Although next-generation sequencing has emerged as a powerful tool for diagnosing rare diseases (RD), many cases of inherited metabolic diseases (IMD) remain unsolved, hindering the diagnosis, clinical and therapeutic management of the patients. The primary aim of this study is to address the most elusive cases by applying long-read sequencing (LRS) targeted to the gene of interest on seven patients (FARS2, GYS2, PEX1, SLC2A1, AGL, ACAT1, and ACADM), identifying six novel pathogenic variants including two intronic variants, a structural variant and three transposable elements (TE) insertions. In addition, we have demonstrated the effect on splicing of an exonic variant previously reported as missense. Functional genetic tests specific for the expected effect of each variant of uncertain significance were designed, such as minigenes analysis or chromatin conformation capture assay. From the TE insertions, two were located in the genomic region of GYS2 or PEX1, causing a reduction in their mRNA expression. The third was located 7.6 kb downstream of SLC2A1; it alters the interaction between the SLC2A1 promoter and its distal regulatory element via the establishment of a loop with the 3’ border of the native topologically associating domain. This study shows that the combination of LRS and functional genetic assays confers a powerful approach for expanding the mutational spectrum of IMD, adding data to improve the diagnosis of this large group of RD.
ABSTRACT:Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody intended for once-daily subcutaneous prophylactic treatment for people with hemophilia A or B with and without inhibitors. Results from the phase 3 explorer7 study confirmed superiority of concizumab prophylaxis over no prophylaxis in reducing the annualized bleeding rate (ABR) in people with hemophilia A or B with inhibitors (HAwI/HBwI). Male patients aged ≥12 years were randomized 1:2 to no prophylaxis (group 1) or concizumab prophylaxis (group 2), or nonrandomly allocated to concizumab prophylaxis (groups 3 and 4). After ≥24 weeks of treatment, patients in group 1 could switch to concizumab prophylaxis. At the 56-week cutoff (defined as when all patients in groups 2-4 had completed the visit at 56 weeks or permanently discontinued treatment), bleed-related efficacy, pharmacokinetics and pharmacodynamics, and safety were assessed. Of the 133 patients enrolled (HAwI, n = 80; HBwI, n = 53), 114 received concizumab prophylaxis (groups 2-4) and 19 were randomized to no prophylaxis (group 1). After ≥24 weeks, 13 patients from group 1 switched to concizumab. Median ABR for treated spontaneous and traumatic bleeding episodes in patients receiving concizumab was 0.8 (interquartile range [IQR], 0.0-3.2) at the 56-week cutoff, consistent with the low bleeding rates (median ABR, 0.0; IQR, 0.0-3.3) at the 32-week cutoff. Concizumab and free-TFPI concentration remained stable over time. No new safety concerns were reported. Longer-term (≥1 year) efficacy and safety results of concizumab prophylaxis for HAwI/HBwI were consistent with the 32-week cutoff results in explorer7. This trial was registered at www.clinicaltrials.gov as #NCT04083781.
This study aimed to quantify horizontal and vertical bone gain using superimposition of preoperative and postoperative cone beam computed tomography (CBCT) in severe alveolar ridge defects treated with a modified guided bone regeneration (GBR) technique based on customized titanium occlusive barriers with a window design, combined with autologous blood clot and β-tricalcium phosphate (β-TCP). In this prospective case series, 13 patients (28 defects) were treated. Customized titanium barriers were digitally designed based on CBCT data and manufactured by laser sintering. The barriers were fixed over the defects and filled with a mixture of an autologous blood clot and β-TCP, providing an osteoconductive scaffold within a stable regenerative compartment. A standardized window-based follow-up protocol was applied during healing, including irrigation and controlled deepithelialization. Primary outcomes were horizontal and vertical bone gain, assessed by pre- and postoperative CBCT superimposition. Histological evaluation was performed at the time of implant placement. After 8 months, significant bone gain was observed, with a mean horizontal gain of 4.50 ± 2.02 mm and a mean vertical gain of 4.40 ± 2.82 mm (p < 0.0001), confirmed by linear mixed-effects models and patient-level sensitivity analyses (p < 0.001). Histological analysis revealed well-vascularized newly formed bone with active osteoblasts and no inflammatory response. Keratinized gingiva formation was observed at all sites. One minor complication (mild screw loosening) was recorded and successfully resolved. This study is presented as a prospective case series; therefore, the results should be interpreted as exploratory evidence and do not allow direct comparisons or conclusions regarding equivalence or superiority over other GBR techniques. The present report specifically evaluates the regenerative phase prior to functional loading; therefore, although implants were placed according to protocol, implant survival and long-term functional outcomes were not assessed and cannot be inferred from these data. Within the limitations of this prospective case series, customized titanium occlusive barriers with a window design demonstrated promising results for horizontal and vertical bone augmentation and keratinized gingiva formation, without the need for autologous bone grafts or primary wound closure.
