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Objective: To determine whether HIV-infected individuals versus individuals with HIV/HCV coinfection, in the era of interferon-free therapies, exhibit an increased incidence of comorbidities and non-AIDS-related events. Methods: A retrospective analysis was conducted by collecting data from clinical records of Spanish patients at a tertiary hospital involving HIV/HCV-coinfected and HIV-infected patients, all with effectively controlled HIV. Coinfected patients underwent HCV clearance using direct-acting antivirals (DAAs) and had no history of interferon treatment. The incidences of hypertension, diabetes mellitus, cardiovascular disease, kidney disease, liver disease, non-AIDS cancer, and death were compared between the groups. Multivariate adjustments for all factors potentially impacting outcomes were used to assess the risk of clinical event onset. Propensity score (PS) analyses were also conducted to support the multivariate model results. Results: Data were available from 229 HIV/HCV-coinfected patients and 229 HIV-infected patients. Both cohorts were comparable in terms of age, gender distribution, follow-up, and HIV-related characteristics. Multivariate models and PS showed that previous exposure to HCV was not associated with the onset of any clinical events studied. Significant differences between HIV/HCV-coinfected and HIV-infected were not found for survival according to the log-rank test (p = 0.402). Conclusions: Successful HCV elimination using DAAs improved the outlook regarding comorbidities and survival across HIV/HCV-coinfected cohorts. Early HCV detection and DAA therapy could enhance clinical results. These findings provide an optimistic perspective for those living with HIV/HCV coinfection and underscore the importance of continuing efforts toward early detection and DAA treatment initiation.
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We aim to characterize industry-funded trials that have posted the informed consent forms (ICFs), and to assess whether the role played by industry as 'sponsor' or 'collaborator' could impact several relevant variables. A cross-sectional study was conducted on ClinicalTrials.gov on all industry-funded trials registered on or before 25 February 2023. We registered types of intervention, current recruitment status, design, enrollment, and countries involved. For trials with special interest to potential participants and investigators and/or clinicians an analysis of the role played by industry as 'sponsor' or 'collaborator' was performed. Of 116,281 industry-funded trials registered, 741 (0.6%) had posted ICFs. Most of these trials were categorized as 'completed' (n = 408) or 'terminated' (n = 107). The review of a sample of 359 trials showed that most were on drugs and/or biologics (59%), were randomized (51%), conducted exclusively in the USA (72%), and had posted results (79%), protocols (92%), and statistical analysis plans (SAPs) (89%). Trials in which industry participated as 'collaborator' were significantly more likely to post ICFs when trials were in the 'active, not recruiting' phase (OR 4.70, 99.71% CI 1.59-13.9, p < 0.001) than industry-sponsored trials. This was also the case when assessing drugs/biologics (OR 2.64, 99.71% CI 1.25-5.58, p < 0.001). Conversely, companies acting as 'sponsors' were significantly more likely to post ICFs with trials assessing devices, radiation interventions and/or diagnostic tests (OR 0.37, 99.71% CI 0.17-0.79, p < 0.001) than when participating as 'collaborators'. While industry-funded trials rarely post ICFs, when they do, they are highly compliant with transparency requirements. Regulations and ethics codes should consider requiring posting of protocols, SAPs, and ICFs for all clinical trials, regardless the type of sponsor.
