RESUMO
Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (~3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.
RESUMO
BACKGROUND: Heart failure (HF) is associated with high mortality, but there are limited reports on the underlying cause of death. This study reports short-, medium- and long-term cause-specific mortality following first-ever HF hospitalisation in New Zealand. METHOD: First-ever HF hospitalisations were identified from hospital discharge coding between 2010 and 2013. Mortality outcomes were obtained via anonymised linkage to national datasets. Short (0-30 days), medium (31-364 days), and long-term (1-5 years) mortality rates were identified. Cause of death was identified from death certification coding and classified as cardiovascular and non-cardiovascular. Cox regression analysis was performed to adjust for confounding variables. RESULTS: A cohort of 34,264 individuals with first-ever HF hospitalisation were identified. Mean age was 75.8±13 years and 50.5% were male. A total of 21,637 (63.1%) died within 5 years of hospitalisation; 4,122 (12.0%) within the first 30 days, 6,358 (18.6%) between 31-364 days, and 11,157 (32.6%) between 1 and 5 years. Older age, male gender, Maori ethnicity, higher socioeconomic deprivation and increased comorbidity were independent factors associated with higher all-cause mortality. Cardiovascular causes accounted for 51% of total deaths. Cardiovascular mortality was 6.0%, 9.5%, and 16.7% at 30 days, 31-364 days, and 1-5 years, respectively. The most common causes of non-cardiovascular mortality were neoplasms, chronic respiratory diseases and infections, accounting for 14.6%, 11.0%, and 5.5% of total deaths respectively. Comorbidity was associated with higher non-cardiovascular mortality (hazard ratio [HR] 3.35; 95% confidence interval [CI] 3.16-3.55) but not cardiovascular mortality (HR 0.79; 95% CI 0.72-0.86). CONCLUSIONS: In New Zealand, mortality following first-ever HF hospitalisation is high. Non-cardiovascular death is common and there are ethnic inequities.
RESUMO
Heart failure is a major healthcare problem in New Zealand. The Acute Decompensated Heart Failure (ADHF) Registry was introduced in 2015, and has identified the need for quality improvement strategies to improve care of patients hospitalised with heart failure. In this paper, we describe the implementation of the revised ANZACS-QI Heart Failure Registry, which has a primary aim to support evidence-based management of and quality improvement measures for patients who are hospitalised with heart failure in New Zealand. Taking the learnings from the initial experience with the ADHF Registry, the revised ANZACS-QI Heart Failure Registry i) utilises age-stratified sampling of hospital discharge coding to identify a representative heart failure cohort, ii) utilises existing ANZACS-QI infrastructure for data-linkage to reduce the burden of manual data entry, iii) receives governance from the Heart Failure Working Group, and iv) focusses on established quality improvement indicators for heart failure management.
Assuntos
Insuficiência Cardíaca , Alta do Paciente , Melhoria de Qualidade , Sistema de Registros , Humanos , Insuficiência Cardíaca/terapia , Nova Zelândia , Idoso , Fatores Etários , Masculino , FemininoRESUMO
BACKGROUND: Administrative healthcare databases can be utilised for research. The accuracy of the International Statistical Classification of Diseases and Related Health Problems, Tenth Edition, Australian Modification (ICD-10-AM) coding of cardiovascular conditions in New Zealand is not known and requires validation. METHOD: International Statistical Classification of Diseases and Related Health Problems, Tenth Edition, Australian Modification coded discharges for acute coronary syndrome (ACS), heart failure (HF) and atrial fibrillation (AF), in both primary and secondary diagnostic positions, were identified from four district health boards between 1 January 2019 and 31 June 2019. A sample was randomly selected for retrospective clinician review for evidence of the coded diagnosis according to contemporary diagnostic criteria. Positive predictive values (PPVs) for ICD-10-AM coding vs clinician review were calculated. This study is also known as All of New Zealand, Acute Coronary Syndrome-Quality Improvement (ANZACS-QI) 77. RESULTS: A total of 600 cases (200 for each diagnosis, 5.0% of total identified cases) were reviewed. The PPV of ACS was 93% (95% confidence interval [CI] 89%-96%), HF was 93% (95% CI 89%-96%) and AF was 96% (95% CI 92%-98%). There were no differences in PPV between district health boards. PPV for ACS were lower in Maori vs non-Maori (72% vs 96%; p=0.004), discharge from non-Cardiology vs Cardiology services (89% vs 96%; p=0.048) and ICD-10-AM coding for unstable angina vs myocardial infarction (81% vs 95%; p=0.011). PPV for HF were higher in the primary vs secondary diagnostic position (100% vs 89%; p=0.001). CONCLUSIONS: The PPVs of ICD-10-AM coding for ACS, HF, and AF were high in this validation study. ICD-10-AM coding can be used to identify these diagnoses in administrative databases for the purposes of healthcare evaluation and research.
