Subcellular location of source proteins improves prediction of neoantigens for immunotherapy.

Antigen presentation via the major histocompatibility complex (MHC) is essential for anti-tumor immunity. However, the rules that determine which tumor-derived peptides will be immunogenic are still incompletely understood. Here, we investigated whether constraints on peptide accessibility to the MHC due to protein subcellular location are associated with peptide immunogenicity potential. Analyzing over 380,000 peptides from studies of MHC presentation and peptide immunogenicity, we find clear spatial biases in both eluted and immunogenic peptides. We find that including parent protein location improves the prediction of peptide immunogenicity in multiple datasets. In human immunotherapy cohorts, the location was associated with a neoantigen vaccination response, and immune checkpoint blockade responders generally had a higher burden of neopeptides from accessible locations. We conclude that protein subcellular location adds important information for optimizing cancer immunotherapies.

Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility.

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.

Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern.

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to affect the quality of the antibody response focusing it to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and three variants of concern (VOC), B.1.351, B.1.617.2, and BA.1. We demonstrate that immunogens built on structure selection can be used to influence the quality of the antibody response by focusing it to a conserved site of vulnerability shared between wildtype virus and VOCs, resulting in neutralizing antibodies across variants.

Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.

Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

Medical students' and residents' views on euthanasia.

BACKGROUND: Doctors are increasingly faced with end-of-life decisions. Little is known about how medical students approach euthanasia. The objective of this study was to evaluate, among medical students and residents, the view on euthanasia and its variants; correlate such a view with empathy and religiosity/spiritualism; and with the stages of medical training in Brazil. METHODS: This is an exploratory cross-sectional study using an online questionnaire to be filled out on a voluntary basis among medical students and residents, consisting of: socio-demographic data, an empathy questionnaire and questions with elaborate clinical cases that typify situations of the variants of euthanasia. RESULTS: From 1550 invitations, 273 volunteer participants responded (17.6%). The percentages of strong agreement/agreement on the concepts were: passive euthanasia (72.9%); active euthanasia (22.3%), orthothanasia (90.1%), dysthanasia (18.7%), assisted suicide (33%) and sedation (82.8%). Passive euthanasia, active euthanasia, dysthanasia and assisted suicide showed greater refusal with increasing length of medical training. Religious belief and degree of empathy did not significantly influence the opinion about the concepts. Strong agreement/agreement were: passive euthanasia (72.9%); active euthanasia (22.3%), orthothanasia (90.1%), dysthanasia (18.7%), assisted suicide (33%) and sedation (82.8%). CONCLUSIONS: Passive euthanasia, active euthanasia, dysthanasia and assisted suicide showed greater refusal with increasing length of medical training. The external validation of our findings relies on the distinct legal, cultural, and religious frameworks found across various countries.

A Novel Tri-Hydroxy-Methylated Chalcone Isolated from Chromolaena tacotana with Anti-Cancer Potential Targeting Pro-Survival Proteins.

