Search

Objetivo: Evaluar el efecto de la suplementación con vitamina D en las complicaciones musculoesqueléticas relacionadas con el tratamiento con inhibidores de la aromatasa (IA) en pacientes con cáncer de mama. Material y métodos: Estudio observacional prospectivo de mujeres en tratamiento con IA, reclutadas en la cohorte B-ABLE. Las pacientes con niveles séricos iniciales de 25(OH)D (25-hidroxivitamina D) 0 a los 3 meses, mediante regresión logística. Resultados: La suplementación con vitamina D al inicio del tratamiento con IA disminuyó el riesgo tanto de artralgia incidente como de su empeoramiento. El umbral efectivo de 25(OH)D en suero para reducir el dolor articular se estableció en 40 ng/ml. Sin embargo, este umbral no se relacionó significativamente con los cambios óseos al año de seguimiento. No obstante, los niveles de vitamina D se correlacionaron inversamente con la pérdida ósea de la columna lumbar (CL) (β=0,177% [IC 95%: 0,014 a 0,340]). Conclusiones: La administración de suplementos de vitamina D con el objetivo de alcanzar niveles séricos de 25OHD de al menos 40 ng/ml es protectora para la artralgia. Los niveles de vitamina D a los tres meses podrían predecir el riesgo de pérdida ósea en CL al año de tratamiento con IA. Por lo tanto, se recomiendan dosis altas de vitamina D en estas pacientes, que son más propensas a sufrir afecciones musculoesqueléticas.

Objetivo: Evaluar la persistencia a la terapia con inhibidores de la aromatasa (IA), la mortalidad asociada a la discontinuidad al tratamiento y la influencia de los bifosfonatos (BF) orales, en la práctica clínica habitual. Material y métodos: Estudio prospectivo observacional de mujeres con cáncer de mama en tratamiento con IA entre enero de 2006 y diciembre de 2015, registradas en la base de datos SIDIAP. Se excluyeron aquellas tratadas previamente con tamoxifeno. Se estudió la persistencia al tratamiento con IA con un análisis de supervivencia: se calculó el estimador de Kaplan-Meier, y se realizó un modelo de los riesgos proporcionales (regresión de Cox) entre usuarias y no usuarias de BF ajustando por edad. Se llevó a cabo un análisis de sensibilidad teniendo en cuenta la mortalidad como riesgo competitivo (modelos de Fine y Gray). Se comparó la diferencia de mortalidad entre grupos mediante una prueba Chi cuadrado. Resultados: Se observó una persistencia a los IA del 87% a 5 años de tratamiento, con una mortalidad global del 19,75%. Se registró un 7,7% menos de mortalidad en aquellas pacientes que completaron los 5 años de tratamiento respecto a las que no. Las pacientes con BF mostraron una disminución de la mortalidad (6,6%) y una disminución del riesgo de abandono de la terapia (SHR ajustado: 0,62 [IC 95%: 0,55 a 0,70]) respecto a las no usuarias. Conclusiones: La permanencia a los IA y el uso de BF está asociada a una disminución de la mortalidad global. Además, el uso de BF resulta en un aumento de la adherencia al tratamiento con IA.

Objetivo: Los inhibidores de la aromatasa (IA) se han asociado con una pérdida de masa ósea acelerada y un mayor riesgo de fracturas osteoporóticas. Con este trabajo se pretendió evaluar los factores de riesgo de fractura incidente en pacientes con cáncer de mama que reciben IA. Material y métodos: Estudio prospectivo-observacional de cohorte de mujeres con cáncer de mama que inician tratamiento con IA (cohorte B-ABLE). Las pacientes realizaron tratamiento durante 5 años o bien 2 ó 3 años si habían recibido previamente tamoxifeno. Se les evaluó la salud ósea desde el inicio del tratamiento hasta un año después de finalizar dicho tratamiento mediante densitometría ósea, marcadores de remodelado óseo, niveles de vitamina D y una radiografía antero-posterior y otra lateral de columna. Se realizó el cálculo de riesgo de fractura mediante la herramienta FRAX® antes de iniciar IA. Se utilizaron modelos de Cox para calcular los ratios de riesgo (HR [IC 95%]) de fractura. Resultados: Un total de 943 pacientes fueron incluidas en el estudio. El 5,4% sufrieron una fractura incidente, la mayoría durante el tratamiento con IA, aunque un 21,5% ocurrieron durante el primer año después de finalizar la terapia. La mayoría de las fracturas incidentes fueron vertebrales clínicas (29,4%) y de Colles (31,4%). El 86,3% de las pacientes tenían un diagnóstico de osteopenia u osteoporosis en el momento de la fractura y el 33% tenían los niveles de β-CTX (isómero β del telopéptido carboxiterminal del colágeno tipo I) por encima de la normalidad. Las pacientes diagnosticadas de osteoporosis o con riesgo de fractura al inicio del estudio fueron tratadas con antirresortivos óseos. No se encontraron diferencias significativas en el riesgo de fractura entre pacientes con y sin tratamiento antirresortivo: HR=1,75 [IC 95%: 0,88 a 3,46]. Tampoco se encontraron diferencias entre las pacientes que habían hecho tratamiento previo con tamoxifeno respecto a las que no (HR=1,00 [IC 95%: 0,39 a 2,56]). La herramienta FRAX® dio valores de media dentro del rango de riesgo intermedio, con 13 pacientes con valores de alto riesgo de fractura principal. Conclusiones: El principal factor de riesgo detectado para fractura incidente en pacientes tratadas con IA es el diagnóstico de osteopenia u osteoporosis. El cálculo de la herramienta FRAX® y la determinación de los niveles de β-CTX son herramientas útiles para identificar a pacientes de alto riesgo.