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Ensaios Clínicos como Assunto , Termos de Consentimento , Indústria Farmacêutica , Estudos Transversais , Humanos , Ensaios Clínicos como Assunto/ética , Indústria Farmacêutica/economia , Consentimento Livre e Esclarecido , Sistema de RegistrosRESUMO
PURPOSE: While tuberculosis remains a significant global health concern, prosthetic joint infections (PJIs) caused by members of the Mycobacterium tuberculosis complex are exceptionally rare. Our objective is to perform a retrospective search of new cases of this disease and analyze all cases available in the literature of tuberculous PJIs, aiming to detect factors that may influence patient outcomes. METHODS: The ESGIAI and ESGMYC study groups were used to collect information on non-published cases of tuberculous prosthetic joint infections (PJIs). Additionally, a literature review of all published cases of tuberculous PJIs was conducted. All identified cases in the retrospective study and in the literature review were merged and included in the statistical analysis, involving both univariate and multivariate analyses. RESULTS: Fifteen previously unreported cases of tuberculous prosthetic joint infections (PJIs) from four countries were detailed. Among them, ten patients were female, with a median age of 76 years. The hip was affected in 13 cases. Seven patients experienced co-infection with another microorganism. Treatment approaches varied, with 13 patients undergoing implant removal, one treated with DAIR (debridement, antibiotics, and implant retention), and one case was treated with an unknown treatment method. All patients received antibiotic therapy and achieved a cure. The literature review that was conducted detected 155 published cases. Univariate analysis revealed a statistical significance for previous tuberculosis, joint, and no importance of surgery for cure. CONCLUSIONS: Tuberculous prosthetic joint infection (PJI) is a rare condition, typically presenting as a localized chronic infection. Antibiotic treatment is essential for the management of these patients, but neither surgical treatment nor duration of treatment seems to have importance in the outcome.
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Background: Mineral metabolism (MM), mainly fibroblast growth factor-23 (FGF-23) and klotho, has been linked to cardiovascular (CV) diseases. Cardiac rehabilitation (CR) has been demonstrated to reduce CV events, although its potential relationship with changes in MM is unknown. Methods: We performed a prospective, observational, case-control study, with acute coronary syndrome (ACS) patients who underwent CR and control patients (matched by age, gender, left ventricular ejection fraction, diabetes, and coronary artery bypass grafting), who did not. The inclusion dates were from August 2013 to November 2017 in CR group and from July 2006 to June 2014 in control group. Clinical, biochemical, and MM biomarkers were collected at discharge and six months later. Our objective was to evaluate differences in the modification pattern of MM in both groups. Results: We included 58 CR patients and 116 controls. The control group showed a higher prevalence of hypertension (50.9% vs. 34.5%), ST-elevated myocardial infarction (59.5% vs. 29.3%), and treatment with angiotensin-converting enzyme inhibitors (100% vs. 69%). P2Y12 inhibitors and beta-blockers were more frequently prescribed in the CR group (83.6% vs. 96.6% and 82.8% vs. 94.8%, respectively). After six months, klotho levels increased in CR patients whereas they were reduced in controls (+63 vs. -49 pg/mL; p < 0.001). FGF-23 was unchanged in the CR group and reduced in controls (+0.2 vs. -17.3 RU/dL; p < 0.003). After multivariate analysis, only the change in klotho levels was significantly different between groups (+124 pg/mL favoring CR group; IC 95% [+44 to +205]; p = 0.003). Conclusions: In our study, CR after ACS increases plasma klotho levels without significant changes in other components of MM. Further studies are needed to clarify whether this effect has a causal role in the clinical benefit of CR.
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BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways. OBJECTIVES: To determine which genes are differentially expressed in MCPyV-positive and MCPyV-negative MCC; to describe the mutational burden and the most frequently mutated genes in both MCC subtypes; and to identify the clinical and molecular factors that may be related to patient survival. METHODS: Ninety-two patients with a diagnosis of MCC were identified from the medical databases of participating centres. To study gene expression, a customized panel of 172 genes was developed. Gene expression profiling was performed with nCounter technology. For mutational studies, a customized panel of 26 genes was designed. Somatic single nucleotide variants (SNVs) were identified following the GATK Best Practices workflow for somatic mutations. RESULTS: The expression of LT enabled the series to be divided into two groups (LT positive, n = 55; LT negative, n = 37). Genes differentially expressed in LT-negative patients were related to epithelial differentiation, especially SOX9, or proliferation and the cell cycle (MYC, CDK6), among others. Congruently, LT displayed lower expression in SOX9-positive patients, and differentially expressed genes in SOX9-positive patients were related to epithelial/squamous differentiation. In LT-positive patients, the mean SNV frequency was 4.3; in LT-negative patients it was 10 (P = 0.03). On multivariate survival analysis, the expression of SNAI1 [hazard ratio (HR) 1.046, 95% confidence interval (CI) 1.007-1.086; P = 0.02] and CDK6 (HR 1.049, 95% CI 1.020-1.080; P = 0.001) were identified as risk factors. CONCLUSIONS: Tumours with weak LT expression tend to co-express genes related to squamous differentiation and the cell cycle, and to have a higher mutational burden. These findings are congruent with those of earlier studies.
