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DNA damage provokes mutations and cancer and results from external carcinogens or endogenous cellular processes. However, the intrinsic instigators of endogenous DNA damage are poorly understood. Here, we identify proteins that promote endogenous DNA damage when overproduced: the DNA "damage-up" proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six function clusters, demonstrating DDP mechanisms in three: reactive oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their RNAs in tumors predict heavy mutagenesis and a poor prognosis. Half of the tested human homologs promote DNA damage and mutation when overproduced in human cells, with DNA damage-elevating mechanisms like those in E. coli. Our work identifies networks of DDPs that provoke endogenous DNA damage and may reveal DNA damage-associated functions of many human known and newly implicated cancer-promoting proteins.
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Dano ao DNA/genética , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Proteínas de Bactérias/metabolismo , Instabilidade Cromossômica/fisiologia , Replicação do DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/metabolismo , Instabilidade Genômica , Humanos , Proteínas de Membrana Transportadoras/fisiologia , Mutagênese , Mutação , Fatores de Transcrição/metabolismoRESUMO
The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.
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Autofagia/fisiologia , Células Endoteliais/fisiologia , Infiltração de Neutrófilos/fisiologia , Migração Transendotelial e Transepitelial/fisiologia , Animais , Quimiotaxia de Leucócito/fisiologia , Células Endoteliais/patologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Junções Intercelulares/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologiaRESUMO
Meiotic drivers bias gametogenesis to ensure their transmission into more than half the offspring of a heterozygote. In Schizosaccharomyces pombe, wtf meiotic drivers destroy the meiotic products (spores) that do not inherit the driver from a heterozygote, thereby reducing fertility. wtf drivers encode both a Wtfpoison protein and a Wtfantidote protein using alternative transcriptional start sites. Here, we analyze how the expression and localization of the Wtf proteins are regulated to achieve drive. We show that transcriptional timing and selective protein exclusion from developing spores ensure that all spores are exposed to Wtf4poison, but only the spores that inherit wtf4 receive a dose of Wtf4antidote sufficient for survival. In addition, we show that the Mei4 transcription factor, a master regulator of meiosis, controls the expression of the wtf4poison transcript. This transcriptional regulation, which includes the use of a critical meiotic transcription factor, likely complicates the universal suppression of wtf genes without concomitantly disrupting spore viability. We propose that these features contribute to the evolutionary success of the wtf drivers.
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Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Schizosaccharomyces/genética , Esporos Fúngicos/genética , Proteínas de Schizosaccharomyces pombe/genética , Meiose , Fatores de Transcrição/genéticaRESUMO
PURPOSE: Stereotactic body radiotherapy (SBRT) has become an excellent non-invasive alternative for many patients with primary renal cell carcinoma (RCC) and adrenal malignancies (AM). The aims of this study were to analyse how tumor-, patient- and treatment-related factors may influence the outcomes and side effects of SBRT and to assess its benefits as an alternative to surgery. METHODS: This retrospective, multicenter study included 25 lesions in 23 patients treated with SBRT using different devices (LINAC, CyberKnife® and Tomotherapy®). A multivariate linear regression was used for the statistical study. RESULTS: Local control time was higher than six months in more than 87% of patients and treatment response was complete for 73.68%. There was an overall 2-year survival of 40% and none of the deaths were secondary to renal or adrenal local progression. Patients treated with lower total radiation dose (mean [m] = 55 Gy) but less fractions with more dose per fraction (> 8.5 Gy) showed better outcome. Patients with previous chemotherapy and surgery treatments also showed higher complete response and disease-free survival (> 6 months). CONCLUSIONS: This study highlights the importance of ultra-hypofractionated regimens with higher doses per session. Thus, the referral of patients with RCC and AM to Radiotherapy and Oncology departments should be encouraged supporting the role of SBRT as a minimally invasive and outpatient treatment.