Chromolaena tacotana (Klatt) R. M. King and H. Rob (Ch. tacotana) contains bioactive flavonoids that may have antioxidant and/or anti-cancer properties. This study investigated the potential anti-cancer properties of a newly identified chalcone isolated from the inflorescences of the plant Chromolaena tacotana (Klatt) R. M. King and H. Rob (Ch. tacotana). The chalcone structure was determined using HPLC/MS (QTOF), UV, and NMR spectroscopy. The compound cytotoxicity and selectivity were evaluated on prostate, cervical, and breast cancer cell lines using the MTT assay. Apoptosis and autophagy induction were assessed through flow cytometry by detecting annexin V/7-AAD, active Casp3/7, and LC3B proteins. These results were supported by Western blot analysis. Mitochondrial effects on membrane potential, as well as levels of pro- and anti-apoptotic proteins were analyzed using flow cytometry, fluorescent microscopy, and Western blot analysis specifically on a triple-negative breast cancer (TNBC) cell line. Furthermore, molecular docking (MD) and molecular dynamics (MD) simulations were performed to evaluate the interaction between the compounds and pro-survival proteins. The compound identified as 2',3,4-trihydroxy-4',6'-dimethoxy chalcone inhibited the cancer cell line proliferation and induced apoptosis and autophagy. MDA-MB-231, a TNBC cell line, exhibited the highest sensitivity to the compound with good selectivity. This activity was associated with the regulation of mitochondrial membrane potential, activation of the pro-apoptotic proteins, and reduction of anti-apoptotic proteins, thereby triggering the intrinsic apoptotic pathway. The chalcone consistently interacted with anti-apoptotic proteins, particularly the Bcl-2 protein, throughout the simulation period. However, there was a noticeable conformational shift observed with the negative autophagy regulator mTOR protein. Future studies should focus on the molecular mechanisms underlying the anti-cancer potential of the new chalcone and other flavonoids from Ch. tacotana, particularly against predominant cancer cell types.

Hospital length of stay for COVID-19 patients: Data-driven methods for forward planning.

BACKGROUND: Predicting hospital length of stay (LoS) for patients with COVID-19 infection is essential to ensure that adequate bed capacity can be provided without unnecessarily restricting care for patients with other conditions. Here, we demonstrate the utility of three complementary methods for predicting LoS using UK national- and hospital-level data. METHOD: On a national scale, relevant patients were identified from the COVID-19 Hospitalisation in England Surveillance System (CHESS) reports. An Accelerated Failure Time (AFT) survival model and a truncation corrected method (TC), both with underlying Weibull distributions, were fitted to the data to estimate LoS from hospital admission date to an outcome (death or discharge) and from hospital admission date to Intensive Care Unit (ICU) admission date. In a second approach we fit a multi-state (MS) survival model to data directly from the Manchester University NHS Foundation Trust (MFT). We develop a planning tool that uses LoS estimates from these models to predict bed occupancy. RESULTS: All methods produced similar overall estimates of LoS for overall hospital stay, given a patient is not admitted to ICU (8.4, 9.1 and 8.0 days for AFT, TC and MS, respectively). Estimates differ more significantly between the local and national level when considering ICU. National estimates for ICU LoS from AFT and TC were 12.4 and 13.4 days, whereas in local data the MS method produced estimates of 18.9 days. CONCLUSIONS: Given the complexity and partiality of different data sources and the rapidly evolving nature of the COVID-19 pandemic, it is most appropriate to use multiple analysis methods on multiple datasets. The AFT method accounts for censored cases, but does not allow for simultaneous consideration of different outcomes. The TC method does not include censored cases, instead correcting for truncation in the data, but does consider these different outcomes. The MS method can model complex pathways to different outcomes whilst accounting for censoring, but cannot handle non-random case missingness. Overall, we conclude that data-driven modelling approaches of LoS using these methods is useful in epidemic planning and management, and should be considered for widespread adoption throughout healthcare systems internationally where similar data resources exist.

Partial-AZFc deletions in Chilean men with primary spermatogenic impairment: gene dosage and Y-chromosome haplogroups.