Merkel cell carcinoma (MCC) is an aggressive form of skin tumour. There are two subtypes of MCC: one of them is related to a virus called Merkel cell polyomavirus (MCPyV); the other one is related to persistent exposure to sunlight. The aim of this research was to find differences between these subtypes in their molecular behaviour (the genes that are expressed and the mutations that may be found). To do this, we carried out two studies, one to investigate gene expression (the process cells use to convert the instructions in our DNA into a functional product such as a protein) and one to look at gene mutations (changes in the DNA sequence). We found that the tumours that were not related to MCPyV expressed genes related to epithelial differentiation (the process by which unspecialized cells gain features characteristics of epithelial cells, which, among other things, make up the outer surface of the body), which means that the origin of both MCC subtypes may be different. We also found that MCPyV-related tumours had fewer mutations. Our findings are important because they help us to understand the biology of the MCC subtypes and could help with the development of new treatments for people diagnosed with skin tumours.
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Antígenos Virais de Tumores , Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Fatores de Transcrição SOX9 , Neoplasias Cutâneas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos Virais de Tumores/genética , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/isolamento & purificação , Mutação , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição SOX9/genética , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologiaRESUMO
(1) Background: Eosinophilia has traditionally been linked to eosinophilic asthma, for which it is the gold-standard prognostic biomarker. However, the association between eosinophilia and the presence of other diseases and comorbidities is yet unclear. (2) Methods: For this retrospective study, we reviewed the electronic medical records of 49,909 subjects with blood eosinophilia to gather data on the presence of asthma, COPD, sleep apnea, tuberculosis, dyslipidemia, hypertension, and other cardiovascular diseases and severe CRSwNP among these subjects. Demographic features including age, sex, and smoking habits were collected, as well as the number of hospitalizations and emergency department visits. T-tests, ANOVA, Fisher test, and logistic regression models were used. (3) Results: For all age groups studied, eosinophilia was significantly more prevalent among asthmatic subjects than nonasthmatics, especially in patients also presenting CRSwNP, hypertension, and dyslipidemia. The likelihood of developing asthma, COPD, and CRSwNP, and hospitalization, was increased when BEC was above 600 eosinophils/µL. The association between asthma, CRSwNP, and BEC was corroborated by multiple logistic regressions models. (4) Conclusions: We demonstrated the association of having over 600 blood eosinophils/µL with a higher number of hospitalizations and comorbidities (CRSwNP and COPD), which proves that BEC is a highly useful parameter to consider in subjects who present blood eosinophilia.