Assuntos
Bases de Dados Factuais , Classificação Internacional de Doenças , Humanos , Estudos Retrospectivos , Nova Zelândia/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/classificação , Austrália/epidemiologia , Feminino , Masculino , Codificação Clínica/métodosRESUMO
Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Proteogenômica , Humanos , Proteogenômica/métodos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Transcriptoma/genética , Masculino , Feminino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão GênicaAssuntos
Hepatectomia , Neoplasias Hepáticas , Veia Cava Inferior , Humanos , Veia Cava Inferior/cirurgia , Veia Cava Inferior/diagnóstico por imagem , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Procedimentos de Cirurgia Plástica/métodos , Resultado do Tratamento , Masculino , Procedimentos Cirúrgicos Vasculares/métodos , Feminino , Pessoa de Meia-IdadeRESUMO
Regular blood glucose monitoring and control is necessary for people with type 1 or advanced type 2 diabetes, yet diagnosing and treating patients with diabetes in an accurate, sustained and patient-friendly manner remains limited. Here, a glucose-responsive bifunctional nanosystem (PGOxMns) is constructed via one-pot biomineralisation of manganese dioxide with glucose oxidase and ε-poly-L-lysine. Under hyperglycaemic conditions, the cascade reactions that occur when glucose interacts with PGOxMns can trigger the production of Mn(II), which enhances the magnetic resonance imaging signal. Simultaneously, manganese dioxide catalyses the decomposition of toxic hydrogen peroxide into oxygen, which also maintains glucose oxidase (GOx) activity. In an in vivo model of diabetes, PGOxMns is used to monitor glucose levels (0-20 mm) and allowed identification of diabetic mice via T1-weighted MRI. Furthermore, PGOxMns is found to have a high insulin-loading capacity (83.6%), likely due to its positive charge. A single subcutaneous injection of insulin-loaded nanosystem (Ins-PGOxMns) into diabetic mice resulted in a rapid and efficient response to a glucose challenge and prolonged blood glucose level control (< 200 mg dL-1) for up to 50 h. Overall, this proof-of-concept study demonstrates the feasibility of using biomineralised nanosystems to develop patient-friendly strategies for glucose monitoring and control.
RESUMO
Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. Design, Setting, and Participants: RNA sequencing analysis of 58â¯724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.
Assuntos
Biomarcadores Tumorais , Gradação de Tumores , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Neoplasias da Próstata/urina , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Idoso , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Detecção Precoce de Câncer/métodosRESUMO
The present study aimed to evaluate the influence of titanium surface nanotopography on the initial bacterial adhesion process by in vivo and in vitro study models. Titanium disks were produced and characterized according to their surface topography: machined (Ti-M), microtopography (Ti-Micro), and nanotopography (Ti-Nano). For the in vivo study, 18 subjects wore oral acrylic splints containing 2 disks from each group for 24 h (n = 36). After this period, the disks were removed from the splints and evaluated by microbial culture method, scanning electron microscopy (SEM), and qPCR for quantification of Streptococcus oralis, Actinomyces naeslundii, Fusobacterium nucleatum, as well as total bacteria. For the in vitro study, adhesion tests were performed with the species S. oralis and A. naeslundii for 24 h. Data were compared by ANOVA, with Tukey's post-test. Regarding the in vivo study, both the total aerobic and total anaerobic bacteria counts were similar among groups (p > 0.05). In qPCR, there was no difference among groups of bacteria adhered to the disks (p > 0.05), except for A. naeslundii, which was found in lower proportions in the Ti-Nano group (p < 0.05). In the SEM analysis, the groups had a similar bacterial distribution, with a predominance of cocci and few bacilli. In the in vitro study, there was no difference in the adhesion profile for S. oralis and A. naeslundii after 24 h of biofilm formation (p > 0.05). Thus, we conclude that micro- and nanotopography do not affect bacterial adhesion, considering an initial period of biofilm formation.