Objetivo: La microindentación de impacto (MII) es una técnica que permite medir in vivo la resistencia tisular mecánica ósea. Se ha demostrado que la MII proporciona información útil sobre la evaluación de enfermedades esqueléticas, pero se desconoce el efecto que la edad puede ejercer sobre la propiedad ósea medida. El objetivo del estudio es analizar la relación entre la edad y la MII. Material y métodos: El índice de Resistencia Mineral Ósea (BMSi), la variable de medición de MII, se midió en 69 mujeres (mediana de edad: 49 años; rango: 30-81 años) y 19 varones (mediana de edad: 34 años; rango: 24-98 años) sanos. La correlación entre BMSi y la edad se analizó mediante regresión lineal. La asociación entre BMSi y edad se evaluó mediante ANOVA tras ajustar por el índice de masa corporal. El posible efecto de depleción estrogénica postmenopáusica sobre el BMSi se estudió comparando el subgrupo de mujeres más jóvenes con las más mayores mediante la prueba t de Student. Resultados: Los análisis de regresión lineal mostraron que la BMSi no se correlaciona con la edad en varones (R2=0,0016, p=0,74) ni en mujeres (R2=0,076, p=0,25). Asimismo, el análisis ajustado de ANOVA no demostró asociación entre la BMSi y la edad ni en varones (p=0,78) ni en mujeres (p=0,73). Finalmente, no se encontraron diferencias entre la BMSi entre las mujeres más jóvenes y las mayores (p=0,8). Conclusiones: La resistencia tisular mecánica ósea en individuos sanos es independiente a la edad y a la depleción estrogénica postmenopáusica.

Objetivo: En las últimas décadas se han identificado genes asociados a la masa ósea y al riesgo de fractura osteoporótica, varios de los cuales pertenecen a la vía de Wnt. En este proyecto se estudió la funcionalidad de 7 mutaciones de cambio de sentido del gen DKK1 –un inhibidor de la vía de Wnt– presentes en la población general. Material y métodos: Se realizaron estudios in vitro del gen reportero luciferasa para medir la actividad de la vía de Wnt en presencia o ausencia de DKK1 silvestre o mutada, y estudios de western blot, para evaluar si las distintas mutaciones afectan a su síntesis y/o a su estabilidad. Resultados: La proteína DKK1 con la variante p.Ala41Thr presenta menor actividad inhibidora de la vía en comparación con la proteína silvestre. También se observaron diferencias significativas entre los experimentos realizados en ausencia de DKK1 y los que incluyen DKK1 con la mutación p.Ala41Thr. Los western blots mostraron que la cantidad de proteína era similar para todas las variantes, tanto las mutadas como la silvestre, por lo que la pérdida de actividad de p.Ala41Thr no parecía deberse a falta de proteína. El resto de las mutaciones no presentaron un comportamiento diferente al de la proteína DKK1 silvestre. Conclusiones: La variante de cambio de sentido p.Ala41Thr de la proteína DKK1, con una frecuencia poblacional de 0,013%, presenta una pérdida parcial de su función inhibidora, que no es debida a la falta de expresión de ésta. Esta variante génica podría conllevar un aumento de la densidad mineral ósea en las personas de la población general portadoras de esta mutación.