PURPOSE: To investigate the association of partial-AZFc deletions in Chilean men with primary spermatogenic failure and their testicular histopathological phenotypes, analyzing the contribution of DAZ dosage, CDY1 copies, and Y-chromosome haplogroups. SUBJECTS AND METHODS: We studied 479 Chilean men: 334 infertile patients with histological examination (233 cases with spermatogenic defects and 101 normal spermatogenesis, obstructive controls, OC), and 145 normozoospermic controls (NC). AZFc subdeletions were detected by single-tagged sequences and single nucleotide variants analysis. DAZ-copy number was quantified by real-time qPCR. Y-chromosome haplogroups (Y-hg) were hierarchically genotyped through 16 biallelic-markers. RESULTS: The prevalence of AZFc-partial deletions was increased in cases (6%) compared with NC (1.4%) (P = 0.035). There was no difference between 143 Sertoli-cell only syndrome, 35 maturation arrest, or 35 mix atrophy patients and controls. However, gr/gr deletions were more frequent in 16 subjects with hypospermatogenesis compared with NC (P = 0.003) and OC (P = 0.013). Y-hg R was the most prevalent (~ 50%), but decreased among gr/gr deletions (21%, P = 0.03). The prevalence of Y-hg M increased in cases versus controls, both in total and non-deleted men (3.9 and 3.7% versus 0.4%, P = 0.009 and P = 0.016, respectively). Among gr/gr deletions, Y-hg H increased compared with non-deleted men (14.3% versus 0.4%, P = 0.0047). CONCLUSION: Partial-AZFc deletions in a Chilean admixed population are associated with secretory azo/oligozoospermia and might have a role in the development of hypospermatogenesis. Low represented haplogroups, Y-hg M and Y-hg H, show an association with the occurrence of spermatogenic failure and gr/gr deletions respectively; however, additional studies are required.

Dentin moisture does not influence postoperative sensitivity in posterior restorations: A double-blind randomized clinical trial.

PURPOSE: This double-blind, randomized clinical trial evaluated the influence of dentin moisture on postoperative sensitivity (POS) in posterior restorations using a simplified etch-and-rinse adhesive, until 12 months of clinical service. METHODS: 90 restorations were inserted in 45 patients to treat carious lesions or to replace existing posterior restorations with a depth ≥ 3 mm. After cavity preparation, the simplified etch-and-rinse adhesive (Adper Single Bond 2) was applied on dry or wet dentin followed by a bulk-fill resin composite (Filtek Bulk Fill) under rubber dam isolation. The patient's spontaneous and stimulated POS was evaluated at baseline and after 7 days, 6 months, and 12 months of clinical evaluation. The secondary parameters (marginal discoloration, marginal adaptation, fracture and recurrence of caries) were evaluated by World Dental Federation (FDI) criteria after 7 days, 6 and 12 months of clinical evaluation. RESULTS: No significant spontaneous and stimulated POS was observed when dry and wet dentin were compared (P> 0.05). A significant and higher risk of spontaneous POS (18.6%; 95% CI 9.7 to 32.6) occurred up to 48 hours after restoration placement for both groups when compared to all evaluation times (P< 0.03). However, the intensity of POS was mild at up to 48 hours with a difference between the dry and wet dentin groups (P> 0.79). When secondary parameters were evaluated, no significant difference between the groups were observed (P> 0.05). CLINICAL SIGNIFICANCE: The moisture level of the dentin substrate in posterior restorations does not influence POS in bulk-fill resin composite posterior restorations when associated with an etch-and-rinse ethanol-based adhesive system.

Effects of experimental intracerebral ventricular injection of amyloid beta peptide (1-42) aggregates on daily rhythms of Aß-degrading enzymes in the hippocampus: Relevance to Alzheimer's disease pathophysiology.

One of the main pathological features in the Alzheimer disease (AD) is the presence of senile plaques, primarily composed of Aß peptide aggregates, in cortex and hippocampus. AD late onset, which constitutes 90% of cases, could be mainly attributable to deficiencies in the clearance of the Aß peptide. Here we show that expression of Aß-degrading enzymes varies on a daily basis in the hippocampus. Interestingly, an intracerebroventricular injection of Aß aggregates modified temporal patterns of Aß-degrading proteases, as well as clock proteins (BMAL1 and RORα) and antioxidant enzymes (CAT and GPx) daily rhythms. Our findings showed that the increase of Aß leads to the alteration of the enzymes involved in the clearance, and, consequently, to an increase of oxidative stress and alteration of the cellular redox state, affecting the functioning of the endogenous clock and daily rhythms of BMAL1, RORα and their target genes, in this disease.

A Sensor Platform for Athletes' Training Supervision: A Proof of Concept Study.

