Baseline computed tomography screening and blood microRNA predict lung cancer risk and define adequate intervals in the BioMILD trial.

BACKGROUND: Large randomized trials have demonstrated that lung cancer (LC) screening with low-dose computed tomography (LDCT) reduces LC mortality in heavy smokers. We previously showed in the MILD screening trial that the combination of a prespecified circulating microRNA (miRNA) signature classifier (MSC) and LDCT improves the accuracy of LDCT alone. The primary aim of the prospective BioMILD study was to assess the additional value of the blood MSC assay at the time of baseline LDCT with the goal of personalizing LC screening intervals. PATIENTS AND METHODS: The study enrolled 4119 volunteers from January 2013 to March 2016, with a median follow-up of 5.3 years. Baseline LDCT and miRNAs stratified participants into four groups: CT-/MSC- (n = 2664; 64.7%); CT-/MSC+ (n = 800; 19.4%); CT+/MSC- (n = 446; 10.8%); and CT+/MSC+ (n = 209; 5.1%). As per the protocol, those in the CT-/MSC- and CT-/MSC+ groups were allocated to LDCT repeat at 3-year and 1-year intervals; CT+ participants were allocated for 1-year or earlier intervals on the basis of LDCT features independent of MSC results. RESULTS: CT+ participants had a 15.8-fold higher 4-year LC incidence than CT- participants (95% confidence interval 10.34-24.05), and MSC+ participants had a 2.0-fold higher 4-year LC incidence than MSC- participants (95% confidence interval 1.40-2.90); there was no evidence that the MSC effect differed between CT+ and CT- participants. LC incidence at 4 years was 0.8% in CT-/MSC-, 1.1% in CT-/MSC+, 10.8% in CT+/MSC-, and 20.1% in CT+/MSC+ participants. LC mortality rates at 5 years in the four risk groups were 0.5 in CT-/MSC-, 1.5 in CT-/MSC+, 4.2 in CT+/MSC-, and 10.1 in CT+/MSC+. CONCLUSION: The combined use of LDCT and blood miRNAs at baseline predicts individual LC incidence and mortality, with a major effect of MSC for LDCT-positive individuals. These findings may have important implications in personalizing screening intervals.

Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study.

BACKGROUND: Making trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials. METHODS: We used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online. RESULTS: We had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs. CONCLUSIONS: We identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of 'dos and don'ts' for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea.

Patient preferences for osteoarthritis pain and chronic low back pain treatments in the United States: a discrete-choice experiment.

OBJECTIVE: To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)-inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. METHODS: We used a discrete-choice experiment (DCE) to elicit preferences for attributes of OA and CLBP pharmaceutical treatments, and a best-worst scaling (BWS) exercise to further characterize the relative importance of treatment-related side-effect risks. The survey was completed online by 602 US residents with self-reported chronic, moderate-to-severe OA pain and/or CLBP who had tried, had contraindications for, or were unwilling to take currently available pharmaceutical therapies. In the DCE, respondents repeatedly chose between two hypothetical treatments defined by six attributes (symptom control; treatment-related risks of (1) severe joint problems, (2) heart attack, and (3) physical dependence; mode/frequency of administration; and cost). In the BWS exercise, respondents evaluated ten side-effect risks. Random-parameters logit models were estimated; conditional relative attribute importance, maximum acceptable risks, and willingness to pay were calculated. RESULTS: The most important DCE attributes were improving symptom control (scaled conditional relative importance, 10.00) and reducing risk of physical dependence (6.99). The three most important BWS attributes were, in rank order, risks of stroke, physical dependence, and heart attack. Respondents were willing to accept a > 4% treatment-related risk of severe joint problems for even modest symptom improvement. CONCLUSION: A pharmaceutical treatment with a risk of severe joint problems was viewed as an acceptable alternative to other treatments with comparable efficacy but risks associated with NSAIDs or opioids.

Ten-year results of the Multicentric Italian Lung Detection trial demonstrate the safety and efficacy of biennial lung cancer screening.