Objetivos: Las fracturas atípicas de fémur (FAF) son un tipo de fracturas poco frecuentes, a menudo relacionadas con un tratamiento prolongado con bisfosfonatos (BPs). Actualmente no se conocen con exactitud sus mecanismos patogénicos y no hay pruebas para identificar aquellos pacientes con un alto riesgo de sufrir una FAF. El objetivo de este trabajo es investigar las bases genéticas de las FAFs. Material y métodos: Se secuenció el exoma completo de 3 hermanas y de 3 pacientes adicionales no relacionadas, todas tratadas con BPs durante más de 5 años. Se seleccionaron variantes compartidas por las hermanas, de baja frecuencia y potencialmente patogénicas, y se construyó una red de interacciones de genes y proteínas con los datos hallados. Resultados: Identificamos 37 variantes raras (en 34 genes) compartidas por las 3 hermanas, algunas de ellas no descritas anteriormente. La variante más llamativa fue la mutación p.Asp188Tyr en el enzima geranilgeranil pirofosfato sintasa (codificada por el gen GGPS1), de la vía del mevalonato y esencial para la función del osteoclasto. Otro hallazgo interesante fueron dos mutaciones (una en las 3 hermanas y una en una paciente no relacionada) en el gen CYP1A1, implicado en el metabolismo de los esteroides. Identificamos otras variantes que también podrían estar involucradas en la susceptibilidad a las FAFs o en el fenotipo osteoporótico subyacente, tales como las presentes en los genes SYDE2, NGEF, COG4 y la FN1. Conclusiones: Nuestros datos son compatibles con un modelo donde la acumulación de variantes de susceptibilidad podría participar en la base genética de las FAFs.

Objetivos: Los inhibidores de la aromatasa (AI) son terapias endocrinas adyuvantes eficaces para pacientes con cáncer de mama, aunque se han asociado a un mayor riesgo de fractura osteoporótica. Previamente se ha demostrado una pérdida en el Trabecular Bone Score (TBS) que puede variar entre las pacientes tratadas con IA. El estudio pretendió identificar la base genética asociada al cambio en el TBS mediante el estudio de genes de la vía esteroidogénica. Material y métodos: La cohorte B-ABLE estudia de forma prospectiva a mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. Se calculó el TBS a partir de los datos adquiridos en la densitometría mediante absorciometría radiológica dual (DXA) realizada al inicio y al final del tratamiento con IA. El cambio relativo del TBS se calculó como la variación porcentual del valor de TBS al final de tratamiento respecto al TBS basal. Para estudiar la posible asociación genética se genotiparon los polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR y CYP24A1. Se estudió mediante regresión lineal múltiple la posible relación entre genes y cambios en TBS contemplando los modelos de herencia genética dominante, recesivo y aditivo. Resultados: Se incluyeron en el estudio un total de 212 mujeres no tratadas con bisfosfonatos en las que pudo calcularse el TBS. La mitad de las pacientes habían recibido tratamiento previo con tamoxifeno. El porcentaje de cambio intra-individual del TBS fue del -0,04% [IC del 95%: -0,05 a -0,03; p

Objetivos: Identificar putativas variantes funcionales en los genes CYP11A1 y CYP17A1 asociadas a efectos musculoesqueléticos (pérdida acelerada de la masa ósea y artralgias) derivados del tratamiento con inhibidores de la aromatasa (IA). Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama en tratamiento con IA. La densidad mineral ósea en columna lumbar y cuello femoral se midió mediante densitometría, y el dolor articular mediante escala analógica visual. A partir de polimorfismos de cambio de un nucleótido (SNPs) en los genes CYP11A1 (rs4077581, rs11632698 y rs900798) y CYP17A1 (rs4919686, rs4919683, rs4919687, rs3781287, rs10786712, rs6163, rs743572), asociados previamente con eventos musculoesqueléticos, se construyeron los haplotipos para cada paciente de la cohorte, y se seleccionaron aquellos que mostraron mayor diferencia fenotípica (p

FLJ42280 es un posible gen de susceptibilidad a la osteoporosis. Distintos estudios de GWAs han identificado 4 SNPs no-codificantes en este gen que se asocian a la densidad mineral ósea (DMO) y el riesgo de fractura. Para descubrir la causa de la asociación entre estos SNPs y la osteoporosis, se realizó una búsqueda de variantes genéticas mediante resecuenciación de 28 kb que contienen el gen, en una selección truncada de mujeres con DMO muy baja (n=50) o muy alta (n=50) de la cohorte BARCOS (Barcelona Cohorte Osteoporosis, cohorte de mujeres postmenopáusicas de Barcelona). Las variantes encontradas se filtraron y se analizó su frecuencia en cada grupo. Se analizó el solapamiento de las variantes con elementos funcionales del proyecto ENCODE y también se calculó el desequilibrio de ligamiento entre los SNPs de la región. Finalmente, se hizo un análisis de eQTL de los 4 SNPs no-codificantes respecto a los niveles de expresión de genes cercanos a FLJ42280 en linfoblastos. Se seleccionaron 110 variantes. Las diferencias de sus frecuencias entre los dos grupos estuvieron por debajo del poder estadístico del diseño experimental. Sin embargo, 3 variantes solaparon con posibles enhancers y una solapó con un enhancer activo en osteoblastos (rs4613908). Se observó un fuerte desequilibrio de ligamiento entre los 4 SNPs no-codificantes y el SNP rs4613908, que pertenecen a un bloque que abarca el gen casi por completo. Ninguno de los SNPs no-codificantes mostró asociación con los niveles de expresión de genes cercanos a FLJ42280. En conclusión, el SNP rs4613908 podría estar implicado funcionalmente en la determinación de la DMO. Serán necesarios experimentos concretos para confirmarlo.

