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Prostate cancer screening using prostate-specific antigen (PSA) has been shown to reduce mortality but with substantial overdiagnosis, leading to unnecessary biopsies. The identification of a highly specific biomarker using liquid biopsies, represents an unmet need in the diagnostic pathway for prostate cancer. In this study, we employed a method that enriches for methylated cell-free DNA fragments coupled with a machine learning algorithm which enabled the detection of metastatic and localized cancers with AUCs of 0.96 and 0.74, respectively. The model also detected 51.8% (14/27) of localized and 88.7% (79/89) of patients with metastatic cancer in an external dataset. Furthermore, we show that the differentially methylated regions reflect epigenetic and transcriptomic changes at the tissue level. Notably, these regions are significantly enriched for biologically relevant pathways associated with the regulation of cellular proliferation and TGF-beta signaling. This demonstrates the potential of circulating tumor DNA methylation for prostate cancer detection and prognostication.
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The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Próstata/metabolismo , Mutação , Genômica , Evolução MolecularRESUMO
Background: In low- and middle-income countries, antibiotics are often prescribed for patients with symptoms of urinary tract infections (UTIs) without microbiological confirmation. Inappropriate antibiotic use can contribute to antimicrobial resistance (AMR) and the selection of MDR bacteria. Data on antibiotic susceptibility of cultured bacteria are important in drafting empirical treatment guidelines and monitoring resistance trends, which can prevent the spread of AMR. In East Africa, antibiotic susceptibility data are sparse. To fill the gap, this study reports common microorganisms and their susceptibility patterns isolated from patients with UTI-like symptoms in Kenya, Tanzania and Uganda. Within each country, patients were recruited from three sites that were sociodemographically distinct and representative of different populations. Methods: UTI was defined by the presence of >104â cfu/mL of one or two uropathogens in mid-stream urine samples. Identification of microorganisms was done using biochemical methods. Antimicrobial susceptibility testing was performed by the Kirby-Bauer disc diffusion assay. MDR bacteria were defined as isolates resistant to at least one agent in three or more classes of antimicrobial agents. Results: Microbiologically confirmed UTI was observed in 2653 (35.0%) of the 7583 patients studied. The predominant bacteria were Escherichia coli (37.0%), Staphylococcus spp. (26.3%), Klebsiella spp. (5.8%) and Enterococcus spp. (5.5%). E. coli contributed 982 of the isolates, with an MDR proportion of 52.2%. Staphylococcus spp. contributed 697 of the isolates, with an MDR rate of 60.3%. The overall proportion of MDR bacteria (nâ=â1153) was 50.9%. Conclusions: MDR bacteria are common causes of UTI in patients attending healthcare centres in East African countries, which emphasizes the need for investment in laboratory culture capacity and diagnostic algorithms to improve accuracy of diagnosis that will lead to appropriate antibiotic use to prevent and control AMR.
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BACKGROUND: A key factor driving the development and maintenance of antibacterial resistance (ABR) is individuals' use of antibiotics (ABs) to treat illness. To better understand motivations and context for antibiotic use we use the concept of a patient treatment-seeking pathway: a treatment journey encompassing where patients go when they are unwell, what motivates their choices, and how they obtain antibiotics. This paper investigates patterns and determinants of patient treatment-seeking pathways, and how they intersect with AB use in East Africa, a region where ABR-attributable deaths are exceptionally high. METHODS: The Holistic Approach to Unravelling Antibacterial Resistance (HATUA) Consortium collected quantitative data from 6,827 adult outpatients presenting with urinary tract infection (UTI) symptoms in Kenya, Tanzania, and Uganda between February 2019- September 2020, and conducted qualitative in-depth patient interviews with a subset (n = 116). We described patterns of treatment-seeking visually using Sankey plots and explored explanations and motivations using mixed-methods. Using Bayesian hierarchical regression modelling, we investigated the associations between socio-demographic, economic, healthcare, and attitudinal factors and three factors related to ABR: self-treatment as a first step, having a multi-step treatment pathway, and consuming ABs. RESULTS: Although most patients (86%) sought help from medical facilities in the first instance, many (56%) described multi-step, repetitive treatment-seeking pathways, which further increased the likelihood of consuming ABs. Higher socio-economic status patients were more likely to consume ABs and have multi-step pathways. Reasons for choosing providers (e.g., cost, location, time) were conditioned by wider structural factors such as hybrid healthcare systems and AB availability. CONCLUSION: There is likely to be a reinforcing cycle between complex, repetitive treatment pathways, AB consumption and ABR. A focus on individual antibiotic use as the key intervention point in this cycle ignores the contextual challenges patients face when treatment seeking, which include inadequate access to diagnostics, perceived inefficient public healthcare and ease of purchasing antibiotics without prescription. Pluralistic healthcare landscapes may promote more complex treatment seeking and therefore inappropriate AB use. We recommend further attention to healthcare system factors, focussing on medical facilities (e.g., accessible diagnostics, patient-doctor interactions, information flows), and community AB access points (e.g., drug sellers).