One of the basic needs of professional athletes is the real-time and non-invasive monitoring of their activities. The use of these kind of data is necessary to develop strategies for specific tailored training in order to improve performances. The sensor system presented in this work has the aim to adopt a novel approach for the monitoring of physiological parameters, and athletes' performances, during their training. The anaerobic threshold is herein identified with the monitoring of the lactate concentration and the respiratory parameters. The data collected by the sensor are used to build a model using a supervised method (based on the partial least squares method, PLS) to predict the values of the parameters of interest. The sensor is able to measure the lactate concentration from a sample of saliva and it can estimate a respiratory parameter, such as maximal oxygen consumption, maximal carbon dioxide production and respiratory rate from a sample of exhaled breath. The main advantages of the device are the low power; the wireless communication; and the non-invasive sampling method, which allow its use in a real context of sport practice.

First - line, non - cryopreserved autologous stem cell transplant for poor - risk germ - cell tumors: Experience in a developing country.

PURPOSE: The current first - line treatment for non - seminomatous germ cell tumor (NSGCT) consists of four cycles of cisplatin, etoposide, and bleomycin (BEP), which results in 5 - year overall survival < 60% in patients with poor - risk features. Autologous hematopoietic stem cell transplantation (auto - HSCT) as a method for overcoming high toxicity after high dose chemotherapy (HDC) has been explored in different solid tumors, but has remained standard practice only for NSGCT. Our objective was to describe outcomes of patients with poor - risk NSGCT who underwent first - line autologous HSCT in a tertiary center in Mexico. PATIENTS AND METHODS: Twenty nine consecutive patients with NSGCT who received first - line, non - cryopreserved autologous HSCT at the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City, Mexico, from November 1998 to June 2016, were retrospectively analyzed. RESULTS: The median age at transplantation was 23 (15 - 39) years. Most patients (n = 18, 62%) had testicular primary tumor, and 23 had metastases (79%). Complete response after auto - HSCT was observed in 45%. Non - relapse mortality was 0. Five - year relapse / progression free and overall survival were 67% and 69%, respectively. CONCLUSIONS: This small single limited - resource institution study demonstrated that patients with poor - risk NSGCT are curable by first - line HDC plus autologous HSCT and that this procedure is feasible and affordable to perform using non - cryopreserved hematopoietic stem cells.

[Risk factors for suicide attempts in people with depressive disorders treated in secondary health care]. / Factores de riesgo para intento de suicidio en personas con trastorno depresivo en atención secundaria.

BACKGROUND: Depression is the most common psychiatric disorder in people with suicidal behavior. The knowledge of its risk factors should help to design preventive strategies. AIM: To describe suicidal behavior and risk factors for attempted suicide in people with major depressive disorders (MDD). MATERIAL AND METHODS: A 12-month follow-up study was conducted in 112 outpatients at three psychiatric care centers of Ñuble, Chile, with baseline and quarterly assessments. Demographic, psychosocial and clinical factors as potential risk factors of suicide attempts, were assessed. A clinical interview with DSM-IV diagnostic criteria checklist, Hamilton Depression Scale and the List of Threatening Experiences and Multidimensional Scale of Perceived Social Support were applied. RESULTS: Sixty seven percent of participants had suicidal ideation and 43.8% had attempted suicide. Suicide risk was significantly higher in participants with a single major depressive episode (odds ratio [OR] = 3.98; 95% confidence intervals [CI] = 1,29-12,32 p = 0.02) and those with previous suicide attempts (OR = 13.15; 95% CI = 3,87-44.7 p < 0.01). Young age, not having a partner, being unemployed, having a severe major depressive episode, having psychotic symptoms, having a personality disorder and being devoid of medical illness increased the risk of suicide attempts, but they did not reach statistical significance. CONCLUSIONS: Significant risk factors should be specially considered when designing suicide preventive strategies in patients with MDD.