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Neoplasias das Glândulas Suprarrenais , Carcinoma de Células Renais , Neoplasias Renais , Radiocirurgia , Humanos , Radiocirurgia/métodos , Neoplasias Renais/cirurgia , Neoplasias Renais/radioterapia , Neoplasias Renais/patologia , Estudos Retrospectivos , Neoplasias das Glândulas Suprarrenais/radioterapia , Neoplasias das Glândulas Suprarrenais/cirurgia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/radioterapia , Resultado do Tratamento , Idoso de 80 Anos ou mais , Fracionamento da Dose de Radiação , Adulto , Taxa de SobrevidaRESUMO
CLINICAL IMPACT: Mechanical thrombectomy using a thromboaspiration catheter can be an effective alternative in the treatment of subacute pulmonary embolism.
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BACKGROUND: Evidence regarding long-term therapeutic outcomes and disease-specific survival (DSS) in Extramammary Paget's disease (EMPD) is limited. OBJECTIVES: To assess the DSS and outcomes of surgical and nonsurgical therapeutic modalities in a large cohort of EMPD patients. METHODS: Retrospective chart review of EMPD patients from 20 Spanish tertiary care hospitals. RESULTS: Data on 249 patients with a median follow-up of 60 months were analyzed. The estimated 5-, 10-, and 15-year DSS was 95.9%, 92.9%, and 88.5%, respectively. A significantly lower DSS was observed in patients showing deep dermal invasion (≥1 mm) or metastatic disease (P < .05). A ≥50% reduction in EMPD lesion size was achieved in 100% and 75.3% of patients treated with surgery and topical therapies, respectively. Tumor-free resection margins were obtained in 42.4% of the patients after wide local excision (WLE). The 5-year recurrence-free survival after Mohs micrographic surgery (MMS), WLE with tumor-free margins, WLE with positive margins, radiotherapy, and topical treatments was 63.0%, 51.4%, 20.4%, 30.1%, and 20.8%, respectively. LIMITATIONS: Retrospective design. CONCLUSIONS: EMPD is usually a chronic condition with favorable prognosis. MMS represents the therapeutic alternative with the greatest efficacy for the disease. Recurrence rates in patients with positive margins after WLE are similar to the ones observed in patients treated with topical agents.
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Doença de Paget Extramamária , Humanos , Estudos Retrospectivos , Doença de Paget Extramamária/cirurgia , Cirurgia de Mohs , Análise de Sobrevida , Margens de Excisão , Resultado do Tratamento , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/patologiaRESUMO
BACKGROUND: The interrelation of cancer with venous thromboembolism is established, yet the specific impact on the incidence and progression of superficial vein thrombosis (SVT) remains unclear. OBJECTIVES: To investigate the association between SVT and malignancies, focusing on risk factors, presentation, course and complications. METHODS: A single-center prospective observational study of patients diagnosed with DVT or SVT referred to a venous thromboembolism clinic between January 2013 and April 2018. RESULTS: Of the 632 patients, 205 presented with SVT at referral, 16.6% having active cancer. Significant associations were found between active cancer and the risk of developing proximal SVT (RR 1.54 [1.18-2.03] p < 0.01), SVT within 3 cm from junction (RR 2.01 [1.13-3.72] p = 0.019), bilateral SVT (RR 8.38 [2.10-33.43] p < 0.01) and SVT affecting multiple veins (RR 2.42 [1.40-4.20] p < 0.01), with a higher risk of persistence (RR 1.51 [1.18-1.95] p < 0.01) and progression (RR 5.75 [2.23-14.79] p < 0.01) at initial assessment. Patients with SVT and no malignancy history demonstrated an elevated risk for new-onset cancer during follow-up (RR 1.43 [1.13-1.18] p = 0.022), especially in cases of proximal or bilateral SVT, initial progression or subsequent DVT or PE. No significant differences were observed in persistence, recurrence or complications during initial evaluation or follow-up across different pharmacological treatments. CONCLUSIONS: Research suggests a probable link between cancer history and the development of SVT. SVT presented more severely in cancer patients. SVT, especially in its more complex forms, could serve as a predictive marker for the future development of cancer. Treatment approaches varied, no significant differences in outcomes were noted.