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Antibacterianos , Atenção à Saúde , Adulto , Humanos , Pesquisa Qualitativa , Teorema de Bayes , Uganda , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND: Poverty is a proposed driver of antimicrobial resistance, influencing inappropriate antibiotic use in low-income and middle-income countries (LMICs). However, at subnational levels, studies investigating multidimensional poverty and antibiotic misuse are sparse, and the results are inconsistent. We aimed to investigate the relationship between multidimensional poverty and antibiotic use in patient populations in Kenya, Tanzania, and Uganda. METHODS: In this mixed-methods study, the Holistic Approach to Unravelling Antimicrobial Resistance (HATUA) Consortium collected data from 6827 outpatients (aged 18 years and older, or aged 14-18 years and pregnant) with urinary tract infection (UTI) symptoms in health-care facilities in Kenya, Tanzania, and Uganda. We used Bayesian hierarchical modelling to investigate the association between multidimensional poverty and self-reported antibiotic self-medication and non-adherence (ie, skipping a dose and not completing the course). We analysed linked qualitative in-depth patient interviews and unlinked focus-group discussions with community members. FINDINGS: Between Feb 10, 2019, and Sept 10, 2020, we collected data on 6827 outpatients, of whom 6345 patients had complete data; most individuals were female (5034 [79·2%]), younger than 35 years (3840 [60·5%]), worked in informal employment (2621 [41·3%]), and had primary-level education (2488 [39·2%]). Antibiotic misuse was more common among those least deprived, and lowest among those living in severe multidimensional poverty. Regardless of poverty status, difficulties in affording health care, and more familiarity with antibiotics, were related to more antibiotic misuse. Qualitative data from linked qualitative in-depth patient interviews (n=82) and unlinked focus-group discussions with community members (n=44 groups) suggested that self-medication and treatment non-adherence were driven by perceived inconvenience of the health-care system, financial barriers, and ease of unregulated antibiotic access. INTERPRETATION: We should not assume that higher deprivation drives antibiotic misuse. Structural barriers such as inefficiencies in public health care, combined with time and financial constraints, fuel alternative antibiotic access points and treatment non-adherence across all levels of deprivation. In designing interventions to reduce antibiotic misuse and address antimicrobial resistance, greater attention is required to these structural barriers that discourage optimal antibiotic use at all levels of the socioeconomic hierarchy in LMICs. FUNDING: UK National Institute for Health Research, UK Medical Research Council, and the Department of Health and Social Care.
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Antibacterianos , Pobreza , Gravidez , Humanos , Feminino , Masculino , Quênia , Antibacterianos/uso terapêutico , Uganda , Tanzânia , Teorema de Bayes , Pesquisa QualitativaRESUMO
BACKGROUND: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. RESULTS: Single nucleotide variants (P = 7.0 × 10-03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10-06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10-05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10-09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. CONCLUSIONS: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.
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Hiperplasia Prostática , Neoplasias da Próstata , Células Clonais/patologia , Humanos , Masculino , Nucleotídeos , Próstata/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell's genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. RESULTS: We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman's rank correlation coefficient, rs=0.94) between conliga's inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (rs=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (rs=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga's hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. CONCLUSIONS: We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.