Objetivos: Identificar microRNAs (miRNAs) diferencialmente expresados en muestras óseas con fractura osteoporótica respecto a huesos sanos.Material y métodos: Se extrajo RNA total a partir de hueso trabecular fresco del cuello femoral de mujeres sometidas a reemplazo de cadera, ya sea debido a fractura osteoporótica (n=6) o por artrosis en ausencia de osteoporosis (según la DMO) (n=6). Las muestras se hibridaron en un array de miRNAs y se realizaron diagramas de PCA y de mapa de calor. Para la comparación de los niveles de expresión, se fijó como significativo un umbral de cambio de >1,5 veces y un valor p

Objetivos: El objetivo del estudio fue analizar los cambios en la densidad mineral ósea (DMO) a lo largo del tratamiento con inhibidores de aromatasa (IA) en la práctica clínica y evaluar la asociación entre el gen CYP11A1 y la variación de DMO al final del tratamiento. Material y métodos: La cohorte B-ABLE es un estudio prospectivo de mujeres postmenopáusicas con cáncer de mama, en tratamiento con IA. Se analizó la variación de DMO durante todo el tratamiento con IA, así como las diferencias entre las pacientes tratadas y no-tratadas previamente con tamoxifeno (TMX). Tres polimorfismos (rs4077581, rs11632698 y rs900798) del gen CYP11A1, fueron genotipados para su asociación con la variación de DMO. Resultados: Las pacientes tratadas con TMX mostraron pérdidas más aceleradas de DMO que las no tratadas previamente con TMX (60% menos en columna y 46% en fémur a los 2 años y 70% menos en columna y 63% en fémur a los 3 años). No obstante, al final del tratamiento no se detectaron diferencias significativas en la pérdida de DMO entre ambos grupos de pacientes. Los 3 polimorfismos del gen CYP11A1 resultaron significativamente asociados a la variación de DMO en fémur al final del tratamiento. Conclusiones: La DMO disminuyó de forma más acelerada en las pacientes con tratamiento previo con TMX que en las que solo recibieron AI, a pesar de que no se detectaron diferencias significativas al final de tratamiento. Polimorfismos en el gen CYP11A1 están relacionados con la variación de la DMO en respuesta al tratamiento con IA.

Objetive: Aromatase inhibitors (AI) have been associated with an accelerated loss of bone mass and an increased risk of osteoporosis fractures. This study assesses the risk factors for incident fracture in breast cancer patients receiving AI. Material and methods: Prospective-observational cohort study of women with breast cancer who begin treatment with AI (B-ABLE cohort). Patients were treated for 5 years or 2 or 3 years if they had previously received tamoxifen. Bone health was assessed from the beginning of the treatment until one year post treatment by bone densitometry, bone remodeling markers, vitamin D levels and an anteroposterior and lateral spine radiography. The fracture risk calculation was performed using the FRAX® tool before starting AI. Cox models were used to calculate the risk ratios (HR [95% CI]) of fracture. Results: A total of 943 patients were included in the study. 5.4% suffered an incident fracture, most during AI treatment, although 21.5% occurred during the first year after the end of therapy. Most of the incident fractures were clinical vertebral (29.4%) and Colles (31.4%). 86.3% of the patients had a diagnosis of osteopenia or osteoporosis at the time of the fracture and 33% had the levels of β-CTX (β isomer of the carboxyterminal telopeptide of type I collagen) above normal. Patients diagnosed with osteoporosis or at risk of fracture at the start of the study were treated with bone antiresorptives. No significant differences in fracture risk were found between patients with and without antiresorptive therapy: HR=1.75 [95% CI: 0.88 to 3.46]. Nor were differences found among patients who had previously treated with tamoxifen compared to those who did not (HR=1.00 [95% CI 0.39 to 2.56]). The FRAX® tool gave average values within the intermediate risk range, with 13 patients with high risk of major fracture values. Conclusions: The main risk factor detected for incident fracture in patients treated with AI is the diagnosis of osteopenia or osteoporosis. The calculation of the FRAX® tool and the determination of β-CTX levels are useful tools to identify high-risk patients. [ABSTRACT FROM AUTHOR]