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Neoplasias , Tromboembolia Venosa , Trombose Venosa , Humanos , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/uso terapêutico , Trombose Venosa/diagnóstico , Fatores de Risco , Neoplasias/complicaçõesRESUMO
BACKGROUND: Topical imiquimod has shown to be an effective treatment for EMPD, although available evidence supporting its use is based on case reports and small series of patients. OBJECTIVES: To investigate the therapeutic outcomes and analyze potential clinico-pathological factors associated with imiquimod response in a large cohort of EMPD patients. METHODS: Retrospective chart review of 125 EMPD patients treated with imiquimod at 20 Spanish tertiary-care hospitals. RESULTS: During the study period, patients received 134 treatment regimens with imiquimod, with 70 (52.2%) cases achieving complete response (CR), 41 (30.6%) partial response and 23 (17.2%) no response. The cumulative CR rates at 24 and 48 weeks of treatment were 46.3% and 71.8%, respectively, without significant differences between first-time and previously treated EMPD. Larger lesions (≥6â cm; p = 0.038) and EMPD affecting >1 anatomical site (p = 0.002) were significantly associated with a worse treatment response. However, the CR rate did not differ significantly by the number of treatment applications (≤4 vs. > 4 times/week; p = 0.112). Among patients who achieved CR, 30 (42.9%) developed local recurrences during a mean follow-up period of 36â months, with an estimated 3 and 5-year recurrence free-survival of 55.7% and 36.4%, respectively. CONCLUSIONS: Imiquimod appears as an effective therapeutic alternative for both first-line and previously treated EMPD lesions. However, a less favorable therapeutic response could be expected in larger lesions and those affecting >1 anatomical site. Based on our results, a 3-4 times weekly regimen of imiquimod with a treatment duration of at least 6â months could be considered an appropriate therapeutic strategy for EMPD patients.
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Brassinosteroids (BRs) are an important group of polyhydroxylated naturally occurring steroidal phytohormones found in the plant kingdom in extremely low amounts. Due to the low concentrations in which these compounds are found, much effort has been dedicated to synthesizing these compounds or their structural analogs using natural and abundant sterols. In this work, we report the synthesis of new brassinosteroid analogs obtained from hyodeoxycholic acid, with a 3,6 dioxo function, 24-Nor-22(S)-hydroxy side chain and p-substituted benzoate function at C-23. The plant growth activities of these compounds were evaluated by two different bioassays: rice lamina inclination test (RLIT) and BSI. The results show that BRs' analog with p-Br (compound 41f) in the aromatic ring was the most active at 1 × 10-8 M in the RLIT and BSI assays. These results are discussed in terms of the chemical structure and nature of benzoate substituents at the para position. Electron-withdrawing and size effects seems to be the most important factor in determining activities in the RLIT assay. These results could be useful to propose a new structural requirement for bioactivity in brassinosteroid analogs.
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Benzoatos , Brassinosteroides , Oryza , Brassinosteroides/química , Brassinosteroides/síntese química , Oryza/crescimento & desenvolvimento , Oryza/efeitos dos fármacos , Oryza/metabolismo , Benzoatos/química , Benzoatos/farmacologia , Benzoatos/síntese química , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologia , Desenvolvimento Vegetal/efeitos dos fármacos , Ácido DesoxicólicoRESUMO
This study explores the genetic factors associated with atypical femoral fractures (AFF), rare fractures associated with prolonged anti-resorptive therapy. AFF are fragility fractures that typically appear in the subtrochanteric or diaphyseal regions of the femur. While some cases resemble fractures in rare genetic bone disorders, the exact cause remains unclear. This study investigates 457 genes related to skeletal homeostasis in 13 AFF patients by exome sequencing, comparing the results with osteoporotic patients (n = 27) and Iberian samples from the 1000 Genomes Project (n = 107). Only one AFF case carried a pathogenic variant in the gene set, specifically in the ALPL gene. The study then examined variant accumulation in the gene set, revealing significantly more variants in AFF patients than in osteoporotic patients without AFF (p = 3.7 × 10-5), particularly in ACAN, AKAP13, ARHGEF3, P4HB, PITX2, and SUCO genes, all of them related to osteogenesis. This suggests that variant accumulation in bone-related genes may contribute to AFF risk. The polygenic nature of AFF implies that a complex interplay of genetic factors determines the susceptibility to AFF, with ACAN, SUCO, AKAP13, ARHGEF3, PITX2, and P4HB as potential genetic risk factors. Larger studies are needed to confirm the utility of gene set analysis in identifying patients at high risk of AFF during anti-resorptive therapy.
