pacientes con enfermedad renal crónica en estadios IV y V ante un programa de ejercicio físico domiciliario. Material y Método: Estudio descriptivo transversal en pacientes que realizaron un programa completo de entrenamiento físico domiciliario de 12 semanas de duración. Tras esta intervención, respondieron de forma anónima a un cuestionario ad-hoc validado por expertos, sobre su opinión acerca del programa. Resultados: Participaron 62 pacientes. 24 estaban en programa de hemodiálisis, 17 en diálisis peritoneal y 7 en situación de enfermedad renal crónica estadio IV. 34 eran hombres. La edad media fue de 67,4+/-14,9 años. 52 pacientes realizaron el programa solos en su domicilio. 33 de los pacientes les pareció muy correcto que el programa fuera domiciliario, 15 correcto y 2 poco correcto. 47 de los participantes consideraron muy correcto que la persona que dirigiera el programa fuera una enfermera conocida. 19 consideró que tras el programa habían mejorado mucho, 14 que habían mejorado, 9 que habían mejorado poco y 3 que no habían mejorado. 39 estuvieron muy satisfechos de haber podido participar en el programa, 6 satisfechos, 1 poco satisfecho y 1 de los pacientes no estuvo satisfecho. No hubo diferencias significativas en las respuestas en relación al sexo, edad, tipo de tratamiento, o realizar el programa solo o acompañado. Conclusiones: El programa de ejercicio físico domiciliario fue bien valorado por los pacientes que en su mayoría manifestaron haber mejorado y consideraron adecuado que fuera una enfermera la que dirigiera el programa

Objective: To evaluate patient satisfaction chronic kidney disease in stages IV and V after a home physical exercise program. Material and methods: Descriptive cross-sectional study in patients who carried out a complete 12-week home physical training program. After this intervention, they responded anonymously to an ad-hoc questionnaire validated by experts, about their opinion about the program. Results: 62 patients participated. 24 were on a hemodialysis program, 17 on peritoneal dialysis and 7 on stage IV chronic kidney disease. 34 were men. The mean age was 67.4 +/- 14.9 years. 52 patients carried out the program alone at home. 33 of the patients considered as very correct that the program was domiciliary, 15 correct and 2 not correct. 47 of the participants considered as very correct that the person leading the program was a well-known nurse. 19 responded that after the program the improvement was a lot, 14 a good improvement, 9 little improvement and 3 that had not improved. 39 were very satisfied to participate in the program, 6 satisfied, 1 not very satisfied and 1 of the patients was not satisfied. There were no significant differences in the answers in relation to sex, age, type of treatment, or if the program was done alone or accompanied. Conclusions: The home physical exercise program was well valued by the patients, who mostly said they had improved and considered as appropriate that a nurse leads the program

Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y POS mouse model.

BACKGROUND: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes. METHODS: To investigate the relevance of these VUS in regards to the patient's phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (Y POS ) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-Y B6 and undervirilized B6-Y POS gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-Y POS males). RESULTS: We identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-Y POS mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9. CONCLUSION: The use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation.

Epidemiología de los ingresos por bronquiolitis en el sur de Europa: análisis de las epidemias 2010-2015 / Epidemiology of patients hospitalised due to bronchiolitis in the south of Europe: Analysis of the epidemics, 2010-2015

Introducción. La renovación de las guías de práctica clínica sobre la bronquiolitis aguda (BA) obliga a reevaluar las consecuencias de su implantación. Pretendemos actualizar las principales variables clínico-epidemiológicas en pacientes ingresados por BA en el sur de Europa y analizar las causas de la estancia prolongada. Pacientes y método: Estudio retrospectivo de ingresos por BA durante 5 epidemias (2010-2015), con descripción de las principales variables clínico-epidemiológicas y análisis por regresión logística de los factores asociados a mayor estancia. Resultados: El inicio de la epidemia ocurrió entre las semanas cuarta de septiembre y tercera de octubre. De los menores de 2 años (42.530 niños), el 15,21% (6.468 pacientes) acudieron a urgencias por BA y el 2,36% ingresaron (1.006 pacientes), con un 18,5% de prematuros. El 12,2% tenían peso al nacimiento inferior a 2.300 g. El 21,1% eran menores de un mes, consultaron por apnea asociada el 10,8%, ingesta inferior al 50% en el 31,1% y presentaban sobreinfección bacteriana el 13,1%. Estos factores se asociaron de forma independiente a la estancia prolongada. La mediana de estancia fue de 5 días y la proporción de ingresos en la unidad de cuidados intensivos pediátricos (UCIP) del 8,5% de los casos. Conclusiones: El inicio de la epidemia de la bronquiolitis mostró una variabilidad de hasta 4 semanas en nuestro medio. Tras 5 años de la implantación de la guía de práctica clínica, la incidencia de ingresos está en torno al 2,3% y parece estable respecto a estudios previos. La edad media de los pacientes desciende a 2,4 meses, aunque con una proporción similar de ingresos en la UCIP de un 8,5%. Los factores de riesgo independiente asociados a una estancia hospitalaria más prolongada fueron: bajo peso al nacimiento, edad menor de un mes, apneas previas al ingreso, ingesta inferior al 50% y la sobreinfección bacteriana grave, donde la infección respiratoria superó la prevalencia de infección del tracto urinario grave (AU)