Assuntos
Aderência Bacteriana , Titânio , Humanos , Fusobacterium nucleatum , Microscopia Eletrônica de Varredura , Projetos de PesquisaRESUMO
Repurposing drugs can significantly reduce the time and costs associated with drug discovery and development. However, many drug compounds possess intrinsic fluorescence, resulting in aberrations such as auto-fluorescence, scattering and quenching, in fluorescent high-throughput screening assays. To overcome these drawbacks, time-resolved technologies have received increasing attention. In this study, we have developed a rapid and efficient screening platform based on time-resolved emission spectroscopy in order to screen for inhibitors of the DNA repair enzyme, uracil-DNA glycosylase (UDG). From a database of 1456 FDA/EMA-approved drugs, sodium stibogluconate was discovered as a potent UDG inhibitor. This compound showed synergistic cytotoxicity against 5-fluorouracil-resistant cancer cells. This work provides a promising future for time-resolved technologies for high-throughput screening (HTS), allowing for the swift identification of bioactive compounds from previously overlooked scaffolds due to their inherent fluorescence properties.
Assuntos
Neoplasias da Próstata , Uracila-DNA Glicosidase , Humanos , Masculino , Uracila-DNA Glicosidase/química , Oligonucleotídeos , Gluconato de Antimônio e Sódio , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Detecção Precoce de CâncerRESUMO
Heart failure affects 1-3% of the population and remains a major public health problem, with high rates of hospitalisation and mortality. Health inequities in the incidence of heart failure have widened over the last 13 years in Aotearoa New Zealand. Urgent action is required to address the inequitable burden of heart failure among Maori and Pasifika. Regional and international heart failure guidelines now provide clear and consistent guidance on the contemporary approach to management for patients with heart failure. The purpose of this position statement is to ensure that all people in Aotearoa New Zealand have access to optimal healthcare delivery and pharmacotherapy for contemporary management of heart failure. Three main areas are addressed, including: 1) access to evidence-based pharmacotherapy for patients with heart failure, 2) the importance of early initiation and titration of pharmacotherapy, and 3) the workforce required to ensure timely delivery of heart failure therapies. Implementation of evidence-based healthcare will ensure all patients with heart failure in Aotearoa New Zealand have opportunity for substantial improvement in health.
Assuntos
Insuficiência Cardíaca , Povo Maori , Humanos , Nova Zelândia/epidemiologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Pacientes , HospitalizaçãoRESUMO
The overexpression and overactivation of epidermal growth factor receptor (EGFR) are frequently observed in human cancers, including squamous cell carcinoma and adenocarcinoma. In this study, a covalent EGFR probe was developed by conjugating afatinib to an iridium(III) scaffold. Complex 1 showed enhanced luminescence in living epidermoid squamous carcinoma A431 cells compared to other cell lines, via engaging EGFR as confirmed via CETSA and knockdown experiments. Moreover, complex 1 inhibited downstream targets of EGFR in cellulo with repression persisting after removal of the complex, indicating an irreversible mode of inhibition. Finally, complex 1 showed potent antiproliferative activity against A431 cells with comparable potency to afatinib alone. To our knowledge, complex 1 is the first EGFR covalent inhibitor based on an iridium scaffold reported in the literature, with the potential to be further explored as a theranostic agent in the future.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Afatinib , Irídio/farmacologia , Quinazolinas/farmacologia , Receptores ErbB/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologiaRESUMO
The AtriClip device enables the safe and reproducible epicardial clipping of the left atrial appendage. Transapical off-pump beating heart mitral valve repair using NeoChord DS100 Artificial Chordae Delivery System has matured and become more standardized. We aim to evaluate the feasibility of combining NeoChord repair and left atrial appendage exclusion in a single procedure through the same minithoracotomy in patients with mitral valve prolapse and atrial fibrillation. From 2018 to 2019, seven patients with severe mitral regurgitation and atrial fibrillation underwent transesophageal echocardiography-guided transapical off-pump mitral valve repair with the novel NeoChord DS 1000 system and concomitant left atrial appendage exclusion using the AtriClip Pro II device. Both procedures were performed via left mini-thoracotomy. The AtriClip device was applied after the NeoChord repair was done. All seven patients had less than moderate mitral regurgitation after the NeoChord repair and successful left atrial appendage occlusion. There were no device or procedure-related complications. Clinical follow-up revealed significant symptomatic improvement, and no cardiovascular complications were reported. Transesophageal echocardiography at 6-12 months post-procedure showed stable left atrial appendage occlusion with no residual flow between the left atrium and the left atrial appendage and a stump of less than 5 mm. Beating heart epicardial clipping of the left atrial appendage using AtriClip concomitant with transapical mitral valve repair using Neochord DS 1000 system is a feasible and safe treatment option in mitral valve prolapse and atrial fibrillation in patients with limited indications. However, its safety needs to be confirmed in a larger series of patients.