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Conservadores da Densidade Óssea , Doenças Ósseas , Fraturas do Fêmur , Humanos , Fraturas do Fêmur/genética , Fêmur/patologia , Diáfises , DifosfonatosRESUMO
INTRODUCTION: Cardiogenic shock is associated with high in-hospital morbidity and mortality. Improvements in this care process could lead to better outcomes. METHODS: This retrospective study of patients with cardiogenic shock compared two periods: no specific program to address cardiogenic shock and implementation of a cardiogenic shock program. This program included the establishment of a multidisciplinary team (shock team), early alert to the transplant hospital, initiation of a ventricular assist extracorporeal membrane oxygenation (ECMO) program, and extension of continuous care by acute cardiovascular care specialists. The primary objective was to analyse whether there were differences between in-hospital mortality and mortality during follow-up. Predictors of in-hospital mortality were examined as a secondary objective. RESULTS: A total of 139 patients were enrolled: 69 of them in the previous period and 70 in the cardiogenic shock program period. There was a significant reduction in in-hospital mortality (55.1% vs 37.1%; p=0.03) and mortality during follow-up (62.7% vs 44.6%; p=0.03) in the second period. Diabetes mellitus, ejection fraction, out-of-hospital cardiac arrest, and implementation of the cardiogenic shock program were independent predictors of in-hospital mortality. CONCLUSIONS: The implementation of a comprehensive cardiogenic shock program in a non-transplanting hospital improved in-hospital and follow-up mortality of patients in cardiogenic shock.
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Oxigenação por Membrana Extracorpórea , Parada Cardíaca Extra-Hospitalar , Humanos , Choque Cardiogênico , Estudos Retrospectivos , Mortalidade Hospitalar , Oxigenação por Membrana Extracorpórea/efeitos adversosRESUMO
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by Salmonella, as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in IL12RB1 (n = 13), IFNGR1 (n = 3), and IFNGR2 (n = 1) genes. Interleukin-12Rß1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection.
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Infecções por Mycobacterium , Mycobacterium bovis , Masculino , Feminino , Humanos , Estudos Retrospectivos , Vacina BCG , Predisposição Genética para Doença , México/epidemiologia , Receptores de Interleucina-12/genética , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/genéticaRESUMO
Streptococcus gallolyticus subspecies gallolyticus (Sgg) has a strong clinical association with colorectal cancer (CRC) and actively promotes the development of colon tumors. However, the molecular determinants involved in Sgg pathogenicity in the gut are unknown. Bacterial type VII secretion systems (T7SS) mediate pathogen interactions with their host and are important for virulence in pathogenic mycobacteria and Staphylococcus aureus. Through genome analysis, we identified a locus in Sgg strain TX20005 that encodes a putative type VII secretion system (designated as SggT7SST05). We showed that core genes within the SggT7SST05 locus are expressed in vitro and in the colon of mice. Western blot analysis showed that SggEsxA, a protein predicted to be a T7SS secretion substrate, is detected in the bacterial culture supernatant, indicating that this SggT7SST05 is functional. Deletion of SggT7SST05 (TX20005Δesx) resulted in impaired bacterial adherence to HT29 cells and abolished the ability of Sgg to stimulate HT29 cell proliferation. Analysis of bacterial culture supernatants suggest that SggT7SST05-secreted factors are responsible for the pro-proliferative activity of Sgg, whereas Sgg adherence to host cells requires both SggT7SST05-secreted and bacterial surface-associated factors. In a murine gut colonization model, TX20005Δesx showed significantly reduced colonization compared to the parent strain. Furthermore, in a mouse model of CRC, mice exposed to TX20005 had a significantly higher tumor burden compared to saline-treated mice, whereas those exposed to TX20005Δesx did not. Examination of the Sgg load in the colon in the CRC model suggests that SggT7SST05-mediated activities are directly involved in the promotion of colon tumors. Taken together, these results reveal SggT7SST05 as a previously unrecognized pathogenicity determinant for Sgg colonization of the colon and promotion of colon tumors.