Introduction: The renewal of clinical practice guidelines on acute bronchiolitis (AB) requires the re-assessment of the consequences of their implementation. An update is presented on the main clinical and epidemiological variables in patients hospitalised due to AB in Southern Europe and an analysis made of the causes associated with longer hospital stay. Patients and method: A retrospective study was conducted on patients admitted to hospital due to AB during 5 epidemics (2010-2015), with an analysis of the major clinical and epidemiological variables. A logistic regression analysis was performed on the factors associated with a longer hospital stay. Results: The beginning of the epidemic occurred between the 4th week of September and the 3rd week of October. Of those children under 2 years (42,530), 15.21% (6,468 patients) attended paediatric emergency department due to having AB, and 2.36% (1,006 patients) were admitted. Of these, 18.5% of were premature, 12.2% had a birth weight < 2,300 g, 21.1% were younger than 1 month, 10.8% consulted for associated apnoea, 31.1% had an intake <50%, and 13.1% had bacterial superinfection. These factors were independently associated with prolonged stay. The median length of stay was 5 days, and 8.5% of cases were admitted to a paediatric intensive care unit (PICU). Conclusions: The beginning of the bronchiolitis epidemic showed a variability of up to 4 weeks in this region. Five years after implementing the new guidelines, the incidence of admissions was approximately 2.3%, and appeared stable compared to previous studies. The mean age of the patients decreased to 2.4 months, although with a similar proportion of PICU admissions of 8.5%. Independent factors associated with prolonged stay were: low birth weight, age less than one month, apnoea prior-to-admission, intake of less than 50%, and severe bacterial superinfection. Respiratory bacterial infection exceeded the prevalence of urinary tract infection (AU)

Next-generation mapping: a novel approach for detection of pathogenic structural variants with a potential utility in clinical diagnosis.

BACKGROUND: Massively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient's phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions. However, due to the use of 100-300-bp fragment reads, this platform is not well powered to sensitively identify moderate to large structural variants (SV), such as insertions, deletions, inversions, and translocations. METHODS: To overcome these limitations, we used next-generation mapping (NGM) to image high molecular weight double-stranded DNA molecules (megabase size) with fluorescent tags in nanochannel arrays for de novo genome assembly. We investigated the capacity of this NGM platform to identify pathogenic SV in a series of patients diagnosed with Duchenne muscular dystrophy (DMD), due to large deletions, insertion, and inversion involving the DMD gene. RESULTS: We identified deletion, duplication, and inversion breakpoints within DMD. The sizes of deletions were in the range of 45-250 Kbp, whereas the one identified insertion was approximately 13 Kbp in size. This method refined the location of the break points within introns for cases with deletions compared to current polymerase chain reaction (PCR)-based clinical techniques. Heterozygous SV were detected in the known carrier mothers of the DMD patients, demonstrating the ability of the method to ascertain carrier status for large SV. The method was also able to identify a 5.1-Mbp inversion involving the DMD gene, previously identified by RNA sequencing. CONCLUSIONS: We showed the ability of NGM technology to detect pathogenic structural variants otherwise missed by PCR-based techniques or chromosomal microarrays. NGM is poised to become a new tool in the clinical genetic diagnostic strategy and research due to its ability to sensitively identify large genomic variations.

[Epidemiology of patients hospitalised due to bronchiolitis in the south of Europe: Analysis of the epidemics, 2010-2015]. / Epidemiología de los ingresos por bronquiolitis en el sur de Europa: análisis de las epidemias 2010-2015.

INTRODUCTION: The renewal of clinical practice guidelines on acute bronchiolitis (AB) requires the re-assessment of the consequences of their implementation. An update is presented on the main clinical and epidemiological variables in patients hospitalised due to AB in Southern Europe and an analysis made of the causes associated with longer hospital stay. PATIENTS AND METHOD: A retrospective study was conducted on patients admitted to hospital due to AB during 5 epidemics (2010-2015), with an analysis of the major clinical and epidemiological variables. A logistic regression analysis was performed on the factors associated with a longer hospital stay. RESULTS: The beginning of the epidemic occurred between the 4th week of September and the 3rd week of October. Of those children under 2 years (42,530), 15.21% (6,468 patients) attended paediatric emergency department due to having AB, and 2.36% (1,006 patients) were admitted. Of these, 18.5% of were premature, 12.2% had a birth weight <2,300g, 21.1% were younger than 1 month, 10.8% consulted for associated apnoea, 31.1% had an intake <50%, and 13.1% had bacterial superinfection. These factors were independently associated with prolonged stay. The median length of stay was 5 days, and 8.5% of cases were admitted to a paediatric intensive care unit (PICU). CONCLUSIONS: The beginning of the bronchiolitis epidemic showed a variability of up to 4 weeks in this region. Five years after implementing the new guidelines, the incidence of admissions was approximately 2.3%, and appeared stable compared to previous studies. The mean age of the patients decreased to 2.4 months, although with a similar proportion of PICU admissions of 8.5%. Independent factors associated with prolonged stay were: low birth weight, age less than one month, apnoea prior-to-admission, intake of less than 50%, and severe bacterial superinfection. Respiratory bacterial infection exceeded the prevalence of urinary tract infection.

Atención a la diversidad sexual y de género: un reto para las matronas / No disponible

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