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Asma , Dislipidemias , Hipertensão , Mustelidae , Doença Pulmonar Obstrutiva Crônica , Eosinofilia Pulmonar , Humanos , Animais , Estudos Retrospectivos , Asma/complicações , Asma/epidemiologia , Hospitalização , Dislipidemias/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologiaRESUMO
OBJECTIVE: This study aimed to evaluate the bone microstructure to determine whether curative surgery of primary hyperparathyroidism produces changes in bone mineral density (BMD), trabecular bone score (TBS), and three-dimensional (3D) dual x-ray absorptiometry (DXA) parameters and whether these changes are comparable. METHODS: We retrospectively studied 85 patients (60 women and 25 men, 60.4 ± 12.5 years) diagnosed with primary hyperparathyroidism and undergoing parathyroidectomy. Mean percent changes in BMD (lumbar spine [LS], femoral neck [FN], total hip [TH], and 1/3 radius), TBS and 3D-DXA parameters (trabecular volumetric BMD (vBMD), cortical vBMD, integral vBMD, cortical surface density (sBMD), and cortical thickness at TH) after surgery (12, 24, and/or 36 months) were calculated and compared, and we sought the determinants of these changes. RESULTS: After parathyroidectomy, BMD presented statistically significant mean increases in LS, FN, and TH during the first 3 years after surgery (P < .001), accompanied by an improvement in all 3D-DXA parameters, but there were no significant changes in 1/3 radius BMD or TBS. Cortical sBMD, trabecular vBMD, and integral vBMD reached mean increases of similar magnitude to those of FN and TH BMD. Age and preoperative serum levels of parathyroid hormone and carboxy-terminal telopeptide of type 1 collagen were significantly associated with percent changes after surgery. CONCLUSION: We found a benefit of parathyroidectomy for bone, with significant percent increases in LS, FN, and TH BMD up to the third year after surgery, and a qualitative benefit for the hip in both its trabecular and cortical compartments and bone strength.
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Osso Esponjoso , Hiperparatireoidismo Primário , Masculino , Humanos , Feminino , Absorciometria de Fóton , Estudos Retrospectivos , Paratireoidectomia , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/complicações , Densidade ÓsseaRESUMO
Lumbar fractures and/or multiple fractures at the lumbar or thoracolumbar regions are risk factors for sagittal malalignment in patients older than 70 years old. Although patients with OVF show a huge capacity to compensate after the fractures, lumbar and TL lumbar fractures require closer monitoring. PURPOSE: To assess the impact of osteoporotic vertebral fractures on the sagittal alignment of the elderly and identify risk factors for sagittal malalignment. METHODS: We performed a retrospective study on a cohort of 249 patients older than 70 years old and diagnosed with osteoporosis who suffered chronic vertebral fractures. Demographic and radiological data were collected. Full-spine lateral X-rays were obtained to analyze the sagittal plane. Patients were classified according to the number and location of the fractures. Pearson's correlation coefficient was used to assess the relationships between the type of fractures and sagittal alignment. RESULTS: A total of 673 chronic fractures were detected in 249 patients with a mean number of vertebral fractures per patient of 2.7 ± 1.9. Patients were divided into 9 subgroups according to the location and the number of fractures. Surprisingly, any of the aggregated parameters used to assess sagittal alignment exceeded the threshold defined for malalignment. In the second part of the analysis, 41 patients with sagittal malalignment were identified. In this subpopulation, an overrepresentation of patients with lumbar fractures (34% vs. 11%) and an under-representation of thoracic fractures (9% vs. 34%) were reported. We also observed that patients with 3 or more lumbar or thoracolumbar fractures had an increased risk of sagittal malalignment. CONCLUSIONS: Lumbar fractures and/or multiple fractures at the lumbar or thoracolumbar regions are risk factors for sagittal malalignment in patients older than 70 years old. Although patients show a remarkable capacity to compensate, fractures at the lumbar and thoracolumbar regions need closer monitoring.
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Fraturas Múltiplas , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Idoso , Estudos Retrospectivos , Coluna Vertebral/cirurgia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/complicações , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/cirurgia , Vértebras Lombares/lesões , Vértebras Torácicas/lesõesRESUMO
BACKGROUND: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission. OBJECTIVES: To ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission. METHODS: A multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria. RESULTS: The study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06-1.23; p<0.001), admissions at ICU (2.69; 1.30-5.56; p=0.01), high count of SAE (1.21; 1.03-1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95-0.98; p<0.001), a high ACT score (0.93; 0.88-0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29-0.91; p=0.02) showed strong associations with achieving clinical remission. CONCLUSION: A substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons.