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Proliferação de Células , Neoplasias do Colo/patologia , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Infecções Estreptocócicas/microbiologia , Streptococcus gallolyticus subspecies gallolyticus/fisiologia , Sistemas de Secreção Tipo VII/metabolismo , Animais , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos A , Infecções Estreptocócicas/metabolismoRESUMO
[Figure: see text].
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COVID-19/sangue , COVID-19/imunologia , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Fagócitos/imunologia , Células Cultivadas , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Neutrófilos/imunologia , Neutrófilos/virologia , Fagócitos/virologiaRESUMO
BACKGROUND AND OBJECTIVES: Calculation of blood volume (BV) to be processed to achieve the target number of CD34+ cells can be accomplished by using collection efficiency 2 (CE2) formula. Our aim was to develop a BV web formula. MATERIALS AND METHODS: We calculated CE2 from aphereses performed between January 2015 and March 2020 in allogeneic donors and patients. From May 2020 to May 2021, we validated a formula: BV = ((Target CD34+ cells in the product)/(CD34+ pre-apheresis cells × CE2)) × 100. Subsequently, we compared the outcome of the procedures carried out before formula implementation (pre-formula), when standard three total BV collection was performed. RESULTS: CE2 was assessed in 384 apheresis procedures before formula implementation. CE2 was higher in allogeneic donors than in patients (53% ± 17% vs. 48% ± 15%, p = 0.008). CE2 was higher in multiple myeloma and non-Hodgkin lymphoma than Hodgkin's lymphoma (48% ± 15%, 48% ± 15% and 42% ± 13%, respectively; p = 0.008). Our formula (available on a website: Publisheet) was prospectively used in 54 individuals. The formula was very accurate: predicted versus observed CD34 + cells/kg collected had an r-value of 0.89 (p < 0.0001). We compared their results with 78 pre-formula individuals. In the post-formula group, a greater BV was processed in patients and less BV in allogeneic donors. Among individuals under 60 years of age, it was significantly less frequent than the need for more than one apheresis in the post-formula group. CONCLUSION: Formula calculations were accurate. Formula implementation allowed the optimization of the procedures and reduced the rate of individuals in need of apheresis for more than 1 day.
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Remoção de Componentes Sanguíneos , Mieloma Múltiplo , Humanos , Remoção de Componentes Sanguíneos/métodos , Antígenos CD34 , Doadores de Tecidos , Volume Sanguíneo , Mobilização de Células-Tronco Hematopoéticas/métodosRESUMO
Homologous recombination repairs DNA double-strand breaks and must function even on actively transcribed DNA. Because break repair prevents chromosome loss, the completion of repair is expected to outweigh the transcription of broken templates. However, the interplay between DNA break repair and transcription processivity is unclear. Here we show that the transcription factor GreA inhibits break repair in Escherichia coli. GreA restarts backtracked RNA polymerase and hence promotes transcription fidelity. We report that removal of GreA results in markedly enhanced break repair via the classic RecBCD-RecA pathway. Using a deep-sequencing method to measure chromosomal exonucleolytic degradation, we demonstrate that the absence of GreA limits RecBCD-mediated resection. Our findings suggest that increased RNA polymerase backtracking promotes break repair by instigating RecA loading by RecBCD, without the influence of canonical Chi signals. The idea that backtracked RNA polymerase can stimulate recombination presents a DNA transaction conundrum: a transcription fidelity factor that compromises genomic integrity.
