Overall, this systematic review was limited by the extent of variability in the characteristics of studies. Patients who are single, isolated or jobless, have poorly controlled physical symptoms, or have inadequately treated anxiety and depressive disorders are at increased risk for demoralization. Clinical recognition of demoralization can trigger more focused interventions.

We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3′ and/or 5′ end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5′ differences and in support of this we report that a 5′ isomiR-9–1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5′ isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes.

BackgroundDiagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early.ObjectivesTo estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations.Data sourcesBibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library.MethodsClinical effectiveness – a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness – an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm.ResultsClinical effectiveness – 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness – screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60–75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses.LimitationsClinical effectiveness – the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness – a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included.ConclusionsLDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits.Future workClinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial].Study registrationThis study is registered as PROSPERO CRD42016048530.FundingThe National Institute for Health Research Health Technology Assessment programme.

BACKGROUND:The recently refined Demoralization Scale-II (DS-II) is a 16-item, self-report measure of demoralization. Its 2 factorsMeaning and Purpose and Distress and Coping Ability-demonstrate sound internal validity, including item fit, unidimensionality, internal consistency, and test-retest reliability. The convergent and discriminant validity of the DS-II with various measures is reported here. METHODS: Patients who had cancer or other progressive diseases and were receiving palliative care (n 5 211) completed a battery of questionnaires, including the DS-II and measures of symptom burden, quality of life, depression, and attitudes toward the end of life. Spearman q correlations were determined to assess convergent validity. Mann-Whitney U tests with calculated effect sizes were used to examine discriminant validity and establish the minimal clinically important difference (MCID). Cross-tabulation frequencies with chi-square analyses were used to examine discriminant validity with major depression. RESULTS: The DS-II demonstrated convergent validity with measures of psychological distress, quality of life, and attitudes toward the end of life. It also demonstrated discriminant validity, as the DS-II differentiated patients who had different functional performance levels and high/low symptoms, with a difference of 2 points between groups on the DS-II considered clinically meaningful. Furthermore, discriminant validity was demonstrated, as comorbidity with depression was not observed at moderate levels of demoralization. CONCLUSIONS: The DS-II has sound psychometric properties and is an appropriate measure of demoralization. Given its structural simplicity and brevity, it is likely to be a useful tool in meaning-centered therapies. Cancer 2016;122:2260-7. V C 2016 American Cancer Society.KEYWORDS: cancer, construct validity, convergent validity, demoralization, discriminant validity, external validity, revalidation. INTRODUCTIONThe Demoralization Scale-II (DS-II) is a recently refined and revalidated 16-item, self-report measure of demoralization. 1 Demoralization is a maladaptive coping response conceptualized as a loss of meaning and purpose, with feelings of hopelessness and helplessness. 2 It is understood to arise in response to a stressful event or situation, such as the suffering associated with the diagnosis or experience of an advanced cancer. 2 In our recent systematic 3 and conceptual 4 reviews, we provided a discussion on the differences between demoralization and depression and highlighted the finding that there is a level of overlap between these constructs. In a companion to this article in this issue of Cancer, we report the internal validity of the DS-II as a 2-factor model (comprising two 8-item factors: Meaning and Purpose and Distress and Coping Ability) that demonstrated psychometrically sound item fit, unidimensionality, and reliability in patients receiving palliative care. 1 The reduced number of items and the simplified response format make the DS-II more user-friendly in the advanced...