IntroductionSeveral factors influence mortality and survival after hip fracture, including nutritional status, which is associated with both incidence and prognosis. However, there is little evidence on the impact of oral nutritional supplements (ONS) on the survival of these patients, and the available results are mixed. Our aim was to analyze the effect of adherence to ONS treatment on post-hospital mortality, with the hypothesis that this would be lower in an adherent group.MethodsProspective study of patients aged 65 years or older, admitted for fragility hip fracture. Follow-up was carried out at 3, 6 and 12 months to evaluate retrieval of ONS in pharmacies and survival. Adherence was considered if ONS were withdrawn for 3 months or longer. The sample was divided into four groups: (1) well-nourished patients without prescription of ONS, (2) moderately malnourished patients without prescription of ONS, (3) moderate or severely malnourished patients with prescription of ONS but without adherence, and (4) moderately or severely malnourished patients with prescription of ONS and adherence. Mortality between groups was compared by means of a Cox regression, adjusted for confounding variables.Results300 patients were included (mean age 82.9 years; 79.3% female), with severe malnutrition in 19.7%. Non-adherent malnourished patients showed a significantly higher risk of death than adherent malnourished patients (HR = 3.67; 95% CI: 1.41–9.57; p = 0.008). Non-adherent malnourished patients had a significantly higher risk of death compared to well-nourished patients (HR = 2.95; 95% CI: 1.31–6.65; p = 0.009). Malnourished patients without ONS had a non-significant higher mortality risk than well-nourished patients (HR = 1.66; 95% CI: 0.72–3.84, p = 0.236). Adherent malnourished patients showed a non-significant trend toward lower mortality than well-nourished patients (HR = 0.80; 95% CI: 0.25–2.56; p = 0.712).ConclusionIn our study, 3-month adherence to ONS is associated with a reduction in 3, 6 and 12-month mortality in older patients with a hip fracture when compared to non-adherent patients and shows a trend toward an improved survival rate than that of well-nourished patients.
Healthcare professionals manually review electronic health records to select patients who meet eligibility criteria of clinical trials. Natural language processing offers a complement for this task, although few initiatives exist in Spanish. We present version 3 of the CT-EBM-SP corpus of 1200 clinical trials (292173 tokens), annotated with 23 entity types and 18 relation types, covering Unified Medical Language System (UMLS) semantic groups, drug-related information, temporal data, and negation/speculation. We encoded 11 attributes (e.g., event temporality and experiencer status) and normalized entities to UMLS Concept Unique Identifiers. The corpus contains 87037 entities, including nested and discontinuous entities, 16597 attributes and 68206 relationships. Inter-annotator agreement (IAA) achieved average F1 values of 0.861 (entities), 0.810 (attributes), and 0.791 (relations). 81.75% of entities were normalized (IAA: F1 = 0.966). We benchmarked this dataset by fine-tuning Transformer models for relation extraction (RE) and medical concept normalization (MCN). In RE, the average F1 ranged from 0.858 to 0.879, and for MCN, the accuracy at rank 1 was 0.896. The corpus and models are publicly available.