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Variações do Número de Cópias de DNA , Neoplasias , Sequência de Bases , DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias/genéticaRESUMO
Oesophageal adenocarcinoma (OAC) is an aggressive cancer with a five-year survival of <15%. Current chemotherapeutic strategies only benefit a minority (20-30%) of patients and there are no methods available to differentiate between responders and non-responders. We performed quantitative proteomics using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) on albumin/IgG-depleted and non-depleted plasma samples from 23 patients with locally advanced OAC prior to treatment. Individuals were grouped based on tumour regression (TRG) score (TRG1/2/3 vs TRG4/5) after chemotherapy, and differentially abundant proteins were compared. Protein depletion of highly abundant proteins led to the identification of around twice as many proteins. SWATH-MS revealed significant quantitative differences in the abundance of several proteins between the two groups. These included complement c1q subunit proteins, C1QA, C1QB and C1QC, which were of higher abundance in the low TRG group. Of those that were found to be of higher abundance in the high TRG group, glutathione S-transferase pi (GSTP1) exhibited the lowest p-value and highest classification accuracy and Cohen's kappa value. Concentrations of these proteins were further examined using ELISA-based assays. This study provides quantitative information relating to differences in the plasma proteome that underpin response to chemotherapeutic treatment in oesophageal cancers. SIGNIFICANCE: Oesophageal cancers, including oesophageal adenocarcinoma (OAC) and oesophageal gastric junction cancer (OGJ), are one of the leading causes of cancer mortality worldwide. Curative therapy consists of surgery, either alone or in combination with adjuvant or neoadjuvant chemotherapy or radiation, or combination chemoradiotherapy regimens. There are currently no clinico-pathological means of predicting which patients will benefit from chemotherapeutic treatments. There is therefore an urgent need to improve oesophageal cancer disease management and treatment strategies. This work compared proteomic differences in OAC patients who responded well to chemotherapy as compared to those who did not, using quantitative proteomics prior to treatment commencement. SWATH-MS analysis of plasma (with and without albumin/IgG-depletion) from OAC patients prior to chemotherapy was performed. This approach was adopted to determine whether depletion offered a significant improvement in peptide coverage. Resultant datasets demonstrated that depletion increased peptide coverage significantly. Additionally, there was good quantitative agreement between commonly observed peptides. Data analysis was performed by adopting both univariate as well as multivariate analysis strategies. Differentially abundant proteins were identified between treatment response groups based on tumour regression grade. Such proteins included complement C1q sub-components and GSTP1. This study provides a platform for further work, utilising larger sample sets across different treatment regimens for oesophageal cancer, that will aid the development of 'treatment response prediction assays' for stratification of OAC patients prior to chemotherapy.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Albuminas , Proteínas Sanguíneas/uso terapêutico , Complemento C1q/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , Imunoglobulina G , Proteômica/métodos , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. OBJECTIVE: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling. RESULTS AND LIMITATIONS: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset. CONCLUSIONS: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. PATIENT SUMMARY: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier.
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Fosfatidilinositol 3-Quinases , Neoplasias da Próstata , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Fosfatidilinositol 3-Quinases/genética , Prostatectomia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/terapia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Serina-Treonina Quinases TORRESUMO
BACKGROUND: Bacteria play a suspected role in the development of several cancer types, and associations between the presence of particular bacteria and prostate cancer have been reported. OBJECTIVE: To provide improved characterisation of the prostate and urine microbiome and to investigate the prognostic potential of the bacteria present. DESIGN, SETTING, AND PARTICIPANTS: Microbiome profiles were interrogated in sample collections of patient urine (sediment microscopy: n = 318, 16S ribosomal amplicon sequencing: n = 46; and extracellular vesicle RNA-seq: n = 40) and cancer tissue (n = 204). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Microbiomes were assessed using anaerobic culture, population-level 16S analysis, RNA-seq, and whole genome DNA sequencing. RESULTS AND LIMITATIONS: We demonstrate an association between the presence of bacteria in urine sediments and higher D'Amico risk prostate cancer (discovery, n = 215 patients, p < 0.001; validation, n = 103, p < 0.001, χ2 test for trend). Characterisation of the bacterial community led to the (1) identification of four novel bacteria (Porphyromonas sp. nov., Varibaculum sp. nov., Peptoniphilus sp. nov., and Fenollaria sp. nov.) that were frequently found in patient urine, and (2) definition of a patient subgroup associated with metastasis development (p = 0.015, log-rank test). The presence of five specific anaerobic genera, which includes three of the novel isolates, was associated with cancer risk group, in urine sediment (p = 0.045, log-rank test), urine extracellular vesicles (p = 0.039), and cancer tissue (p = 0.035), with a meta-analysis hazard ratio for disease progression of 2.60 (95% confidence interval: 1.39-4.85; p = 0.003; Cox regression). A limitation is that functional links to cancer development are not yet established. CONCLUSIONS: This study characterises prostate and urine microbiomes, and indicates that specific anaerobic bacteria genera have prognostic potential. PATIENT SUMMARY: In this study, we investigated the presence of bacteria in patient urine and the prostate. We identified four novel bacteria and suggest a potential prognostic utility for the microbiome in prostate cancer.