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Antiasmáticos , Asma , Produtos Biológicos , Humanos , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Imunossupressores/uso terapêutico , Omalizumab/uso terapêuticoRESUMO
Circadian rhythms, which are governed by a circadian clock, regulate important biological processes associated with obesity. SNPs in circadian clock genes have been linked to energy and lipid homeostasis. The aim of our study was to evaluate the associations of CLOCK and REV-ERBα SNPs with BMI and plasma lipid levels in pre-pubertal boys and girls. The study sample population comprised 1268 children aged 6-8 years. Information regarding anthropometric parameters and plasma lipid concentrations was available. Genotyping of CLOCK SNPs rs1801260, rs4580704, rs3749474, rs3736544 and rs4864548 and REV-ERBα SNPs rs2017427, rs20711570 and rs2314339 was performed by RT-PCR. The CLOCK SNPs rs3749474 and rs4864548 were significantly associated with BMI in girls but no in boys. Female carriers of the minor alleles for these SNPs presented lower BMI compared to non-carriers. A significant association of the REV-ERBα SNP rs2071570 with plasma total cholesterol, LDL-cholesterol and Apo B in males was also observed. Male AA carriers showed lower plasma levels of total cholesterol, LDL-cholesterol and Apo B levels as compared with carriers of the C allele. No significant associations between any of the studied REV-ERBα SNPs and plasma lipid levels were observed in females. In summary, CLOCK and REV-ERBα SNPs were associated with BMI and plasma lipid levels respectively in a sex-dependent manner. Our findings suggest that sex-related factors may interact with Clock genes SNPs conditioning the effects of these polymorphisms on circadian alterations.
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Relógios Circadianos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares , Criança , Feminino , Humanos , Masculino , Apolipoproteínas B , Índice de Massa Corporal , LDL-Colesterol , Relógios Circadianos/genética , Ritmo Circadiano/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genéticaRESUMO
Objectives: The aim of this study is to observe and compare the effects of regular yoga practice on the main inspiratory muscle, the diaphragm, by analyzing its thickness, excursion, velocity and contraction time, using ultrasound. Design: A Cross-Sectional Controlled Study. Participants: 80 healthy subjects (40 habitual yoga practitioners and 40 non-practitioners), without previous respiratory pathology participated in this study. During maximum diaphragmatic breathing, the diaphragmatic thickness (at rest and after maximum inspiration), excursion, velocity and contraction time were measured by ultrasound. Results: in the experimental group, practicing yoga, statistically significant differences (p < 0.001) were observed compared to the control group, not practicing, in the thickness of the diaphragm at rest (0.26 ± 0.02 vs 0.22 ± 0.01 cm); the diaphragmatic thickness in maximum inspiration (0.34 ± 0.03 vs 0.28 ± 0.03 cm); contraction velocity (1.54 ± 0.54 vs 2.23 ± 0.86 cm/s), contraction time (3.28 ± 0.45 vs 2.58 ± 0.49 s) and Borg scale of perceived exertion (1.05 ± 1.6 vs 1.70 ± 1.34), p = 0.05. However, the diaphragmatic excursion was greater in the control group (5.45 ± 1.42 vs 4.87 ± 1.33 cm) with no statistically significant differences (p = 0.06). Conclusions: the regular practice of yoga improves the parameters of diaphragm thickness, speed and contraction time measured in ultrasound and the sensation of perceived exertion during a maximum inspiration. So it can be considered as another method for training the inspiratory muscles in clinical practice.