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Reparo do DNA , Proteínas de Escherichia coli/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Quebras de DNA de Cadeia Dupla , RNA Polimerases Dirigidas por DNA/metabolismo , Escherichia coli/enzimologia , Exodesoxirribonuclease V/metabolismo , Ligação Proteica , Recombinases Rec A/metabolismoRESUMO
BACKGROUND: Diagnosing COVID-19-associated pulmonary aspergillosis (CAPA) can be challenging since radiological and clinical criteria in the critically ill patient are nonspecific. Microbiological diagnostic support is therefore crucial. The aim of this study was to document the incidence of aspergillosis using bronchoalveolar lavage (BAL) as the diagnostic method and to determine the performance of the current mycological diagnostic tests most widely used for the diagnosis of CAPA, together with evaluation of the Asp lateral flow device (LFD). METHODS: Prospective cohort study conducted between March 2020 and June 2022. Inclusion criteria were critically ill patients admitted to the ICU with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Diagnostic bronchoscopy and BAL were performed at the beginning of invasive mechanical ventilation. The sensitivity, specificity, positive and negative predictive value (PPV and NPV), positive and negative likelihood ratio (LR + and LR-) of BAL culture, direct examination with calcofluor white stain, ELISA (Platelia) and LFD (AspLFD) for detection of galactomannan (GM) were evaluated. Aspergillus-qPCR was applied when discrepancies between diagnostic tests arose. RESULTS: Of the 244 critically ill patients with SARS-CoV-2 pneumonia admitted to the ICU, the majority (n = 200, 82%) required invasive mechanical ventilation. Diagnostic bronchoscopic procedures were performed in 160 patients (80%), who were enrolled in this study. The incidence of CAPA was 18.7% (n = 30). LFD-GM demonstrated a sensitivity of 84%, specificity of 99%, PPV 94%, NPV 97%, LR(+) of 84, and LR(-) of 0.16. At GM-ELISA indices of ≥ 0.5 and ≥ 1.0, sensitivity was 92% and 79%, specificity was 95% and 99%, PPV 76% and 91%, NPV 99% and 96%, LR(+) 18 and 79, and LR(-) 0.08 and 0.21, respectively. The optimal cut-off index from the ROC curve was 0.48, with sensitivity of 95% and specificity of 95%. CONCLUSIONS: Using a diagnostic strategy based on bronchoscopy and BAL, we documented a high incidence of pulmonary aspergillosis in patients with severe SARS-CoV-2 pneumonia. Asp-LFD showed moderate sensitivity and excellent specificity, with a high PPV, and could be used for rapid diagnosis of patients with suspected CAPA.
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Aspergilose , COVID-19 , Aspergilose Pulmonar Invasiva , Humanos , SARS-CoV-2 , Estado Terminal , Estudos Prospectivos , Líquido da Lavagem Broncoalveolar/microbiologia , Sensibilidade e Especificidade , COVID-19/complicações , COVID-19/diagnóstico , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/microbiologia , Mananas/análise , Teste para COVID-19RESUMO
Drug use before or during sex is a high-risk sexual behavior associated with adverse health risks and outcomes, such as increasing the likelihood of overdoses and of acquiring sexually-transmitted diseases. This systematic review and meta-analysis of three scientific databases examined the prevalence of the use of intoxicating substances, those tending to excite or stupefy the user on a psychoactive level, before or during sex, among young adults (18-29 years old). A total of 55 unique empirical studies met the inclusion criteria (48,145 individuals; 39% males), were assessed for risk of bias using the tools of Hoy et al. (2012), and were analyzed via a generalized linear mixed-effects model. The results produced a global mean prevalence of this sexual risk behavior of 36.98% (95% CI: 28.28%, 46.63%). Nonetheless, significant differences were identified between different intoxicating substances, with the use of alcohol (35.10%; 95% CI: 27.68%, 43.31%), marijuana (27.80%; 95% CI: 18.24%, 39.92%), and ecstasy (20.90%; 95% CI: 14.34%, 29.45%) significantly more prevalent than that of cocaine (4.32%; 95% CI: 3.64%, 5.11%), heroin (.67%; 95% CI: .09%, 4.65%), methamphetamine (7.10%; 95% CI: 4.57%, 10.88%), and GHB (6.55%; 95% CI: 4.21%, 10.05%). Moderator analyses showed that the prevalence of alcohol use before or during sex differed according to geographical sample origin, and increased as the proportion of ethnic whites in samples increased. The remaining demographic (e.g., gender, age, reference population), sexual (e.g., sexual orientation, sexual activity), health (e.g., drug consumption, STI/STD status), methodological (e.g., sampling technique), and measurement (e.g., timeframe) variables that were examined did not moderate prevalence estimates. Implications for sexual development interventions were discussed.