Objectives: Aromatase inhibitors (AI) are effective adjuvant endocrine therapies for breast cancer patients, although they have been associated with an increased risk of osteoporotic fracture. Trabecular Bone Score (TBS) loss has been previously demonstrated, although it may vary among AI-treated patients. This study aims to identify the genetic basis associated with TBS change by studying steroidogenic pathway genes. Material and methods: The B-ABLE cohort studies prospectively postmenopausal women with breast cancer under treatment with AI. TBS is calculated from the raw data acquired in dual-energy x-ray absorptiometry (DXA) scan at the outset of the study and at the end of AI-treatment. The relative TBS change was calculated as the percentage variation of the TBS value at the end of treatment from baseline. To study the possible genetic association, nucleotide polymorphisms (SNPs) were genotyped in genes CYP11A1, CYP17A1, HDE3B2, HDE17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, GC, CYP27B1, VDR and CYP24A1. The possible relationship between genes and TBS changes was studied by multiple linear regression, considering models of dominant, recessive and additive genetic inheritance. Results: The study included 212 women that had not been treated with bisphosphonates and had available TBS data. Half of the patients had been treated previously with tamoxifen. The percentage of intraindividual TBS change was -0.04% [95% CI: -0.05 to -0.03; p<0.001] at the end of AI treatment. The SNP rs6013897 in the gene CYP24A1 showed a significant association with TBS reduction [p=0.03565; coefficient ß (95% CI) = -1.55 (-2.98 to -0.11)]. Conclusions: The CYP24A1 gene could be involved in the phenotypic variability found in bone microarchitecture deterioration during AI treatment. [ABSTRACT FROM AUTHOR]

Summary: Camurati-Engelmann (CE) is a very rare disease affecting one in every million persons worldwide. It is characterized by an enlargement of long bones. We aimed to assess bone characteristics in three siblings with different tools. Even if there was an excess of bone density, quality seemed to be deteriorated. Introduction: CE disease is a rare monogenic disorder affecting approximately one in every million persons worldwide. It is mainly characterized by a progressive hyperostosis of the periosteum and endosteum of the diaphysis of long bones. Limited data are available about bone characteristics in these patients. In three siblings with CE disease, we aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) by dual-energy X-ray absorptiometry (DXA) and material characteristics at tissue level using bone impact reference point indentation. Methods: Clinical data were collected and a general laboratory workup was performed. At the lumbar spine and hip, BMD and TBS were measured using DXA imaging. Bone material strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. Results: All three cases had densitometric values consistent with high bone mass (sum of Z-score at the lumbar spine and hip > 4). Hip BMD was extremely high in all three siblings at both total hip and femoral neck, while at the lumbar spine, two of them had normal values but the third again had very high BMD. TBS values were in the normal range. In contrast, BMSi measurements were at low or very low levels, compared with normal controls. Conclusion: Despite strikingly increased BMD and normal microarchitecture, BMSi is affected in patients with CE. Microindentation could be an appropriate tool for assessing bone fragility in these patients. Bone disease in this group of patients requires further study to better understand the underlying regulatory mechanisms and their alterations. [ABSTRACT FROM AUTHOR]

Objectives: To identify microRNAs (miRNAs) differentially expressed in bone samples with osteoporotic fracture compared with healthy bones. Methods: Total RNA was extracted from fresh trabecular bone of the femoral neck of women undergoing hip replacement surgery, either because to osteoporotic fracture (n=6) or in the absence of osteoarthritis osteoporosis (based on BMD) (n=6). The samples were hybridized on an array of miRNAs and PCA diagrams and heat map were made. To compare expression levels, >1.5 times and a value p<0.05 Student's T test (corrected for multiple testing) was set as a threshold of significant change. Results: Both PCA analysis and the heat map showed a samples grouping whether there was fracture or not. 790 were detected miRNAs in bone samples, 82 of which were altered in the osteoporotic samples. After validation in another panel of 6 samples 6 osteoporotic and non-osteoporotic by PCR real time of the most significant miRNAs, and for which there was a test available, the miRNAs, miR-320a and miR-22-3p were confirmed. These two miRNAs were detected in cultures of primary osteoblasts, although they did not maintain the same pattern of expression in total bone samples. Conclusions: We have shown that there are differences in the expression of miRNAs in samples with osteoporotic fracture. This opens prospects for research and design of new therapies. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to analyze bone mineral density (BMD) changes throughout aromatase inhibitor (AI) treatment in clinical cases and also consider its association with the CYP11A1 gene and the BMD variation after treatment. Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer, in AI treatment. BMD variation was analyzed during AI treatment, as well as the differences those patients who were treated and not treated previously with tamoxifen (TMX). Three polymorphisms (rs4077581, rs11632698 and rs900798) of the CYP11A1 gene were genotyped for their association with BMD variation. Results: TMX-treated patients presented more rapid BMD loss than those who did not undergo prior TMX treatment (60% less in spine and 46% in femur at 2 years and 70% less in the spine and 63% in the femur at 3 years). However, no significant BMD loss was detected after treatment in either group. The 3 CYP11A1 gene polymorphisms were significantly associated with BMD variation in the femur at the end of the treatment. Conclusions: BMD was reduced more rapidly in patients with prior TMX treatment than in those who only received AI, although no significant differences were detected after treatment. The 3 CYP11A1 gene polymorphisms were associated with BMD variation in response to AI treatment. [ABSTRACT FROM AUTHOR]