Assuntos
Apêndice Atrial , Fibrilação Atrial , Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Prolapso da Valva Mitral , Humanos , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/cirurgia , Prolapso da Valva Mitral/complicações , Prolapso da Valva Mitral/cirurgia , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Fibrilação Atrial/complicações , Fibrilação Atrial/cirurgia , Estudos de Viabilidade , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Resultado do Tratamento , Cordas TendinosasRESUMO
Hepatocellular carcinoma (HCC) is a major contributor to global mortality rates, but current treatment options have limitations. Advanced theranostics are needed to effectively integrate diagnosis and therapeutic of HCC. Glycyrrhetinic acid (GA) has abundant binding sites with glycyrrhetinic acid receptors (GA-Rs) on the surface of HCC cells and has also been reported to possess ligands with mitochondrial-targeting capability but with limited efficacy. Herein, we report a near-infrared (NIR) luminescent theranostic complex 1 through conjugating an iridium(III) complex to GA, which exhibits the desired photophysical properties and promotes mitochondrial-targeting capability. Complex 1 was selectively taken up by HepG2 liver cancer cells and was imaged within mitochondria with NIR emission. Complex 1 targeted mitochondria and opened mitochondrial permeability transition pores (MPTPs), resulting in ROS accumulation, mitochondrial damage, disruption of Bax/Bcl-2 equilibrium, and tumor cell apoptosis, resulting in significantly improved anticancer activity compared to GA. This work offers a methodology for developing multifunctional theranostic probes with amplified specificity and efficacy.
Assuntos
Carcinoma Hepatocelular , Ácido Glicirretínico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Medicina de Precisão , Irídio/farmacologia , Irídio/química , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/química , Mitocôndrias/metabolismo , Linhagem Celular TumoralRESUMO
OBJECTIVES: To determine platelet function and assess fibrinolysis in dogs following trauma using multiple electrical impedance aggregometry and a modified thromboelastographic (TEG) technique. To determine if the severity of trauma, as assessed by the Animal Trauma Triage (ATT) score and clinicopathological markers of shock, is associated with a greater degree of platelet dysfunction and fibrinolysis. SETTING: University teaching hospital. ANIMALS: Twenty client-owned dogs with trauma (occurring <24 h prior to admission and blood sampling) and ATT score of >4 were prospectively recruited. A control group of 10 healthy dogs was included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Platelet function was measured using multiple electrode platelet aggregometry (MEPA) utilizing arachidonic acid, ADP, and collagen agonists. Fibrinolysis was assessed in citrated whole blood with the addition of tissue plasminogen activator (tPA; 50 U/mL) using kaolin-activated TEG. Conventional statistical analysis was performed to compare coagulation parameters between the groups and assess linear correlations. Median (interquartile range) ATT score was 5 (5-7), and 65% (n = 13) of dogs suffered polytrauma. Mean (± SD) time from trauma to blood sampling was 9 hours (± 6). Median (interquartile range) shock index and plasma lactate concentration were 1.1 (0.7-2.0, n = 16) and 2.9 mmol/L (0.9-16.0, n = 18), respectively. Four dogs did not survive to discharge (20%). There were no differences between the trauma and control group coagulation variables. A moderate negative correlation between ATT score and area under the curve for ADP was found (P = 0.043, r2 = -0.496). CONCLUSIONS: Preliminary evaluation of platelet function measured by MEPA, and fibrinolysis measured by tPA-modified TEG, is not significantly different in this population of dogs with traumatic injury compared to healthy dogs.