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Infecções Sexualmente Transmissíveis , Transtornos Relacionados ao Uso de Substâncias , Humanos , Masculino , Feminino , Adulto Jovem , Adolescente , Adulto , Prevalência , Comportamento Sexual , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Consumo de Bebidas AlcoólicasRESUMO
BACKGROUND: The best use of perioperative cardiac biomarkers assessment is still under discussion. Massive postoperative troponin surveillance can result in untenably high workloads and costs for health care systems and potentially harmful interventions for patients. In a cohort of patients at risk for major adverse cardiovascular and cerebrovascular events (MACCEs), we aimed to (1) determine whether preoperative biomarkers can identify patients at major risk for acute myocardial injury in noncardiac surgery, (2) develop a risk model for acute myocardial injury prediction, and (3) propose an algorithm to optimize postoperative troponin surveillance. METHODS: Prospective, single-center cohort study enrolling consecutive adult patients (≥45 years) at risk for MACCE scheduled for intermediate-to-high-risk noncardiac surgery. Baseline high-sensitivity troponin T (hsTnT) and N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP), as well as hsTnT on the first 3 postoperative days were obtained. The main outcome was the occurrence of acute myocardial injury. Candidate predictors of acute myocardial injury were baseline concentrations of hsTnT ≥14 ng/L and NT-proBNP ≥300 pg/mL and preoperative and intraoperative variables. A multivariable risk model and a decision curve were constructed. RESULTS: Of 732 patients, 42.1% had elevated hsTnT and 37.3% had elevated NT-proBNP levels at baseline. Acute myocardial injury occurred in 161 patients (22%). Elevated baseline hsTnT, found in 84% of patients with acute myocardial injury, was strongly associated with this outcome: odds ratio (OR), 12.08 (95% confidence interval [CI], 7.78-19.42). Logistic regression identified 6 other independent predictors for acute myocardial injury: age, sex, estimated glomerular filtration rate (eGFR) <45 mL·min -1 ·1.73 m -2 , functional capacity <4 METs or unknown, NT-proBNP ≥300 pg/mL, and estimated intraoperative blood loss. The c -statistic for the risk model was 77% (95% CI, 0.73-0.81). The net benefit of the model began at a risk threshold of 7%. CONCLUSIONS: Baseline determination of cardiac biomarkers in patients at risk for MACCE shortly before intermediate- or high-risk noncardiac surgery helps identify those with the highest risk for acute myocardial injury. A baseline hsTnT ≥14 ng/L indicates the need for postoperative troponin surveillance. In patients with baseline hsTnT <14 ng/L, our 6-predictor model will identify additional patients at risk for acute myocardial injury who may also benefit from postoperative surveillance.
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Sistema Cardiovascular , Adulto , Humanos , Estudos de Coortes , Estudos Prospectivos , Biomarcadores , Troponina TRESUMO
PURPOSE: There is strong evidence supporting the presence of fluctuating asymmetry (FA) in Adolescents with Idiopathic Scoliosis (AIS). Additionally, recent research investigating the relationship between vitamin D and AIS found a relation between them. We hypothesize a negative correlation between FA and vitamin D. METHODS: We performed a surface scan of the torso of 53 AIS patients, a blood test to measure vitamin D and the radiographic Cobb angle. A correlation analysis between vitamin D and FA was carried out to test our hypothesis, and a regression of vitamin D on 3D shape was performed to observe shape differences between the vitamin D deficiency and insufficiency groups. RESULTS: There was no correlation between vitamin D and FA. We found a strong negative correlation between vitamin D and the Cobb angle only in the premenarche group (n = 7; r = - 0.92). Differences in shape were observed between the deficiency and insufficiency groups, and that differences were related to the width of the torso, but not the rotation or lateral flexion. CONCLUSIONS: Our results do not support the massive screening of vitamin D in AIS. Shape analysis revealed differences between the shape of the deficiency and insufficiency groups related to robustness. However, this finding had no relation with the scoliosis characteristics, it just reflected different body composition, and its importance should be explored in future.