Introduction: People with HIV (PWH) with poor immune response despite adequate antiretroviral treatment (ART) are susceptible to non-AIDS-related health issues. This study seeks to evaluate bone quality in Immunological Non-Responders (INRs) in comparison to those with proper immune response (IRs) using in vivo microindentation to quantify bone quality, in addition to conventional bone mineral density (BMD) evaluations., Methods: A cross-sectional study was conducted at Hospital del Mar in Barcelona from January 2019 to June 2023. Participants were matched in a 1:2-ratio (INRs:IR) based on age, sex, body mass index (BMI), and ART. Participants underwent bone quality assessment using in vivo microindentation, BMD and analysis of bone turnover and inflammation markers. Statistical analyses involved multivariable regression to adjust for potential confounding variables., Results: A total of 159 PWH were included, 53 INRs and 106 IRs. INRs had worse bone quality, with lower median Bone Material Strength index (BMSi) compared to IRs (79 (76-87) vs. 86 (82-89); p<0.001), and similar BMD. INRs shown increased high-sensitive C-Reactive Protein levels with lower 25-(OH)-Vitamin D3. A significant negative correlation between inflammation and bone quality was found, especially noticeable in INRs. Multivariable linear regression shown that INR status is a major predictor of decreased bone quality, regardless of conventional risk factors., Conclusion: INRs condition is significantly associated with higher inflammatory levels, which may contribute to a deleterious effect on bone quality as measured by in vivo microindentation. Further studies are needed to confirm these results and to focus on non-AIDS comorbidities in this subgroup of PWH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

People living with human immunodeficiency virus (HIV) are the individuals most affected by the current Monkeypox virus outbreak that was first announced in May 2022. Here we report Pan-pox-specific T-cell responses in a cohort of HIV-1-infected individuals after receiving the nonreplicative, attenuated smallpox vaccine JYNNEOS from Bavarian Nordic. Intradermal (i.d.) and subcutaneous (s.c.) vaccination was safe without major side effects. Dose-sparing i.d. vaccination was superior to s.c. vaccination and promoted T-cell polyfunctionality, and the expression of the gut-homing marker α4β7 integrin on lymphocytes. HIV-1-infected individuals with CD4 T-cell counts ≤500/mm 3 blood required at least a booster vaccination to exhibit efficient virus-specific T-cell responses. The magnitude of the Th1 response after this booster directly correlated with the CD4 T-cell count of the vaccinees. Further studies with a larger number of participants are warranted to confirm and expand our observations., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: CD4/CD8 ratio has been used as a quantitative prognostic risk factor in patients with viral infections. This study aims to assess the association between in-hospital mortality and at admission CD4/CD8 ratio among individuals with acute SARS-CoV-2 infection., Methods: This is a longitudinal cohort study with data of all consecutive patients admitted to the COVID-19 unit at Hospital del Mar, Barcelona, Spain for ≥48 h between March to May 2020. The CD4+ CD8+ T-cell subset differentiation was assessed by flow cytometry at admission as well as a complete blood test. Patients were classified according to CD4/CD8 ratio tertiles. The primary outcome was in-hospital mortality and the secondary outcome was acute respiratory distress (ARDS)., Results: A total of 338 patients were included in the cohort. A high CD4/CD8 ratio (third tertile) was associated with a higher in-hospital mortality [adjusted Cox model hazard ratio (HR) 4.68 (95%CI 1.56-14.04, p = 0.006), reference: second tertile HR 1]. Similarly, a high CD4/CD8 ratio (third tertile) was associated with a higher incidence of ARDS [adjusted logistic regression model OR 1.97 (95%CI 1.11-3.55, p = 0.022) reference: second tertile HR 1]. There was a trend of higher in-hospital mortality and incidence of ARDS in patients within the first tertile of CD4/CD8 ratio compared with the second one, but the difference was not significant. No associations were found with total lymphocyte count or inflammatory parameters, including D-dimer., Conclusion: CD4/CD8 ratio is a prognostic factor for the severity of COVID-19, reflecting the negative impact on prognosis of those individuals whose immune response has abnormal CD8+ T-cell expansion during the early response to the infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pascual-Dapena, Chillaron, Llauradó, Arnau-Barres, Flores, Lopez-Montesinos, Sorlí, Luis Martínez-Pérez, Gómez-Zorrilla, Du, García-Giralt and Güerri-Fernández.)