[Clinical features of major depressive disorders treated in secondary health care facilities in Chile]. / Características clínicas del trastorno depresivo mayor en tratamiento en el nivel secundario de atención.

BACKGROUND: Depression is considered the second leading cause of disability worldwide. AIM: To describe the clinical characteristics and the evolution of major depressive disorder (MDD) in secondary care. To evaluate the association between socio-demographic and clinic variables with the first or recurrent major depressive events (MDE). MATERIAL AND METHODS: Clinical features, treatment, remission and duration of MDE were evaluated during a follow up lasting 12 months in 112 participants aged 44 ± 15 years (79% women). Patients were assessed as outpatients every three months at three psychiatric care centers of Chile. Clinical interviews were carried out using DSM-IV diagnostic criteria checklists and the Hamilton Depression Scale was applied. RESULTS: Most patients were referred from primary care. The mean time lapse for referral to the secondary level was 10.8 months. Most patients had episodes that were recurrent, severe, with a high rate of psychosis, with suicide attempts and melancholic features and with psychiatric and medical comorbidities. Remission rate was 27.5%. In only 16 % of patients, the episode lasted six months or less. The group with recurrent episodes had different age, sex and clinical features. CONCLUSIONS: MDD treated at the secondary care level is severe and its symptoms are intense. The time lapse prior to referral was prolonged. Primary care management and referral of these patients should be studied more closely.

[Predictors of remission from major depressive disorder in secondary care]. / Predictores de remisión del trastorno depresivo mayor en tratamiento en el nivel secundario de atención.

Background The knowledge of predictive factors in depression should help to deal with the disease. Aim To assess potential predictors of remission of major depressive disorders (MDD) in secondary care and to propose a predictive model. Material and Methods A 12 month follow-up study was conducted in a sample of 112 outpatients at three psychiatric care centers of Chile, with baseline and quarterly assessments. Demographic, psychosocial, clinical and treatment factors as potential predictors, were assessed. A clinical interview with the checklist of DSM-IV diagnostic criteria, the Hamilton Depression Scale and the List of Threatening Experiences and Multidimensional Scale of Perceived Social Support were applied. Results The number of stressful events, perceived social support, baseline depression scores, melancholic features, time prior to beginning treatment at the secondary level and psychotherapeutic sessions were included in the model as predictors of remission. Sex, age, number of previous depressive episodes, psychiatric comorbidity and medical comorbidity were not significantly related with remission. Conclusions This model allows to predict depression score at six months with 70% of accuracy and the score at 12 months with 72% of accuracy.

[Body image, psychological symptoms and eating disorders among Chilean adolescents and young adults]. / Comparación por sexo en imagen corporal, síntomas psicopatológicos y conductas alimentarias en jóvenes entre 14 y 25 años.

UNLABELLED: The construction of body image is crucial during adolescent development. Several studies show that body dissatisfaction is common, especially among women. This is a risk factor for eating behavior disorders. AIM: To describe psychological variables and dimensions about body image among adolescents and young adults. MATERIAL AND METHODS: Three self-administered questionnaires, MBSRQ (Multidimensional Body Self Relations Questionnaire) that measures body image, Symptom Checklist (SCL-90) that measures the presence of psychological and psychiatric symptoms and the Eating Disorder Inventory (EDI-2), which measures eating problems, were applied to 1,438 students aged 19 ± 2.7 years (53% women) from three Chilean regions. RESULTS: Sixty five percent of respondents would like to weigh less. Compared with men, women have greater psychological distress, concerns about their appearance and their weight, are more obsessed with thinness, and have fewer behaviors aimed at solving these problems. CONCLUSIONS: A high percentage of respondents want to lose weight. In addition, women have serious desires and search for thinness.

CAG and GGN repeat polymorphisms in the androgen receptor gene of a Chilean pediatric cohort with idiopathic inguinal cryptorchidism.