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Microbiota , Neoplasias da Próstata , Bactérias/genética , Humanos , Masculino , Microbiota/genética , Próstata/patologia , Neoplasias da Próstata/patologia , RNA Ribossômico 16S/genéticaRESUMO
The prostate gland produces prostatic fluid, high in zinc and citrate and essential for the maintenance of spermatozoa. Prostate cancer is a common condition with limited treatment efficacy in castration-resistant metastatic disease, including with immune checkpoint inhibitors. Using single-cell RNA-sequencing to perform an unbiased assessment of the cellular landscape of human prostate, we identify a subset of tumor-enriched androgen receptor-negative luminal epithelial cells with increased expression of cancer-associated genes. We also find a variety of innate and adaptive immune cells in normal prostate that were transcriptionally perturbed in prostate cancer. An exception is a prostate-specific, zinc transporter-expressing macrophage population (MAC-MT) that contributes to tissue zinc accumulation in homeostasis but shows enhanced inflammatory gene expression in tumors, including T cell-recruiting chemokines. Remarkably, enrichment of the MAC-MT signature in cancer biopsies is associated with improved disease-free survival, suggesting beneficial antitumor functions.
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Células Epiteliais/metabolismo , Macrófagos/metabolismo , Próstata/imunologia , Próstata/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Transcriptoma , Idoso , Animais , Células Epiteliais/imunologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RNA-Seq , Receptores Androgênicos/metabolismo , Análise de Célula Única/métodos , Zinco/metabolismoRESUMO
INTRODUCTION: Antimicrobial resistance (AMR) is a global health threat that requires urgent research using a multidisciplinary approach. The biological drivers of AMR are well understood, but factors related to treatment seeking and the social contexts of antibiotic (AB) use behaviours are less understood. Here we describe the Holistic Approach to Unravel Antibacterial Resistance in East Africa, a multicentre consortium that investigates the diverse drivers of drug resistance in urinary tract infections (UTIs) in East Africa. METHODS AND ANALYSIS: This study will take place in Uganda, Kenya and Tanzania. We will conduct geospatial mapping of AB sellers, and conduct mystery client studies and in-depth interviews (IDIs) with drug sellers to investigate AB provision practices. In parallel, we will conduct IDIs with doctors, alongside community focus groups. Clinically diagnosed patients with UTI will be recruited from healthcare centres, provide urine samples and complete a questionnaire capturing retrospective treatment pathways, sociodemographic characteristics, attitudes and knowledge. Bacterial isolates from urine and stool samples will be subject to culture and antibiotic sensitivity testing. Genomic DNA from bacterial isolates will be extracted with a subset being sequenced. A follow-up household interview will be conducted with 1800 UTI-positive patients, where further environmental samples will be collected. A subsample of patients will be interviewed using qualitative tools. Questionnaire data, microbiological analysis and qualitative data will be linked at the individual level. Quantitative data will be analysed using statistical modelling, including Bayesian network analysis, and all forms of qualitative data analysed through iterative thematic content analysis. ETHICS AND DISSEMINATION: Approvals have been obtained from all national and local ethical review bodies in East Africa and the UK. Results will be disseminated in communities, with local and global policy stakeholders, and in academic circles. They will have great potential to inform policy, improve clinical practice and build regional pathogen surveillance capacity.