Serum albumin levels have been associated with prognosis in several conditions among older adults. The aim of this study is to assess the prognostic value in mortality of serum albumin in older adults with SARS-CoV-2 infection., Methods: Cohort observational study with consecutive older-adults (≥65 years old), with confirmed SARS-CoV-2 infection admitted to a university hospital between March-May 2020. A logistic regression model was fitted to assess the impact of albumin levels on in-hospital mortality adjusted by potential confounders., Results: Among a total of 840 patients admitted to the hospital, 405 (48%) were older adults with a total of 92 deaths (23%) among them. Those who died were older, had more comorbidities, higher inflammation status and lower levels of serum albumin at admission [3.10 g/dL (0.51) vs. 3.45 g/dL (0.45); p < 0.01. Serum albumin levels at admission were negatively correlated with inflammatory markers such as C-Reactive protein (Pearson Coeff -0.4634; p < 0.001) or IL-6 (Pearson's Coeff -0.244; p = 0.006) at admission but also to other clinical outcomes such time to clinical stability (Pearson's Coeff -0.259; p < 0.001). Severe hypoalbuminemia associated with increased risk of mortality was defined as ≤3 g/dL at admission according to the AUC/ROC analysis (0.72 95% CI 0.63-0.81) In a multivariate logistic regression model adjusting by age, inflammation, comorbidities and severity at admission severe hypoalbuminemia was a strong predictor of in-hospital mortality (OR 2.18 95% CI 1.03-4.62; p = 0.039)., Conclusion: Severe hypoalbuminemia with ≤3 g/dL is an independent risk factor for mortality among older adults with SARS-CoV-2 infection. There is a consistent correlation between albumin levels and inflammatory biomarkers. Further studies are needed to determine whether the supplementation of albumin as coadjuvant treatment will have a positive impact on the prognosis of this infection.

Myocardial involvement during SARS-CoV-2 infection has been reported in many prior publications. We aim to study the prevalence and the clinical implications of acute myocardial injury (MIN) during SARS-CoV-2 infection, particularly in older patients. The method includes a longitudinal observational study with all consecutive adult patients admitted to a COVID-19 unit between March-April 2020. Those aged ≥65 were considered as older adult group. MIN was defined as at least 1 high-sensitive troponin (hs-TnT) concentration above the 99th percentile upper reference limit with different sex-cutoff. Results. Among the 634 patients admitted during the period of observation, 365 (58%) had evidence of MIN, and, of them, 224 (61%) were older adults. Among older adults, MIN was associated with longer time to recovery compared to those without MIN (13 days (IQR 6-21) versus 9 days (IQR 5-17); p < 0.001, respectively. In-hospital mortality was significantly higher in older adults with MIN at admission versus those without it (71 (31%) versus 11 (12%); p < 0.001). In a logistic regression model adjusting by age, sex, severity, and Charlson Comorbidity Index, the OR for in-hospital mortality was 2.1 (95% CI: 1.02-4.42; p = 0.043) among those older adults with MIN at admission. Older adults with acute myocardial injury had greater time to clinical recovery, as well as higher odds of in-hospital mortality.

Background: Zinc is an essential micronutrient that impacts host-pathogen interplay at infection. Zinc balances immune responses, and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with an increased risk for severe severe coronavirus disease 2019 (COVID-19) outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression, and thus might represent a useful biomarker., Methods: We ran an observational cohort study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel, we have studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) replication in the Vero E6 cell line modifying zinc concentrations., Findings: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV-2 infected cells., Interpretation: Low SZC is a risk factor that determines COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.