BACKGROUND: The Multicentric Italian Lung Detection (MILD) trial demonstrated that prolonged low-dose computed tomography (LDCT) screening could achieve a 39% reduction in lung cancer (LC) mortality. We have here evaluated the long-term results of annual vs. biennial LDCT and the impact of screening intensity on overall and LC-specific mortality at 10 years. PATIENTS AND METHODS: Between 2005 and 2018, the MILD trial prospectively randomised the 2376 screening arm participants to annual (n = 1190) or biennial (n = 1186) LDCT, for a median screening period of 6.2 years and 23,083 person-years of follow-up. The primary outcomes were 10-year overall and LC-specific mortality, and the secondary end-points were the frequency of advanced-stage and interval LCs. RESULTS: The biennial LDCT arm showed a similar overall mortality (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.57-1.12) and LC-specific mortality at 10 years (HR 1.10, 95% CI 0.59-2.05), as compared with the annual LDCT arm. Biennial screening saved 44% of follow-up LDCTs in subjects with negative baseline LDCT, and 38% of LDCTs in all participants, with no increase in the occurrence of stage II-IV or interval LCs. CONCLUSIONS: The MILD trial provides original evidence that prolonged screening beyond five years with biennial LDCT can achieve an LC mortality reduction comparable to annual LDCT, in subjects with a negative baseline examination.

Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.

BACKGROUND: The National Lung Screening Trial showed that lung cancer (LC) screening by three annual rounds of low-dose computed tomography (LDCT) reduces LC mortality. We evaluated the benefit of prolonged LDCT screening beyond 5 years, and its impact on overall and LC specific mortality at 10 years. DESIGN: The Multicentric Italian Lung Detection (MILD) trial prospectively randomized 4099 participants, to a screening arm (n = 2376), with further randomization to annual (n = 1190) or biennial (n = 1186) LDCT for a median period of 6 years, or control arm (n = 1723) without intervention. Between 2005 and 2018, 39 293 person-years of follow-up were accumulated. The primary outcomes were 10-year overall and LC specific mortality. Landmark analysis was used to test the long-term effect of LC screening, beyond 5 years by exclusion of LCs and deaths that occurred in the first 5 years. RESULTS: The LDCT arm showed a 39% reduced risk of LC mortality at 10 years [hazard ratio (HR) 0.61; 95% confidence interval (CI) 0.39-0.95], compared with control arm, and a 20% reduction of overall mortality (HR 0.80; 95% CI 0.62-1.03). LDCT benefit improved beyond the 5th year of screening, with a 58% reduced risk of LC mortality (HR 0.42; 95% CI 0.22-0.79), and 32% reduction of overall mortality (HR 0.68; 95% CI 0.49-0.94). CONCLUSIONS: The MILD trial provides additional evidence that prolonged screening beyond 5 years can enhance the benefit of early detection and achieve a greater overall and LC mortality reduction compared with NLST trial. CLINICALTRIALS.GOV IDENTIFIER: NCT02837809.

Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction.

Lung cancer represents the leading cause of cancer-related death in developed countries. Despite the advances in diagnostic and therapeutic techniques, the 5-year survival rate remains low. The research for novel therapies directed to biological targets has modified the therapeutic approach, but the frequent engagement of resistance mechanisms and the substantial costs, limit the ability to reduce lung cancer mortality. MicroRNAs (miRNAs) are small noncoding RNAs with known regulatory functions in cancer initiation and progression. In this study we found that mir-660 expression is downregulated in lung tumors compared with adjacent normal tissues and in plasma samples of lung cancer patients with poor prognosis, suggesting a potential functional role of this miRNA in lung tumorigenesis. Transient and stable overexpression of mir-660 using miRNA mimics reduced migration, invasion, and proliferation properties and increased apoptosis in p53 wild-type lung cancer cells (NCI-H460, LT73, and A549). Furthermore, stable overexpression using lentiviral vectors in NCI-H460 and A549 cells inhibited tumor xenograft growth in immunodeficient mice (95 and 50% reduction compared with control, respectively), whereas the effects of mir-660 overexpression were absent in H1299, a lung cancer cell line lacking p53 locus, both in in vitro and in vivo assays. We identified and validated mouse double minute 2 (MDM2) gene, a key regulator of the expression and function of p53, as a new direct target of mir-660. In addition, mir-660 expression reduced both mRNA and protein expression of MDM2 in all cell lines and stabilized p53 protein levels resulting in an upregulation of p21(WAF1/CIP1) in p53 wild-type cells. Our finding supports that mir-660 acts as a tumor suppressor miRNA and we suggest the replacement of mir-660 as a new therapeutic approach for p53 wild-type lung cancer treatment.

