171 research outputs found
Complement Binding Anti-HLA Antibodies and the Survival of Kidney Transplantation
Background: Antibody-mediated rejection (AMR) is one of the most important challenges in
the context of renal transplantation, because the binding of de novo donor-specific antibodies (dnDSA)
to the kidney graft triggers the activation of the complement, which in turn leads to loss of transplant.
In this context, the objective of this study was to evaluate the association between complement-fixing
dnDSA antibodies and graft loss as well as the possible association between non-complement-fixing
antibodies and transplanted organ survival in kidney transplant recipients. Methods: Our study
included a cohort of 245 transplant patients over a 5-year period at Virgen de las Nieves University
Hospital (HUVN) in Granada, Spain. Results: dnDSA was observed in 26 patients. Of these patients,
17 had non-complement-fixing dnDSA and 9 had complement-fixing dnDSA. Conclusions: Our study
demonstrated a significant association between the frequency of rejection and renal graft loss and
the presence of C1q-binding dnDSA. Our results show the importance of the individualization of
dnDSA, classifying them according to their ability to activate the complement, and suggest that the
detection of complement-binding capacity by dnDSA could be used as a prognostic marker to predict
AMR outcome and graft survival in kidney transplant patients who develop dnDSA
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Critical illness in COVID-19 is an extreme and clinically homogeneous disease
phenotype that we have previously shown1 to be highly efficient for discovery of
genetic associations2. Despite the advanced stage of illness at presentation, we have
shown that host genetics in patients who are critically ill with COVID-19 can identify
immunomodulatory therapies with strong beneficial effects in this group3. Here we
analyse 24,202 cases of COVID-19 with critical illness comprising a combination of
microarray genotype and whole-genome sequencing data from cases of critical illness
in the international GenOMICC (11,440 cases) study, combined with other studies
recruiting hospitalized patients with a strong focus on severe and critical disease:
ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results
in the context of existing work, we conduct a meta-analysis of the new GenOMICC
genome-wide association study (GWAS) results with previously published data. We
find 49 genome-wide significant associations, of which 16 have not been reported
previously. To investigate the therapeutic implications of these findings, we infer the
structural consequences of protein-coding variants, and combine our GWAS results
with gene expression data using a monocyte transcriptome-wide association study
(TWAS) model, as well as gene and protein expression using Mendelian randomization.
We identify potentially druggable targets in multiple systems, including inflammatory
signalling ( JAK1), monocyte–macrophage activation and endothelial permeability
(PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral
entry and replication (TMPRSS2 and RAB2A)
Incidence, Management Experience and Characteristics of Patients with Giardiasis and Common Variable Immunodeficiency
Common variable immunodeficiency (CVID) is an antibody immunodeficiency with a
wide variety of clinical and immunological manifestations, and whose genetic cause is found in
about 25% of diagnosed cases. Giardia lamblia is one of the main causes of gastrointestinal infections
in CVID. 5-Nitroimidazoles are the most used first-line treatment, but nitroimidazole-refractory
giardiasis is increasing. Nevertheless, only a few cases of refractory giardiasis in CVID have been
reported. This study aimed to determine the incidence of Giardia infection in our CVID cohort, shows
our management experience and describes patients’ phenotypic features. Clinical data collection,
immunological, immunogenetics and microbiology assays were performed, and previous cases
of giardiasis in CVID were reviewed. The incidence of symptomatic giardiasis was 12.9%. The
main immunological features were undetectable or decreased IgA levels and reduced switched
memory B cells. A probable PTEN pathogenic variant was detected in one. Three patients responded
to metronidazole but suffered reinfections, and one was a refractory giardiasis eradicated with
innovative quinacrine plus paromomycin combination. This work could contribute to the decisionmaking
and therapeutic management of future patients with CVID and giardiasis, highlighting the
importance of the early detection and treatment of infections in patients with CVID to ensure a good
quality of life
Clinical Case: Patient with Mixed Graft Rejection Four Days after Kidney Transplantation Developed Specific Antibodies against Donor Bw4 Specificities.
