Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in ...combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.
BACKGROUNDThe real predictive prognostic capacity of cellular indices (or ratios) is unclear in SARS-CoV-2 infection. This study aimed to assess the prognostic role of previously well-known ...laboratory indices and new ones in hospitalized COVID-19 patients. METHODSA retrospective observational study from March to May 2022 evaluated laboratory indices on admission (neutrophil to lymphocyte-, derived neutrophil to lymphocyte-, platelet to lymphocyte-, CRP to lymphocyte-, CRP to albumin-, fibrinogen to lymphocyte-, d-dimer to lymphocyte-, ferritin to lymphocyte-, LDH to lymphocyte-, and IL-6 to lymphocyte ratios), in patients hospitalized due to SARS-CoV2 infection to determine the association with mortality, admission to an intensive care unit (ICU), need for non-invasive mechanical ventilation (NIMV), orotracheal intubation (OTI), or combined event at 30 days follow-up. RESULTSA total of 1113 COVID-19 patients were evaluated with a mean age of 64.1 ± 15.9 years (58.49% male), 166 (14.91%) patients died, 58 (5.21%) required ICU admission, 73 (6.56%) needed NIMV, 46 (4.23%) needed OTI, and 247 (22.19%) presented the combined event. All the ratios evaluated in this study showed statistical significance in the univariate analysis for mortality and combined event; however, only d-dimer to lymphocyte ratio >0.6 presented an independent association in the multivariate analysis for 30-day mortality (adjusted OR 2.32; p = .047) and 30-day combined event (adjusted OR 2.62; p = .014). CONCLUSIONSLaboratory indices might be a potential biomarker for better prognosis stratification in hospitalized COVID-19 patients. d-Dimer to lymphocyte ratio presents an independent association for 30-day mortality and 30-day adverse outcomes in hospitalized COVID-19 patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evidence is scant regarding the long-term humoral and cellular responses Q7 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in cancer patients after repeated ...booster doses. The possibility of T-cell exhaustion following these booster doses in this population has not yet been fully studied and remains uncertain.
In this single-center prospective observational study, we explored the specific humoral and cellular response to S1 antigen in 36 patients with solid malignancies at baseline, and after the second and third doses of the mRNA-1273 vaccine.
A dual behavior was observed: 24 (66.7%) patients showed partial specific IFN-γ response after the second dose that was further enhanced after the third dose; and 11 (30.5%) already showed an optimal response after the second dose and experienced a marked fall-off of specific IFN-γ production after the third (4 patients negativization), which might suggest T cell exhaustion due to repetitive priming to the same antigen. One (2.8%) patient had persistently negative responses after all three doses. Seroconversion occurred in all patients after the second dose. We then studied circulating exhausted CD8+ T-cells in 4 patients from each of the two response patterns, those with increase and those with decrease in cellular response after the third booster. The patients with decreased cellular response after the booster had a higher expression of PD1
CD8
and CD57
PD1
CD8
exhausted T cells compared with those with an increased cellular response both
and
. The proportion of PD1
CD8
and CD57
PD1
CD8
exhausted T cells inversely correlated with IFN-γ production.
Our preliminary data show that the two-dose SARS-CoV-2 vaccine regimen was beneficial in all cancer patients of our study. An additional booster seems to be beneficial in suboptimal vaccine seroconverters, in contrast to maximal responders that might develop exhaustion. Our data should be interpreted with caution given the small sample size and highlight the urgent need to validate our results in other independent and larger cohorts. Altogether, our data support the relevance of immunological functional studies to personalize preventive and treatment decisions in cancer patients.
Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms ...(SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.
Cantabria Cohort stems from a research and action initiative lead by researchers from Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital and University of Cantabria, ...supported by the regional Goverment. Its aim is to identify and follow up a cohort that would provide information to improve the understanding of the etiology and prognosis of different acute and chronic diseases. The Cantabria Cohort will recruit between 40,000-50,000 residents aged 40-69 years at baseline, representing 10-20% of the target population. Currently, more than 30,000 volunteers have been enrolled. All participants will be invited for a re-assessment every three years, while the overall duration is planned for twenty years. The repeated collection of biomaterials combined with broad information from participant questionnaires, medical examinations, actual health system records and other secondary public data sources is a major strength of its design, which will make it possible to address biological pathways of disease development, identify new factors involved in health and disease, design new strategies for disease prevention, and advance precision medicine. It is conceived to allow access to a large number of researchers worldwide to boost collaboration and medical research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Quantitative real-time PCR (qPCR) is now commonly used as a method to confirm diagnosis of malaria and to differentiate recrudescence from re-infection, especially in clinical trials and in reference ...laboratories where precise quantification is critical. Although anti-malarial drug discovery is based on in vivo murine efficacy models, use of molecular analysis has been limited. The aim of this study was to develop qPCR as a valid methodology to support pre-clinical anti-malarial models by using filter papers to maintain material for qPCR and to compare this with traditional methods.
FTA technology (Whatman) is a rapid and safe method for extracting nucleic acids from blood. Peripheral blood samples from mice infected with Plasmodium berghei, P. yoelii, or P. falciparum were kept as frozen samples or as spots on FTA cards. The extracted genetic material from both types of samples was assessed for quantification by qPCR using sets of specific primers specifically designed for Plasmodium 18S rRNA, LDH, and CytB genes.