Assuntos
Transtornos da Coagulação Sanguínea , Doenças do Cão , Humanos , Cães , Animais , Fibrinólise , Ativador de Plasminogênio Tecidual , Hemostasia , Tromboelastografia/veterinária , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/veterináriaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, partly because it is frequently identified at an advanced stage, when surgery is no longer feasible. Therefore, early detection using minimally invasive methods such as blood tests may improve outcomes. However, studies to discover molecular signatures for the early detection of PDAC using blood tests have only been marginally successful. In the current study, a quantitative glycoproteomic approach via data-independent acquisition mass spectrometry was utilized to detect glycoproteins in 29 patient-matched PDAC tissues and sera. A total of 892 N-linked glycopeptides originating from 141 glycoproteins had PDAC-associated changes beyond normal variation. We further evaluated the specificity of these serum-detectable glycoproteins by comparing their abundance in 53 independent PDAC patient sera and 65 cancer-free controls. The PDAC tissue-associated glycoproteins we have identified represent an inventory of serum-detectable PDAC-associated glycoproteins as candidate biomarkers that can be potentially used for the detection of PDAC using blood tests.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Biomarcadores Tumorais/metabolismo , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Glicoproteínas , Espectrometria de MassasRESUMO
OBJECTIVE: Ethnic inequities in heart failure (HF) have been documented in several countries. This study describes New Zealand (NZ) trends in incident HF hospitalisation by ethnicity between 2006 and 2018. METHODS: Incident HF hospitalisations in ≥20-year-old subjects were identified through International Classification of Diseases, 10th Revision-coded national hospitalisation records. Incidence was calculated for different ethnic, sex and age groups and were age standardised. Trends were estimated with joinpoint regression. RESULTS: Of 116 113 incident HF hospitalisations, 12.8% were Maori, 5.7% Pacific people, 3.0% Asians and 78.6% Europeans/others. 64% of Maori and Pacific patients were aged <70 years, compared with 37% of Asian and 19% of European/others. In 2018, incidence rate ratios compared with European/others were 6.0 (95% CI 4.9 to 7.3), 7.5 (95% CI 6.0 to 9.4) and 0.5 (95% CI 0.3 to 0.8) for Maori, Pacific people and Asians aged 20-49 years; 3.7 (95% CI 3.4 to 4.0), 3.6 (95% CI 3.2 to 4.1) and 0.5 (95% CI 0.4 to 0.6) for Maori, Pacific people and Asians aged 50-69 years; and 1.5 (95% CI 1.4 to 1.6), 1.5 (95% CI 1.3 to 1.7) and 0.5 (95% CI 0.5 to 0.6) for Maori, Pacific people and Asians aged ≥70 years. Between 2006 and 2018, ethnicity-specific rates diverged in ≥70-year-old subjects due to a decline in European/others (annual percentage change (APC) -2.0%, 95% CI -2.5% to -1.6%) and Asians (APC -3.3%, 95% CI -4.4% to -2.1%), but rates remained unchanged for Maori and Pacific people. In contrast, regardless of ethnicity, rates either increased or remained unchanged in <70-year-old subjects. CONCLUSION: Ethnic inequities in incident HF hospitalisation have widened in NZ over the past 13 years. Urgent action is required to address the predisposing factors that lead to development of HF in Maori and Pacific people.
Assuntos
Desigualdades de Saúde , Insuficiência Cardíaca , Povo Maori , Adulto , Idoso , Humanos , Adulto Jovem , Etnicidade , Insuficiência Cardíaca/epidemiologia , Incidência , Nova Zelândia/epidemiologiaRESUMO
BACKGROUND: There is currently a lack of consensus regarding the timing of ventral hernia repair relative to bariatric surgery. OBJECTIVES: To compare outcomes between patients undergoing simultaneous and selectively deferred ventral hernia repair and bariatric surgery. SETTING: High volume UPPER gastrointestinal and Bariatric Unit. Sydney, Australia. METHODS: A retrospective case series from a single institution's prospectively collected database (2003-21) was performed to determine the characteristics and outcomes in patients having simultaneous and deferred hernia repair relative to their bariatric surgery. RESULTS: In our patient cohort (N = 134), 111 patients underwent simultaneous repair and 23 had a deferred procedure. Of the simultaneous patients, 95 (85.6%) underwent resection bariatric surgery. The median operative time in the simultaneous versus deferred groups was 155 versus 287 minutes and the length of stay was 3 versus 7 days. There has been one (.9%) mesh infection requiring explant, in an open, simultaneous repair undertaken in a gastric band patient, 3 (2.8%) infected seromas, 1 (.9%) surgical site infection, and 8 (7.5%) hernia recurrences in the simultaneous group. The deferred group has had no mesh infections, no hernia recurrence, and 2 (9.5%) infected seromas to date. There was 1 mortality in the simultaneous cohort (simultaneous gastric bypass group), from a massive Pulmonary Embolism (<30 days postoperatively) and one in the deferred group from an interval small bowel obstruction. CONCLUSIONS: Simultaneous ventral hernia repair with bariatric surgery had a low rate of infection and a low mesh explant rate, even when coupled with resection bariatric surgery in this series. A combined approach may be safe, even in the clean-contaminated surgical context.