Background: Bone mineral density (BMD) decreases with ART initiation with a tenofovir disoproxil fumarate-containing regimen, although bone tissue quality increases. The impact of dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC)-based ART initiation on bone health parameters is not clear., Objectives: To study the impact of DTG/ABC/3TC-based therapy on bone health parameters in ART-naive individuals with HIV after 48 weeks of treatment., Methods: An observational, prospective and analytical study of treatment-naive patients with HIV undergoing a DTG/ABC/3TC-based regimen at 48 week follow-up. Changes in bone strength parameters (BMD, bone microarchitecture and bone tissue quality) were assessed with non-parametric methods., Results: Sixteen HIV-infected ART-naive patients starting DTG/ABC/3TC were included. BMD in the lumbar spine showed a significant decrease of -2.25% (P = 0.007) and -4.1% in the femoral neck (P = 0.007). Bone microarchitecture, as measured by trabecular bone score, also decreased significantly by -2.5% (P = 0.03). In contrast, bone quality [bone material strength index (BMi)], as measured by microindentation, significantly increased with respect to baseline after 48 weeks of treatment, showing better bone properties of +6.53% (P < 0.001). No significant changes were found in bone turnover markers. In addition, a positive significant correlation between the CD4/CD8 cell count ratio at baseline and changes in BMSi after 48 weeks of treatment was observed (Spearman's rho = 0.4974; P = 0.04)., Conclusions: After a 48 week treatment with DTG/ABC/3TC-based ART, BMD and trabecular bone score decreased while bone tissue quality, as measured by microindentation, improved significantly. The state of the immune system at ART initiation is related to bone quality recovery. An overarching approach to assess bone toxicity in ART-treated patients is needed., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Monoclonal gammopathy of uncertain significance (MGUS) is highly prevalent in older adults and affects bone structure, with osteoporosis and increased risk of fractures in up to 14% of affected patients. Dual-energy X-ray absorptiometry (DXA), the standard technique for diagnosing osteoporosis, is ineffective to reveal microstructure and bone quality in this disease., Materials and Methods: We conducted a cross-sectional study of patients with MGUS, recruited consecutively from the Hematology and Internal Medicine Departments of Hospital del Mar, Barcelona, between January 2011 and January 2018. Medical records, clinical results and spinal X-ray images were collected. Bone mineral density (BMD) at hip and spine was measured by DXA and Bone Material Strength index (BMSi) by impact microindentation on the tibial mid-shaft., Results: Thirty-nine patients with MGUS and 65 age-matched controls without previous fractures were included. In the MGUS group, 11 (28.2%) patients had prevalent fractures, nearly half of them vertebral (n = 5, 45.45%). Compared to controls, MGUS patients had significantly lower BMSi, a mean (SD) of 70.72 (9.70) vs. 78.29 (8.70), p = 0.001, and lower spinal BMD values (0.900 [0.159] vs. 1.003 [0.168], respectively, p = 0.012), but no significant differences at femoral neck and total hip. No association was observed between BMSi and DXA. Bone remodeling markers (procollagen type-1 N propeptide, bone-alkaline phosphatase and C-terminal telopeptide of type I collagen) did not differ between the two groups., Conclusions: Spinal BMD and mechanical properties of bone tissue, as measured by impact microindentation, were impaired in patients with MGUS. These changes in bone tissue mechanical resistance were independent of DXA levels.

Background Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis. Aims Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters. Patients and methods Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR. Results In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001). Conclusions Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.

Numerous GWAS and candidate gene studies have highlighted the role of the Wnt pathway in bone biology. Our objective has been to study in detail the allelic architecture of three Wnt pathway genes: WNT16, DKK1 and SOST, in the context of osteoporosis. We have resequenced the coding and some regulatory regions of these three genes in two groups with extreme bone mineral density (BMD) (n = ∼50, each) from the BARCOS cohort. No interesting novel variants were identified. Thirteen predicted functional variants have been genotyped in the full cohort (n = 1490), and for ten of them (with MAF > 0.01), the association with BMD has been studied. We have found six variants nominally associated with BMD, of which 2 WNT16 variants predicted to be eQTLs for FAM3C (rs55710688, in the Kozak sequence and rs142005327, within a putative enhancer) withstood multiple-testing correction. In addition, two rare variants in functional regions (rs190011371 in WNT16b 3'UTR and rs570754792 in the SOST TATA box) were found only present in three women each, all with BMD below the mean of the cohort. Our results reinforce the higher importance of regulatory versus coding variants in these Wnt pathway genes and open new ways for functional studies of the relevant variants.

Objecive: Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is used to assess bone health in HIV patients. DXA measures the amount of mineral, but not other key aspects of bone strength such as bone microarchitecture or bone quality. Trabecular bone score (TBS) and in-vivo microindentation directly measure trabecular microarchitecture and bone tissue quality, respectively. The aim of this study is to measure bone strength properties using these techniques., Results: Forty naive HIV patients who were going to start antiretroviral therapy (ART), a single pill treatment with elvitegravir/cobicistat, tenofovir disoproxil fumarate (TDF), emtricitavine (FTC) were included. A significant reduction in BMD at spine (-3.25%, P < 0.001) and in femoral neck (-3.82%, P = 0.016) between baseline and 48 weeks of treatment were found. Bone microarchitecture score at the spine, as measured by TBS, also significantly decreased from 1.357 (0.09) to 1.322 (0.09) (-2.5%, P = 0.011) between baseline to 48 weeks of treatment. Microindentation (BMSi) values were significantly higher than at baseline [89.04 (4.2) versus 86.07 (6.1); 3.49%, P < 0.001] after 48 weeks of TDF-based ART treatment, indicating improved bone material properties CONCLUSION:: A significant decrease in BMD and TBS were observed after 1 year of TDF therapy. However, tissue quality significantly improved after 1 year of treatment, suggesting a recovery of bone material properties following the control of the infection despite the significant reduction of BMD. These techniques provide additional and necessary information to DXA about bone health in treated HIV patients, and because of its convenience and feasibility they could be routinely apply to assess bone in clinical practice.