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BACKGROUND: In the United Kingdom (UK), cancer screening invitations are based on general practice (GP) registrations. We hypothesize that GP electronic medical records (EMR) can be utilised to calculate a lung cancer risk score with good accuracy/clinical utility. METHODS: The development cohort was Secure Anonymised Information Linkage-SAIL (2.3 million GP EMR) and the validation cohort was UK Biobank-UKB (N = 211,597 with GP-EMR availability). Fast backward method was applied for variable selection and area under the curve (AUC) evaluated discrimination. RESULTS: Age 55-75 were included (SAIL: N = 574,196; UKB: N = 137,918). Six-year lung cancer incidence was 1.1% (6430) in SAIL and 0.48% (656) in UKB. The final model included 17/56 variables in SAIL for the EMR-derived score: age, sex, socioeconomic status, smoking status, family history, body mass index (BMI), BMI:smoking interaction, alcohol misuse, chronic obstructive pulmonary disease, coronary heart disease, dementia, hypertension, painful condition, stroke, peripheral vascular disease and history of previous cancer and previous pneumonia. The GP-EMR-derived score had AUC of 80.4% in SAIL and 74.4% in UKB and outperformed ever-smoked criteria (currently the first step in UK lung cancer screening pilots). DISCUSSION: A GP-EMR-derived score may have a role in UK lung cancer screening by accurately targeting high-risk individuals without requiring patient contact.
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Medicina Geral , Neoplasias Pulmonares , Humanos , Pessoa de Meia-Idade , Idoso , Registros Eletrônicos de Saúde , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Fatores de Risco , Medição de RiscoRESUMO
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). RESULTS: Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P < 0.0001). CONCLUSIONS: PARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.
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Benzimidazóis/administração & dosagem , Carboplatina/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Benzimidazóis/química , Carboplatina/química , Linhagem Celular Tumoral , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Camundongos , Penetrância , Inibidores de Poli(ADP-Ribose) Polimerases/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Self-reported health is a widely used health indicator in surveys and questionnaires. The measure gained attention when research identified its association with mortality in the 1970s and 1980s. The measure is also associated with morbidity and other health outcomes such as the utilisation of health services. Self-reported health is a particularly useful measure for young people because this age group is generally clinically healthy. However, it is known that many chronic conditions have long latency periods that are initiated early in life. Because of its predictive nature, self-reported health can be used to estimate young people's current and future health. Despite its widespread use, however, self-reported health remains a poorly understood concept. This paper presents the protocol for a systematic review that will identify and synthesise qualitative studies that investigate the factors that are considered by young people when they assess their health, and when they talk about health overall. METHODS: The population of the review is young people aged 10-24 years, with or without health conditions. We will search the databases of MEDLINE (Ovid®), PsycINFO (APA PsycNet), ProQuest Sociology Collection, and Web of Science Core Collection™. We will also utilise techniques of reference checking and forward citation searching, as this strategy has been shown to result in a higher number of high-quality studies in social science systematic reviews. Google Scholar and Google Search were used during preliminary searches; Google Scholar will be utilised for forward citation searching. We will include studies written in English, German, or Finnish; there will be no lower date limit. One reviewer will screen all citations. A second reviewer will independently screen a sample of 20% of the abstracts. Data will be extracted by one researcher, two other researchers will independently review all data extracted, and quality appraisal will be completed by the first reviewer. We will utilise the Quality Framework for the appraisal of included articles and thematic synthesis of qualitative studies. DISCUSSION: The results of this systematic review will improve the understanding of the factors that are considered during the self-assessments of health; this will improve the interpretation of the results of quantitative research. Also, an improved understanding of the conceptualisation of health will inform the development of health policies and interventions that support young people's health. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022367519.
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Pesquisa Qualitativa , Revisões Sistemáticas como Assunto , Humanos , Adolescente , Adulto Jovem , Nível de Saúde , Autorrelato , Criança , Projetos de PesquisaRESUMO
Lung cancer screening trials using low-dose computed tomography (LDCT) show reduced late-stage diagnosis and mortality rates. These trials have identified high-risk groups that would benefit from screening. However, these sub-populations can be difficult to access and retain in trials. Implementation of national screening programmes further suggests that there is poor uptake in eligible populations. A new approach to participant selection may be more effective. Electronic medical records (EMRs) are a viable alternative to population-based or health registries, as they contain detailed clinical and demographic information. Trials have identified that e-screening using EMRs has improved trial retention and eligible subject identification. As such, this paper argues for greater use of EMRs in trial recruitment and screening programmes. Moreover, this opinion paper explores the current issues in and approaches to lung cancer screening, whether records can be used to identify eligible subjects for screening and the challenges that researchers face when using EMR data.
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BACKGROUND: Many studies focus on interventions that reduce the processes that lead to adverse drug events (ADEs), such as inappropriate or high-risk prescribing, without assessing whether they result in a reduction in ADEs or associated adverse health outcomes. OBJECTIVES: Our objective was to systematically review interventions to reduce the incidence of ADEs measured by health outcomes in older patients in primary care settings. METHODS: The review included randomised controlled trials, controlled clinical trials, controlled before and after studies, interrupted time series studies and cohort studies conducted in the community care setting. Older patients (aged ≥ 65 years) receiving medical treatment in primary care were included. Interventions were aimed at reducing adverse health outcomes associated with ADEs in older patients. Risk of bias was assessed using the Cochrane Collaboration's tool. Outcomes were measured by reductions in hospitalisation, emergency department (ED) visits, mortality and improvements in quality of life (QoL), mental health and physical function. Fixed and random-effects models were used to calculate pooled effect estimates comparing interventions and control groups for the outcomes, where feasible. RESULTS: The literature search identified 1566 abstracts, seven of which were included in the systematic review. The interventions for reducing ADEs included prescription or medication reviews by a pharmacist (n = 4), primary care physician (n = 1) or research team (n = 1), and an educational intervention (n = 1) for nursing staff to improve the recognition of potentially harmful medications and corresponding ADEs. Meta-analysis found no statistically significant benefit from any interventions on hospitalisation, ED visits, mortality, QoL or mental health and physical function. CONCLUSIONS: No significant benefit was gained from any of the interventions in terms of the outcomes considered. New approaches are required to reduce ADEs in older adults.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Prescrição Inadequada/efeitos adversos , Farmacêuticos/normas , Papel Profissional , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Humanos , Atenção Primária à Saúde/estatística & dados numéricos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Unfortunately, the co-author name was incorrectly published as ' 'Lamona'' instead of ' 'Lamorna'' in the original article.
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Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.