Kidney transplantation, like other transplants, has the risk of producing graft rejection due to genetic differences between donor and recipient. The three known types of renal rejection are listed in the Banff classification: T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), and mixed rejection. The human leukocyte antigens (HLA) are highly polymorphic and may be the targets of donor-specific antibodies, resulting in ABMR. Therefore, prior to transplantation, it is necessary to analyze the HLA genotype of the donor and recipient, as well as the presence of DSA, in order to avoid hyperacute rejection. However, due to the shortage of kidneys, it is very difficult to find a donor and a recipient with completely matched HLA genotypes. This can trigger a future rejection of the kidney, as is reported in this work. We describe a patient who received a kidney transplant after a negative DSA test, who developed graft rejection with antibodies against the donor's HLA-Bw4 public epitope and lymphocytic infiltrate four days after transplantation, whose differential diagnosis was mixed rejection
Major Histocompatibility Complex Class I Chain-Related (MICA) STR Polymorphisms in COVID-19 Patients
The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and
being overweight are well established risk factors for severe disease. However, innate immunity plays
a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural
Killer (NK) cells are part of innate immunity and are important in the control of virus infection by
killing infected cells and participating in the development of adaptive immunity. Therefore, we
studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility
complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among
other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy
controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele
is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9
allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease.Instituto de Salud Carlos III - FEDER funds (European Union) PI 16/00752
B-CTS-410-UGR-20Junta de Andalucia CTS-143
C-0013-201
Negative Clinical Evolution in COVID-19 Patients Is Frequently Accompanied With an Increased Proportion of Undifferentiated Th Cells and a Strong Underrepresentation of the Th1 Subset
The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most profound alteration affected the Th1 subset, which may explain the poor T cells responses and the persistent blood virus load. Finally, the decrease in Th1 cells may also explain the low frequency of CD4+ and CD8+ T cells that express the HLA-DR and CD38 activation markers observed in numerous patients who showed minimal or no lymphocyte activation response. We also identified the percentage of HLA-DR+CD4+ T cells, PD-1+CD+4/CD8+ T cells in blood, and the neutrophil/lymphocyte ratio as useful factors for predicting critical illness and fatal outcome in patients with confirmed COVID-1
Study of HLA-A, -B, -C, -DRB1 and -DQB1 polymorphisms in COVID-19 patients
Background: Human leukocyte antigen (HLA) plays an important role in immune responses
to infections, especially in the development of acquired immunity. Given the high degree
of polymorphisms that HLA molecules present, some will be more or less effective in
controlling SARS-CoV-2 infection. We wanted to analyze whether certain polymorphisms may
be involved in the protection or susceptibility to COVID-19.
Methods: We studied the polymorphisms in HLA class I (HLA-A, -B and -C) and II (HLA-DRB1 and
HLA-DQB1) molecules in 450 patients who required hospitalization for COVID-19, creating one
of the largest HLA-typed patient cohort to date.
Results: Our results show that there is no relationship between HLA polymorphisms or haplotypes
and susceptibility or protection to COVID-19. Conclusion: Our results may contribute to resolve the contradictory data on the role of HLA
polymorphisms in COVID-19 infection.Instituto de Salud Carlos III - FEDER funds (European Union) PI 16/00752Junta de Andalucia CTS-143
C-0013-2018RAFER S.L
Clinical guidelines for late-onset Pompe disease
English version available
at www.neurologia.comHasta 2006, la enfermedad de Pompe o glucogenosis tipo II era una enfermedad incurable y con tratamiento
meramente paliativo. El desarrollo de la terapia de sustitución con la enzima α-glucosidasa recombinante humana ha
constituido el primer tratamiento específico para esta enfermedad. El objetivo de esta guía es servir de referencia en el
manejo de la variedad de inicio tardío de la enfermedad de Pompe, es decir, la que aparece después del primer año de
vida. En la guía, un grupo de expertos españoles hace recomendaciones específicas en cuanto a diagnóstico, seguimiento
y tratamiento de esta enfermedad. En cuanto al diagnóstico, el método de la muestra en sangre seca es imprescindible
como primer paso para el diagnóstico de la enfermedad de Pompe, y el diagnóstico de confirmación de la enfermedad de
Pompe debe realizarse mediante un estudio de la actividad enzimática en muestra líquida en linfocitos aislados o mediante