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Background: patient-derived xenografts (PDXs) have defined the field of translational cancer research in recent years, becoming one of the most-used tools in early drug development. The process of establishing cancer models in mice has turned out to be challenging, since little research focuses on evaluating which factors impact engraftment success. We sought to determine the clinical, pathological, or molecular factors which may predict better engraftment rates in PDXs. Methods: between March 2017 and January 2021, tumor samples obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. A full comprehensive evaluation of baseline factors associated with the patients and patients' tumors was performed, with the goal of potentially identifying predictive markers of engraftment. We focused on clinical (patient factors) pathological (patients' tumor samples) and molecular (patients' tumor samples) characteristics, analyzed either by immunohistochemistry (IHC) or next-generation sequencing (NGS), which were associated with the likelihood of final engraftment, as well as with tumor growth rates in xenografts. Results: a total of 585 tumor samples were collected and implanted. Twenty-one failed to engraft, due to lack of malignant cells. Of 564 tumor-positive samples, 187 (33.2%) grew at time of analysis. The study was able to find correlation and predictive value for engraftment for the following: the use of systemic antibiotics by the patient within 2 weeks of sampling (38.1% (72/189) antibiotics- group vs. 30.7% (115/375) no-antibiotics) (p = 0.048), and the administration of systemic steroids to the patients within 2 weeks of sampling (41.5% (34/48) steroids vs. 31.7% (153/329), no-steroids) (p = 0.049). Regarding patient's baseline tests, we found certain markers could help predict final engraftment success: for lactate dehydrogenase (LDH) levels, 34.1% (140/411) of tumors derived from patients with baseline blood LDH levels above the upper limit of normality (ULN) achieved growth, against 30.7% (47/153) with normal LDH (p = 0.047). Histological tumor characteristics, such as grade of differentiation, were also correlated. Grade 1: 25.4% (47/187), grade 2: 34.8% (65/187) and grade 3: 40.1% (75/187) tumors achieved successful growth (p = 0.043), suggesting the higher the grade, the higher the likelihood of success. Similarly, higher ki67 levels were also correlated with better engraftment rates: low (Ki67 < 15%): 8.9% (9/45) achieved growth vs. high (Ki67 ≥ 15%): 31% (35/113) (p: 0.002). Other markers of aggressiveness such as the presence of lymphovascular invasion in tumor sample of origin was also predictive: 42.2% (97/230) with lymphovascular vs. 26.9% (90/334) of samples with no invasion (p = 0.0001). From the molecular standpoint, mismatch-repair-deficient (MMRd) tumors showed better engraftment rates: 62.1% (18/29) achieved growth vs. 40.8% (75/184) of proficient tumors (p = 0.026). A total of 84 PDX were breast models, among which 57.9% (11/19) ER-negative models grew, vs. 15.4% (10/65) of ER-positive models (p = 0.0001), also consonant with ER-negative tumors being more aggressive. BRAFmut cancers are more likely to achieve engraftment during the development of PDX models. Lastly, tumor growth rates during first passages can help establish a cutoff point for the decision-making process during PDX development, since the higher the tumor grades, the higher the likelihood of success. Conclusions: tumors with higher grade and Ki67 protein expression, lymphovascular and/or perineural invasion, with dMMR and are negative for ER expression have a higher probability of achieving growth in the process of PDX development. The use of steroids and/or antibiotics in the patient prior to sampling can also impact the likelihood of success in PDX development. Lastly, establishing a cutoff point for tumor growth rates could guide the decision-making process during PDX development.
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PURPOSE: A study analyzing the application of a protocol of comprehensive geriatric assessment (CGA) in older patients with lymphoma was carried out to allow frailty-based patient classification and individualized treatment. METHODS: Lymphoma patients older than 70 years referred to the Geriatric Clinic at a tertiary hospital between May 2016 and March 2021 were included. The assessment protocol included comorbidity, polypharmacy, nutritional, functional, and mental status, geriatric syndromes, and life expectancy. CGA enabled patient classification into four groups (Type I to Type IV) based on frailty assessment instrument scoring and clinical, functional, and mental status. Variables were compared using parametric and non-parametric statistical tests and Kaplan-Meier survival curves. RESULTS: Ninety-three patients (55.9% women) were included. Median age was 81.1 years (± 5.7). 23 patients (24.7%) were classified as robust (type I), 30 (32.3%) as pre-frail (type II) with potentially reversable deficits, 38 (40.9%) as frail (type III), and 2 (2.2%) as requiring palliative care (type IV). Patients received oncospecific treatment with modifications carried out in 64.5% of cases based on CGA results. Differences in overall survival (p = 0.002), response to treatment (p < 0.001) and likelihood of increased frailty (p = 0.024) were observed, with type III-IV patients showing significantly worse outcomes. CONCLUSION: Performance of standardized, systematic CGA by geriatricians permits older lymphoma patients to be classified according to frailty, with significant differences in terms of clinical outcomes across groups. We propose incorporating CGA performed by geriatricians as part of the multidisciplinary care team to optimize therapeutic strategy for these patients.