Poly-Drug Use among Ecstasy Users: Separate, Synergistic, and Indiscriminate Patterns.

The main objective of this paper is to explore poly-drug use among young adult ecstasy users. This phenomenon of using multiple substances within a specific time period is multi-faceted. In this paper, we focus on the various patterns of poly-drug use and the reasons for combining multiple drugs among ecstasy users. Using a mixed-methods design, we conducted interviews with young adults who used ecstasy and other licit and illicit drugs in the past 90 days. Based on the qualitative analyses, we define three distinct types of poly-drug experiences: separate, synergistic, and indiscriminate use. While separate and synergistic poly-drug use tended to be intentional, indiscriminate poly-drug use often was unintentional. These findings show the importance of recognizing poly-drug use as a common phenomenon. The findings presented here suggest areas for further research aimed at identifying risk and protective behaviors and risk reduction strategies.

Alteraciones en el eje hipotálamo-tejido adiposo y su relación con el riesgo para la aterosclerosis coronaria / Alterations in hypothalamus-adipose tissue axis in relation with the risk of coronary atherosclerosis

Recent population studies in Southern Argentina have found a sharp rise in prevalence of overweight and obesity in both sexes and specially after fifty years of age. Hence, the obesity in itself was found associated with the presence of metabolic syndrome (MS) and coronary heart disease, which have been demonstrated by angiography studies. The regulation of energy homeostasis is controlled by interactions between the central nervous system (neurotransmitters and neuropeptides) and the peripheric system (hormones) through very complex mechanisms. Genetics or acquired alterations in these regulation systems can be the origin of obesity and specially of central obesity. The visceral adipose tissue can be considered a secretor organ and its mass increment could generate insulin-resistance (IR) state, which directly or indirectly, could develop into endothelial dysfunction and coronary atherosclerosis. Although some studies estimate that 40% of IR are of genetic origin, a high proportion of these are acquired by inadequate habits in life style (specially excess of food intake and low physical activity). Finally, a better knowledge of the central and peripheric regulations in alimentation habits and energetic balance could help to develop treatments to decrease the incidence of these metabolic alterations and, consequently the morbidity and mortality due to coronary atherosclerosis.

Estudios poblacionales en la región sur de Argentina mostraron una elevada prevalencia de sobrepeso y obesidad en sujetos de ambos sexos, sobre todo luego de los 50 años de edad; laobesidad central se halló fuertemente asociada con la presencia del síndrome metabólico (SM) y con la enfermedadcoronaria demostrada por angiografía. La regulación de la homeostasis de la energía se realiza a travésde la interacción entre el sistema nervioso central (neurotransmisores y neuropéptidos) y el sistema periférico(hormonas) mediante complejos mecanismos. Alteraciones genéticas o adquiridas en estos sistemas deregulación pueden conducir a la obesidad y en especial a la obesidad central. Considerando al tejido adiposovisceral como un órgano secretor, incrementos de su masa pueden generar estados de insulino-resistencia (IR),la cual directa o indirectamente puede conducir a la disfunción endotelial y a la aterosclerosis coronaria. Aunqueun 40% de IR serían de origen genético, una elevada proporción de ellos son adquiridos por conductasinadecuadas en el estilo de vida (exceso de ingesta de calorías y baja actividad física). Un mayor conocimientode la regulación central y periférica de los hábitos alimentarios y del balance energético podría ayudar a desarrollartratamientos para disminuir la incidencia de estas alteraciones metabólicas y con ello la probabilidad deenfermar o morir por enfermedad coronaria.