el análisis mutacional del gen de la alfa-glucosidasa. En cuanto al tratamiento de la enfermedad con terapia de sustitución
enzimática, los expertos afirman que es eficaz en la mejoría o estabilización de la función motora y pulmonar, y debe
iniciarse cuando aparezcan los síntomas atribuibles a la enfermedad de PompeBefore 2006, Pompe disease or glycogenosis storage disease type II was an incurable disease whose treatment
was merely palliative. The development of a recombinant human alpha-glucosidase enzymatic replacement therapy has
become the first specific treatment for this illness. The aim of this guide is to serve as reference for the management of the
late-onset Pompe disease, the type of Pompe disease that develops after one year of age. In the guide a group of Spanish
experts make specific recommendations about diagnosis, follow-up and treatment of this illness. With regard to diagnosis,
the dried blood spots method is essential as the first step for the diagnosis of Pompe disease. The confirmation of the
diagnosis of Pompe disease must be made by means of an study of enzymatic activity in isolated lymphocytes or a
mutation analysis of the alpha-glucosidase gene. With regard to treatment with enzymatic replacement therapy, the
experts say that is effective improving or stabilizating the motor function and the respiratory function and it must be
introduced when the first symptoms attributable to Pompe disease appea
Plan financiero de la empresa Alicorp S.A.A y subsidiarias
En el presente trabajo de investigación, se examina la situación financiera de la
empresa Alicorp S.A.A., para lo cual se partió de un riguroso análisis de los estados
financieros de los últimos cinco años, realizando una proyección de los mismos al año 2021.
El análisis se profundiza en las diferentes decisiones gerenciales y financieras que fueron
trascendentales desde los inicios de Alicorp. Asimismo, se enfatiza en los sucesos que
conllevaron a la situación del año 2016.
Las cifras que fueron materia de estudio muestran que las decisiones tomadas
originaron un incremento en el valor de la empresa. Así, se examina la política de
endeudamiento y apalancamiento a través de la emisión de acciones y bonos corporativos.
Para elaborar las propuestas de generación de valor para la empresa Alicorp, se analizó el
mercado del sector de una nueva línea de negocios en la cual la empresa no tiene
participación, a fin de que pueda cumplir con el objetivo establecido por la compañía para los
siguientes años.
Finalmente, se plantean propuestas y recomendaciones que Alicorp podría ejecutar
para mejorar el rendimiento de su gestión operativa y financieraIn this research, the financial situation of the company Alicorp S.A.A. is examined.
for which it was based on a rigorous analysis of the financial statements of the last five years,
making a projection of them to the year 2021. The analysis goes deeper into the different
managerial and financial decisions that were transcendental since the beginning of Alicorp.
Likewise, it emphasizes the events that led to the current situation of the period 2016.
The figures that were the subject of study, show that the decisions taken originated an
increase in the value of the company. It examines the policy of indebtedness and leverage
through the issuance of shares and corporate bonds. To elaborate the proposals for the
generation of value for the company Alicorp, the market of the sector of a new line of
business was analyzed in which Alicorp has no participation and thus can meet the objective
established by the company for the following years.
Finally, proposals and recommendations are proposed that Alicorp has to execute to
improve the performance of its operational and financialTesi
Study of humoral and cellular immunity in vaccinated with mRNA-1273
This work was supported by "Investigacion y Desarrollo (I + D) del Sistema Andaluz de Salud (SAS)" and Instituto de Salud Carlos III (Proyecto FIS PI21/01708).The new vaccines against SARS-CoV-2 have raised a lot of expectations about their ability to induce immunity and the
duration of this. This is the case of mRNA vaccines such as Moderna’s mRNA-1273. Therefore, it is necessary to study
the humoral and cellular immunity generated by these vaccines. Our objectives are determining what is the normal
response of antibody production, and what is the level of protective antibodies and monitoring patients in case of subsequent
infection with COVID-19. We present the first results of a longitudinal study of the humoral response in 601
health workers vaccinated with Moderna. The results show a humoral immunity at 90 days after the second dose of
100%, with a strong decrease between the levels of circulating anti-S IgG antibodies between days 30 and 90 postvaccination.
Observing a steeper decline in those who had higher titles at the beginning. In addition, we present a cellular
response of 86% at three months after the second dose, which is related to low humoral response.Investigacion y Desarrollo (I + D) del Sistema Andaluz de Salud (SAS)Instituto de Salud Carlos III
European Commission FIS PI21/0170
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