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Fragilidade , Linfoma , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Comorbidade , Linfoma/terapia , Atividades Cotidianas , Avaliação Geriátrica/métodosRESUMO
PURPOSE: Clinical trials transparency requires trial registration and the posting of results on a public register. US regulations also require the posting of protocols and statistical analysis plans (SAPs). For US Federal agency funded trials to be started on or after 21 January 2019, informed consent forms (ICFs) must also be posted. Posting these documents is not mandatory in other countries. We aimed to assess compliance with US regulations of trials conducted in the US or in other countries with respect to ICFs, protocols, SAPs, and results. METHODS: This cross-sectional analysis (27 April 2023) comprised completed medicines trials to be started on or after 21 January 2019 registered on ClinicalTrials.gov. Trial data were registered by funder type (i.e., 'US federal agencies', industry, and 'all others') and development phase. RESULTS: Of 5,584 trials, 40% were conducted solely in the US. 47% and 12% of US and non-US trials had posted results. Some 40% of US trials had posted protocols and SAPs as did 9% of trials conducted in other countries. Only 10% (US) and 2% (other countries) of trials had posted ICFs. When the margin of the last 2 and 12 months after primary completion date were considered in the analysis, ICF posting rate did not change, but posting results increased to 64% for US trials. 'US Federal agencies' funded trials were significantly more likely to post ICFs than industry [OR 23.9 (12.5-45.7; <.001)] or 'all others' [OR 3.16 (1.79-5.56; <.001)]. CONCLUSION: Future interventions should be considered to encourage timely posting of trial results and information.
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Termos de Consentimento , Humanos , Estudos TransversaisRESUMO
BACKGROUND: Small for gestational age (SGA) perform a postnatal catch-up growth to recover their genetic trajectory. We studied the postnatal catch-up growth pattern of fetuses born with an appropriate-for-gestational-age (AGA) weight but with fetal growth deceleration (FGD) to explore whether they catch up. METHODS: Nine hundred and sixty-six newborns at Villalba University General Hospital (HUGV), were followed from 34 to 37 weeks to birth. Z-scores, adjusted for sex and age, of weight, length, and BMI at 3, 6, 9, and 12 months were calculated. We define catch-up as an increase in z-score greater than 0.67 SD in the growth curves. RESULTS: AGA FGD had lower mean weight and length than AGA non-FGD at all time points; BMI was lower until 3 months. AGA FGD had a lower weight, length, and BMI z-score (until 9, 6 months, and at birth, respectively) than AGA non-FGD. AGA FGD newborns had a significantly increased likelihood of weight catch-up at 3 months (OR 1.79; 95% CI: 1.16, 2.78; p = 0.009) and BMI in all investigated periods (OR 1.90; 95% CI 1.30, 2.78; p < 0.001 at 3 months), compared to AGA non-FGD newborns. CONCLUSIONS: AGA FGD newborns perform catch-up growth, especially in weight and BMI, in the first year of life, compared to AGA non-FGD. IMPACT: Appropriate-for-gestational-age (AGA) newborns with fetal growth deceleration (FGD), between the third trimester of pregnancy and delivery, present a lower weight and height, during the first year of life, compared to AGA non-FGD. Appropriate-for-gestational-age (AGA) newborns with fetal growth deceleration (FGD), between the third trimester of pregnancy and delivery, present a higher likelihood of weight catch-up in the first 3 months of life and of BMI in the first year compared to AGA non-FGD. AGA FGD experienced early weight and BMI catch-up, especially in the first 3 months of life, like SGA. This finding should be considered in the future follow-up.