The optimal conditions for nucleic acid extraction from FTA cards and qPCR amplification were set up, and were confirmed to be suitable for parasite quantification using DNA as template after storage at room temperature for as long as 26 months in the case of P. berghei samples and 52 months for P. falciparum and P. yoelii. The quality of DNA extracted from the FTA cards for gene sequencing and microsatellite amplification was also assessed.
This is the first study to report the suitability of FTA cards and qPCR assay to quantify parasite load in samples from in vivo efficacy models to support the drug discovery process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Early abdominal complications are frequent after lung transplantation.•A high percentage of abdominal complications require invasive treatment.•Hemodynamic instability is a risk factor for abdominal ...complications.
Patients undergoing lung transplantation (LT) are at high risk of developing serious abdominal complications, which can lead to higher rates of morbidity and mortality. The aim of this study was to investigate the incidence and spectrum of these complications when they develop during the first 30 days after LT, as well as their possible association with possible risk factors.
A retrospective study of 552 patients undergoing LT between 01/02/2006 and 06/03/2021 was carried out. A descriptive and analytical evaluation of the patients who experienced complications and those who did not was performed comparatively. Data related to patient characteristics and the lung transplantation procedure were collected.
Overall, 8.2% of patients developed severe abdominal complications during the first 30 days; paralytic ileus was the most frequent (31.1%), closely followed by visceral perforation (26.7%). The percentage of patients who required an invasive procedure to manage post-transplant complications was 57.8%. Surgical intervention was required in 39.8%. The variables that showed a significant relationship with the development of severe short-term abdominal complications in the univariate analysis were the time of surgery, the use of ECMO/ ECC and red blood cell transfusion during or after surgery. In the multivariate study, however, only duration of surgery remained significant (p=0.03).
The incidence of severe short-term abdominal complications after LT period was 8%. The commonest complications were paralytic ileus and intestinal perforation. Most patients did not require surgery. The only risk factor found associated with these complications was the duration of the surgical intervention.
Background Prolonged confinement can lead to personal deterioration at various levels. We studied this phenomenon during the nationwide COVID-19 lockdown in a functionally dependent population of the ...Orcasitas neighborhood of Madrid, Spain, by measuring their ability to perform basic activities of daily living and their mortality rate. Methods A total of 127 patients were included in the Orcasitas cohort. Of this cohort, 78.7% were female, 21.3% were male, and their mean age was 86 years. All participants had a Barthel index of ≤ 60. Changes from pre- to post-confinement and 3 years afterward were analyzed, and the effect of these changes on survival was assessed (2020–2023). Results The post-confinement functional assessment showed significant improvement in independence over pre-confinement for both the Barthel score ( t = −5.823; p < 0.001) and the classification level ( z = −2.988; p < 0.003). This improvement progressively disappeared in the following 3 years, and 40.9% of the patients in this cohort died during this period. These outcomes were associated with the Barthel index ( z = −3.646; p < 0.001) and the level of dependence (hazard ratio 2.227; CI 1.514–3.276). Higher mortality was observed among men (HR 1.745; CI 1.045–2.915) and those with severe dependence (HR 2.169; CI 1.469–3.201). Setting the cutoff point of the Barthel index at 40 provided the best detection of the risk of death associated with dependence. Conclusions Home confinement and the risk of death due to the COVID-19 pandemic awakened a form of resilience in the face of adversity among the population of functionally dependent adults. The Barthel index is a good predictor of medium- and long-term mortality and is a useful method for detecting populations at risk in health planning. A cutoff score of 40 is useful for this purpose. To a certain extent, the non-institutionalized dependent population is an invisible population. Future studies should analyze the causes of the high mortality observed.
RESUMEN Introducción y objetivos: La rehabilitación vestibular (RV) basada en la terapia física, tiene el objetivo, en el caso de patología vestibular, de inducir la compensación del sistema nervioso ...central (SNC) a nivel de núcleos vestibulares y de otros niveles del SNC. Incluye ejercicios de habituación, adaptación y sustitución vestibular, ejercicios para mejorar el equilibrio y el control postural dinámico y ejercicios para el acondicionamiento general. En este capítulo discutimos los recientes avances sobre el adiestramiento del equilibrio y de la marcha, la estabilidad de la mirada y la habituación, en el contexto de los trastornos vestibulares uni y bilaterales. Material y métodos: Revisión narrativa. Resultados: Los ejercicios se prescriben para mejorar la función; fortaleciendo, y favoreciendo la flexibilidad y la resistencia, a través de la adaptación del RVO, la habituación, la sustitución sensorial, la marcha y el equilibrio postural. Son más eficaces los programas personalizados que los genéricos. El cumplimiento mejora con la personalización y las visitas de seguimiento a un fisioterapeuta. Conclusiones: La RV permite mejorar el déficit funcional y los síntomas subjetivos derivados de la hipofunción vestibular periférica uni y bilateral, así como las alteraciones del equilibrio de origen central. Los objetivos de la RV consisten en reducir los síntomas para mejorar la estabilidad postural y de la mirada (particularmente durante los movimientos de la cabeza) y devolver al individuo a sus actividades normales, incluyendo la actividad física, la conducción y el trabajo habitual. Los médicos deben ofrecer la RV a quienes muestren limitaciones funcionales relacionadas con un déficit vestibular, pues actualmente se considera el tratamiento estándar en la disfunción vestibular periférica.
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