Alteraciones en el eje hipotálamo-tejido adiposo y su relación con el riesgo para la aterosclerosis coronaria / Alterations in hypothalamus-adipose tissue axis in relation with the risk of coronary atherosclerosis

Recent population studies in Southern Argentina have found a sharp rise in prevalence of overweight and obesity in both sexes and specially after fifty years of age. Hence, the obesity in itself was found associated with the presence of metabolic syndrome (MS) and coronary heart disease, which have been demonstrated by angiography studies. The regulation of energy homeostasis is controlled by interactions between the central nervous system (neurotransmitters and neuropeptides) and the peripheric system (hormones) through very complex mechanisms. Genetics or acquired alterations in these regulation systems can be the origin of obesity and specially of central obesity. The visceral adipose tissue can be considered a secretor organ and its mass increment could generate insulin-resistance (IR) state, which directly or indirectly, could develop into endothelial dysfunction and coronary atherosclerosis. Although some studies estimate that 40% of IR are of genetic origin, a high proportion of these are acquired by inadequate habits in life style (specially excess of food intake and low physical activity). Finally, a better knowledge of the central and peripheric regulations in alimentation habits and energetic balance could help to develop treatments to decrease the incidence of these metabolic alterations and, consequently the morbidity and mortality due to coronary atherosclerosis.(AU)

Estudios poblacionales en la región sur de Argentina mostraron una elevada prevalencia de sobrepeso y obesidad en sujetos de ambos sexos, sobre todo luego de los 50 años de edad; laobesidad central se halló fuertemente asociada con la presencia del síndrome metabólico (SM) y con la enfermedadcoronaria demostrada por angiografía. La regulación de la homeostasis de la energía se realiza a travésde la interacción entre el sistema nervioso central (neurotransmisores y neuropéptidos) y el sistema periférico(hormonas) mediante complejos mecanismos. Alteraciones genéticas o adquiridas en estos sistemas deregulación pueden conducir a la obesidad y en especial a la obesidad central. Considerando al tejido adiposovisceral como un órgano secretor, incrementos de su masa pueden generar estados de insulino-resistencia (IR),la cual directa o indirectamente puede conducir a la disfunción endotelial y a la aterosclerosis coronaria. Aunqueun 40% de IR serían de origen genético, una elevada proporción de ellos son adquiridos por conductasinadecuadas en el estilo de vida (exceso de ingesta de calorías y baja actividad física). Un mayor conocimientode la regulación central y periférica de los hábitos alimentarios y del balance energético podría ayudar a desarrollartratamientos para disminuir la incidencia de estas alteraciones metabólicas y con ello la probabilidad deenfermar o morir por enfermedad coronaria.(AU)

Inhibition of in vitro adherence of antibody-coated red cells to monocytes by the dialyzable leukocyte extract.

The red cell-monocyte assay (RMA), which has been used to evaluate the clinical significance of red cell (RBC) antibodies, was employed to test the effect of the dialyzable leukocyte extract (DLE) on in vitro adherence to monocytes of human RBCs coated with alloantibodies or autoantibodies. The total association index (TAI) of the RMA, expressing the number of RBCs adhering to or phagocytosed by 100 monocytes, indicated a potent inhibitory activity of DLE in the test system. TAI values of 100.4 +/- 20.1 (mean +/- SD) in the control sample, consisting of RBCs coated in vitro with anti-D, dropped to 4.0 +/- 2.1 when DLE was present in the assay medium at a concentration of 0.5 U per mL. Similar results were obtained with RBCs coated with IgG antibodies in vivo. The inhibition was dose dependent and was associated with a thermolabile component of DLE. This study establishes that DLE can modulate monocyte function by inhibiting the recognition of IgG sensitized red cells.