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Estatura , Peso Fetal , Gravidez , Feminino , Recém-Nascido , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Retardo do Crescimento Fetal , Idade GestacionalRESUMO
ADAM10 is the main α-secretase acting in the non-amyloidogenic processing of APP. We hypothesized that certain rare ADAM10 variants could increase the risk for AD by conferring the age-related downregulation of α-secretase. The ADAM10 gene was sequenced in 103 AD cases (82% familial) and 96 cognitively preserved nonagenarians. We examined rare variants (MAF < 0.01) and determined their potential association in the AD group with lower CSF protein levels, as analyzed by means of ELISA, and Western blot (species of 50 kDa, 55 kDa, and 80 kDa). Rare variants were found in 15.5% of AD cases (23% early-onset, 8% late-onset) and in 12.5% of nonagenarians, and some were group-specific. All were intronic variants except Q170H, found in three AD cases and one nonagenarian. The 3'UTR rs74016945 (MAF = 0.01) was found in 6% of the nonagenarians (OR 0.146, p = 0.057). Altogether, ADAM10 total levels or specific species were not significantly different when comparing AD with controls or carriers of rare variants versus non-carriers (except a Q170H carrier exhibiting low levels of all species), and did not differ according to the age at onset or APOE genotype. We conclude that ADAM10 exonic variants are uncommon in AD cases, and the presence of rare intronic variants (more frequent in early-onset cases) is not associated with decreased protein levels in CSF.
Assuntos
Doença de Alzheimer , Idoso de 80 Anos ou mais , Humanos , Proteínas ADAM/metabolismo , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Líquido Cefalorraquidiano/análise , Proteínas do Líquido Cefalorraquidiano/metabolismoRESUMO
Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV1/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.
Assuntos
Asma , MicroRNAs , Humanos , Glucocorticoides/uso terapêutico , MicroRNAs/metabolismo , Pulmão/metabolismo , Biomarcadores , Asma/tratamento farmacológico , Asma/genéticaRESUMO
The issue of how to identify newly diagnosed multiple myeloma (NDMM) patients requiring thromboprophylaxis remains unsolved. Several changes in thrombin generation (TG)-derived parameters have been described in multiple myeloma (MM) patients recently. Assessment of prothrombotic risk with a fully automated TG analyzer could reduce interlaboratory variability. Our objective was to determine whether ST-Genesia® could reveal a hypercoagulable state in NDMM compared to healthy controls. We conducted a multicenter observational study of NDMM requiring initial treatment to compare TG parameters obtained with ST-Genesia® analyzer and ST-ThromboScreen® reagent with a control group. Clinical data were obtained from medical records and blood samples were collected before initial anti-myeloma therapy. A thrombophilia panel was performed in all patients. Compared to age- and sex-matched controls (n = 83), NDMM patients (n = 83) had significantly higher peak height, higher velocity index, shorter time-to-peak and lower percentage of endogenous thrombin potential (ETP) inhibition after adding thrombomodulin (TM) (ETP%inh). NDMM on prophylactic low molecular weight heparin (LMWH) showed reduced both peak height and velocity index compared to NDMM who had not yet started VTE prophylaxis, similar to that of controls. Moreover, partial correction of ETP%inh was observed in MM patients on LMWH. The presence of a thrombophilia did not modify the TG phenotype. Untreated NDMM patients showed an enhanced TG, regardless of their thrombophilia status. They generate a higher peak of thrombin, take less time to produce it, and exhibit resistance to TM inhibition. Our findings suggest that standard prophylactic dose of LMWH may reduce TG at levels of healthy controls.