BACKGROUND: Cryptorchidism is one of the most common congenital disorders in boys and it is associated with a higher risk of sub-fertility and testicular cancer. Testicular descent occurs during embryo-fetal development in two phases, transabdominal and inguino-scrotal. In the latter process, androgens play a leading role. The androgen receptor has in its N-terminal domain, two aminoacidic repeats encoded by polymorphic nucleotide repetitions: (CAG)nCAA and GGN. The number of repetitions of these trinucleotides has been associated with different transactivation capacities and sensitivities of the androgen receptor response. OBJECTIVE: To determine whether pediatric Chilean individuals with idiopathic inguinal cryptorchidism have a different number of CAG and/or GGN repeats polymorphisms compared with controls. MATERIALS AND METHODS: A total of 109 cases with idiopathic inguinal cryptorchidism (26 bilateral and 83 unilateral) were studied by polymerase chain reaction amplification from DNA extracted from peripheral blood, followed by fragment size analysis by capillary electrophoresis, which were compared with 140 controls. RESULTS: The CAG26 repeats allele was increased in the total cases (8.3% vs. 1.4%; p = 0.012; odds ratio = 6.21, 95% confidence interval 1.31-29.4), and in bilateral cases compared to controls (11.5% vs. 1.4%; p = 0.028; odds ratio = 9 CI 95% 1.43-56.8). Similarly, CAG > 22 alleles were increased in the total cases (62.4% vs. 49.3%, p = 0.041), and more significantly in bilateral cases (73.1% vs. 49.3%; p = 0.032; odds ratio = 2.79, 95% confidence interval 1.1-7.1). In addition, CAG < 18 alleles were not observed among cases, but were present in 5.7% of controls (p = 0.01). Regarding the GGN repeats, no differences were observed between cases and controls either when analyzing separately unilateral and bilateral cryptorchidism. The joint analysis of the distribution of CAG and GGN alleles showed that the CAG26 allele was present with GGN23, hence the combination CAG26/GGN23 alleles was equally increased in bilateral cases compared with controls (11.5% vs. 1.4%). In contrast, CAG < 18 was preferably observed in the combination CAG < 18/GGN≠23 and was absent in the total cases (4.3% vs. 0%; p = 0.037). DISCUSSION: These results suggest that greater lengths of CAG alleles may contribute to a diminished androgen receptor function. The CAG26 allele alone or in combination with GGN23 was associated with a higher risk of bilateral cryptorchidism. On the other hand, CAG < 18 and the CAG < 18/GGN≠23 allele combination may reduce the probability of cryptorchidism.

Relative performance evaluation of four bleeding risk scores in atrial fibrillation patients. What does the new DOAC score provide?

BACKGROUND: Recently, the direct oral anticoagulant (DOAC) score was developed and better predicted major bleeding in DOAC-treated patients with atrial fibrillation (AF) than HASBLED did. Little is known on the new score's performance regarding other bleeding risk in AF. METHODS: We studied 14,672 patients diagnosed with AF between 2014 and 2018. During follow-up, we assessed the performance of DOAC score compared with the HASBLED, ORBIT and SWISS scores at predicting major bleeding in DOACs and non-DOACs users. Discrimination, calibration and decision curve analysis (DCA) were used to assess the risk scorer's performance. RESULTS: There were 1484 (10.1%) patients on DOACs, 9730 on vitamin K antagonist (VKA), and 3458 on non-oral anticoagulants. Over a median of 3.5 years of follow-up, 79 major bleedings occurred in the DOAC patients, and 486 in the VKA patients (cumulative incidences = 7.4 and 13.9 per 100 patient-years, respectively). Amongst the DOAC patients, the DOAC score discrimination was moderate (C-statistic = 0.711), but significantly higher than HASBLED (C = 0.640; p = 0.03), ORBIT (C = 0.660; p = 0.04), and SWISS scores (C = 0.637; p = 0.002). The DCA showed higher net benefit using DOAC score compared with the remaining scores. In the VKA patients, DOAC score showed the highest discrimination (c-statistic = 0.709), followed by ORBIT (C = 0.692; p = 0.07), HASBLED and SWISS (C = 0.635 and 0.624, respectively; p < 0.01). All risk scores calibrated well, although HASBLED showed relatively poor calibration. CONCLUSIONS: The new DOAC bleeding risk score is a valid and reasonable predictor of major bleeding over a median of 3.5 years of follow-up. Physicians can be reassured about the applicability of DOAC score for bleeding risk stratification in AF patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04364516.