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Antibacterianos , Farmacorresistência Bacteriana , Antibacterianos/uso terapêutico , Teorema de Bayes , Estudos Transversais , Humanos , Quênia , Estudos Retrospectivos , Tanzânia , Uganda/epidemiologiaRESUMO
PURPOSE: Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS-standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods. EXPERIMENTAL DESIGN: GFR measurements, biometrics, and IDMS- or non-IDMS-standardized creatinine values were collected for adult patients from three cancer centers. Using statistical modeling, an IDMS and non-IDMS creatinine-compatible eGFR model (CamGFR v2) was developed. Its performance was compared with that of the existing models Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund-Malmö revised, and CamGFR v1, using statistics for bias, precision, accuracy, and clinical robustness. RESULTS: A total of 3,083 IDMS- and 4,612 non-IDMS-standardized creatinine measurements were obtained from 7,240 patients. IDMS-standardized creatinine values were lower than non-IDMS-standardized values in within-center comparisons (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in Manchester; P < 0.0001), and more consistent between centers. CamGFR v2 was the most accurate [root-mean-squared error for IDMS, 14.97 mL/minute (95% confidence interval, 13.84-16.13) and non-IDMS, 15.74 mL/minute (14.86-16.63)], most clinically robust [proportion with >20% error of calculated carboplatin dose for IDMS, 0.12 (0.09-0.14) and non-IDMS, 0.17 (0.15-0.2)], and least biased [median residual for IDMS, 0.73 mL/minute (-0.68 to 2.2) and non-IDMS, -0.43 mL/minute (-1.48 to 0.91)] eGFR model, particularly when eGFR was larger than 60 ml/minute. CONCLUSIONS: CamGFR v2 can utilize IDMS- and non-IDMS-standardized creatinine measurements and outperforms previous models. CamGFR v2 should be examined prospectively as a practice-changing standard of care for eGFR-based carboplatin dosing.
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Creatinina/sangue , Creatinina/normas , Taxa de Filtração Glomerular , Modelos Estatísticos , Neoplasias/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , PrognósticoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
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Doenças da Imunodeficiência Primária/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Teorema de Bayes , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteínas de Ligação a RNA/genética , Sequências Reguladoras de Ácido Nucleico/genética , Proteína 1 Supressora da Sinalização de Citocina/genética , Fatores de Transcrição/genéticaRESUMO
The most common way to assess handedness is based on the preferred hand for writing, leading to a binary (left or right) trait. Handedness can also be assessed as a continuous trait with laterality indexes, but these are not time- and cost-effective, and are not routinely collected. Rarely, different handedness measures are collected for the same individuals. Here, we assessed the relationship of preferred hand for writing with four laterality indexes, reported in previous literature, derived from measures of dexterity (pegboard task, marking squares and sorting matches) and strength (grip strength), available in a range of N = 6664-8069 children from the ALSPAC cohort. Although all indexes identified a higher proportion of individuals performing better with their right hand, they showed low correlation with each other (0.08-0.3). Left handers were less consistent compared to right handers in performing better with their dominant hand, but that varied across indexes, i.e. 13% of left handers performed better with their right hand on marking squares compared to 48% for sorting matches and grip strength. Analysis of sex effects on the laterality indexes showed that males and females tend to be, on all measures, more left- and right-lateralized, respectively. Males were also over-represented among the individuals performing equally with both hands suggesting they had a higher tendency to be weakly lateralized. This study shows that different handedness measures tap into different dimensions of laterality and cannot be used interchangeably. The trends observed across indexes for males and females suggest that sex effects should be taken into account in handedness and laterality studies.
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Important oncological management decisions rely on kidney function assessed by serum creatinine-based estimated glomerular filtration rate (eGFR). However, no large-scale multicenter comparisons of methods to determine eGFR in patients with cancer are available. To compare the performance of formulas for eGFR based on routine clinical parameters and serum creatinine not calibrated with isotope dilution mass spectrometry, we studied 3620 patients with cancer and 166 without cancer who had their glomerular filtration rate (GFR) measured with an exogenous nuclear tracer at one of seven clinical centers. The mean measured GFR was 86 mL/min. Accuracy of all models was center dependent, reflecting intercenter variability of isotope dilution mass spectrometry-creatinine measurements. CamGFR was the most accurate model for eGFR (root-mean-squared error 17.3 mL/min) followed by the Chronic Kidney Disease Epidemiology Collaboration model (root-mean-squared error 18.2 mL/min).
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The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer.
Assuntos
Carcinoma in Situ/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Instabilidade Cromossômica/genética , Estudos de Coortes , Variações do Número de Cópias de DNA , Metilação de DNA/genética , Progressão da Doença , Epigenômica , Feminino , Perfilação da Expressão Gênica , Genômica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
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