BACKGROUND:The Demoralization Scale (DS) was initially validated in 2004 to enable the measurement of demoralization in patients with advanced cancer. Subsequent shortcomings indicated the need for psychometric strengthening. Here, the authors report on the refinement and revalidation of the DS to form the DS-II, specifically reporting the scale's internal validity. METHODS: Patients with cancer or other progressive diseases who were receiving palliative care (n 5 211) completed a revised version of the 24-item DS and a measure of symptom burden (the Memorial Symptom Assessment Scale). Exploratory factor analysis and Rasch modeling were used to evaluate, modify, and revalidate the scale, providing information about dimensionality, suitability of response format, item fit, item bias, and item difficulty. Test-retest reliability was examined for 58 symptomatically stable patients at a 5-day follow-up. RESULTS: Exploratory factor analysis supported a 22-item, 2-component model. Separate Rasch modeling of each component resulted in collapsing the response option categories and removing 3 items from each component. Both final 8-item subscales met Rasch model expectations and were appropriate to sum as a 16-item total score. The DS-II demonstrated internal consistency and test-retest reliability (Meaning and Purpose subscale: a 5 .84; intraclass correlation [ICC] 5 0.68; Distress and Coping Ability subscale: a 5 .82; ICC 5 0.82; total DS: a 5 .89; ICC 5 0.80). CONCLUSIONS: The DS-II is a 3-point response, self-report scale comprising 16 items and 2 subscales. Given its revalidation, psychometric strengthening, and simplification, the DS-II is an improved and more practical measure of demoralization for research and clinical use. External validation of the DS-II will be reported subsequently. Cancer 2016;122:2251-9. V C 2016 American Cancer Society.KEYWORDS: psychometrics, cancer, reliability, validity, adjustment, coping behavior, demoralization, Rasch modeling. INTRODUCTIONDemoralization has become increasingly recognized in palliative care as a clinical issue requiring assessment and treatment. 1,2 Understood as a state of maladaptive coping, demoralization develops with symptoms of hopelessness and helplessness associated with loss of purpose and meaning in life. 1 In a recent systematic review of 25 studies, clinical prevalence rates for demoralization ranged from 13% to 18% in patients with progressive diseases like cancer. 3 The morale of any patient fluctuates dimensionally from optimism to mild disheartenment, to greater despondency, and potentially to deep despair, which can be associated with a desire for hastened death. 4 Thus, the importance of measuring demoralization has been emphasized with reference to the risk of suicide and its potential relevance in end-of-life decision making. 1 Access to a psychometrically sound measure aids in the clinical assessment of demoralization. 5 Our preliminary validation of the Demoralization Scale (DS) in 2004 created a 24-item self-report scale that proved to be a use...

Depression, loss of meaning and purpose, loss of control, and low self-worth are strong clinical markers for desire to hasten death. Targeting these symptoms through existentially oriented therapies, such as meaning-centered therapy, may ameliorate suicidal thinking.

Question: Does self-monitoring of blood pressure by pregnant individuals at higher risk of preeclampsia lead to earlier detection of pregnancy hypertension compared to usual antenatal care? Findings: In this randomized clinical trial that included 2441 pregnant individuals at increased risk for pre-eclampsia, use of self-monitoring of BP with telemonitoring compared with usual care resulted in a mean time to clinic-based detection of hypertension of 104 vs 106 days, a difference that was not statistically significant.Meaning: Among pregnant individuals at higher risk of pre-eclampsia, blood pressure selfmonitoring with telemonitoring did not lead to earlier clinic-based detection of hypertension.

Background A systematic review of economic evaluations for lung cancer identified no economic models of the UK setting based on disease natural history. We first sought to develop a new model of natural history for population screening, then sought to explore the cost-effectiveness of multiple alternative potential programmes. Methods An individual patient model (ENaBL) was constructed in MS Excel® and calibrated against data from the US National Lung Screening Trial. Costs were taken from the UK Lung Cancer Screening Trial and took the perspective of the NHS and PSS. Simulants were current or former smokers aged between 55 and 80 years and so at a higher risk of lung cancer relative to the general population. Subgroups were defined by further restricting age and risk of lung cancer as predicted by patient self-questionnaire. Programme designs were single, triple, annual and biennial arrangements of LDCT screens, thereby examining number and interval length. Forty-eight distinct screening strategies were compared to the current practice of no screening. The primary outcome was incremental cost-effectiveness of strategies (additional cost per QALY gained). Results LDCT screening is predicted to bring forward the stage distribution at diagnosis and reduce lung cancer mortality, with decreases versus no screening ranging from 4.2 to 7.7% depending on screen frequency. Overall healthcare costs are predicted to increase; treatment cost savings from earlier detection are outweighed by the costs of over-diagnosis. Single-screen programmes for people 55–75 or 60–75 years with ≥ 3% predicted lung cancer risk may be cost-effective at the £30,000 per QALY threshold (respective ICERs of £28,784 and £28,169 per QALY gained). Annual and biennial screening programmes were not predicted to be cost-effective at any cost-effectiveness threshold. Limitations LDCT performance was unaffected by lung cancer type, stage or location and the impact of a national screening programme of smoking behaviour was not included. Conclusion Lung cancer screening may not be cost-effective at the threshold of £20,000 per QALY commonly used in the UK but may be cost-effective at the higher threshold of £30,000 per QALY.