Latent tuberculosis prevalence, diagnosis and treatment in Multiple Sclerosis as a strategy for reducing infection reactivation during immunosuppressant therapy.

BACKGROUND: Tuberculosis is an infectious disease with a risk of reactivation in Multiple Sclerosis patients on immunosuppressant therapy. Diagnosis and treatment of Latent Tuberculosis Infection (LTBI) prevents the infection. OBJECTIVE: To diagnose and treat LTBI in Multiple Sclerosis (MS). METHODS: Cross-sectional study of the prevalence and treatment of LTBI in MS, between February 2021 and June 2023. LTBI was defined as an absence of symptoms, positive PPD or IGRA and normal chest X-ray. RESULTS: Of the 58 patients with MS, 17 (29.3 %) were diagnosed with LTBI, 15 with PPD > 5 mm and 2 with positive IGRA, 10 (58.8 %) female and 7 (41.1 %) male, mean age of 41.3 (SD ±13.4) years. All patients with LTBI were treated with immunomodulators or immunosuppressants: Fingolimod 5 (29.4 %), Natalizumab 5 (29.4 %), Cladribine 2 (11.8 %), Glatiramer 2 (11.8 %), Ocrelizumab 2 (11.8 %), and Interferon beta 1 (5.9 %). Steroids therapy for relapses, were used in 5/17 (93.8 %) with LTBI and 30/37 (81.1 %) without LTBI. To treat LTBI, 11 (64.7 %) received Isoniazid and 6 (35.3 %) Isoniazid plus Rifapentine. Hepatotoxicity occurred in 3 (17.6 %) with INH. There were no interruptions of ILTB treatment during the study. CONCLUSION: The prevalence of LTBI was found to be high and treatment proved safe.

Differential Effect of 2 Hormonal Contraceptives on the Relative Telomere Length of Youth With Type 1 Diabetes.

Context: Adolescents and young women (AYA) with type 1 diabetes (T1D) may require hormonal contraception for an extended period. However, it is unclear what effect hormonal contraception has on telomere length, a marker of the risk for complications. Objective: To investigate the relative telomere length (RTL) in AYA with T1D (AYA-T1D) and healthy young women (AYA-C) after 18 months of combined oral contraception use (COC) with ethinyl estradiol/desogestrel, or a subdermal etonogestrel implant (IM). Methods: A nonrandomized prospective study was performed in which 39 AYA-T1D and 40 AYA-C chose the COC or the IM. RTL was measured by monochrome multiplex-quantitative PCR in DNA from peripheral blood mononuclear cells (PBMC). The impact of contraceptives and clinical variables on RTL was assessed using lineal regression analysis. Results: Longer RTL compared to baseline was observed in AYA-T1D (P < .05) and AYA-C (P  < .01) after using the IM. However, the total of AYA and the AYA-C group treated with COC decreased RTL after 18 months of treatment compared to baseline (P < .05). The type of contraceptive used was determinant for the changes in RTL compared to baseline in all subjects and controls (P ≤ .006). For AYA-T1D, HbA1c levels were not associated with RTL, but the high-sensitivity C-reactive protein was negatively related with the changes in RTL at 18 months compared to baseline (standardized R2 : 0.230, P  = .003). Conclusion: IM was associated with longer RTL in AYA-T1D and AYA-C. In contrast, a shortening of telomere length in PBMC was observed after using COC.