Whole-body magnetic resonance imaging (WB-MRI) could be an alternative to multi-modality staging of non-small-cell lung cancer (NSCLC), but its diagnostic accuracy, effect on staging times, number of ...tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in NSCLC.
The Streamline L trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed NSCLC that was potentially radically treatable on diagnostic chest CT (defined as stage IIIb or less). Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or histologies other than NSCLC. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs) and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN50436483, and is complete.
Between Feb 26, 2013, and Sept 5, 2016, 976 patients were screened for eligibility. 353 patients were recruited, 187 of whom completed the trial; 52 (28%) had metastasis at baseline. Pathway sensitivity was 50% (95% CI 37–63) for WB-MRI and 54% (41–67) for standard pathways, a difference of 4% (−7 to 15, p=0·73). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (93% 88–96) and standard pathways (95% 91–98, p=0·45). Agreement with the multidisciplinary team's final treatment decision was 98% for WB-MRI and 99% for the standard pathway. Time to complete staging was shorter for WB-MRI (13 days 12–14) than for the standard pathway (19 days 17–21); a 6-day (4–8) difference. The number of tests required was similar WB-MRI (one 1–1) and standard pathways (one 1–2). Mean per-patient costs were £317 (273–361) for WBI-MRI and £620 (574–666) for standard pathways.
WB-MRI staging pathways have similar accuracy to standard pathways, and reduce the staging time and costs.
UK National Institute for Health Research.
Religious Affiliation and Suicide Attempt Dervic, Kanita; Oquendo, Maria A; Grunebaum, Michael F ...
The American journal of psychiatry,
12/2004, Letnik:
161, Številka:
12
Journal Article
Recenzirano
Odprti dostop
OBJECTIVE: Few studies have investigated the association between religion and suicide either in terms of Durkheim's social integration hypothesis or the hypothesis of the regulative benefits of ...religion. The relationship between religion and suicide attempts has received even less attention. METHOD: Depressed inpatients (N=371) who reported belonging to one specific religion or described themselves as having no religious affiliation were compared in terms of their demographic and clinical characteristics. RESULTS: Religiously unaffiliated subjects had significantly more lifetime suicide attempts and more first-degree relatives who committed suicide than subjects who endorsed a religious affiliation. Unaffiliated subjects were younger, less often married, less often had children, and had less contact with family members. Furthermore, subjects with no religious affiliation perceived fewer reasons for living, particularly fewer moral objections to suicide. In terms of clinical characteristics, religiously unaffiliated subjects had more lifetime impulsivity, aggression, and past substance use disorder. No differences in the level of subjective and objective depression, hopelessness, or stressful life events were found. CONCLUSIONS: Religious affiliation is associated with less suicidal behavior in depressed inpatients. After other factors were controlled, it was found that greater moral objections to suicide and lower aggression level in religiously affiliated subjects may function as protective factors against suicide attempts. Further study about the influence of religious affiliation on aggressive behavior and how moral objections can reduce the probability of acting on suicidal thoughts may offer new therapeutic strategies in suicide prevention.
The concepts of high-throughput (HT) screening and combinatorial synthesis have been integrated into the pharmaceutical discovery process, but are not yet commonplace in the pharmaceutical ...development arena. Emerging strategies to speed pharmaceutical development and capture solid form diversity of pharmaceutical substances have resulted in the emergence of HT crystallization technologies. The primary type of diversity often refers to polymorphs, which are different crystal forms of the same chemical composition. However, diverse salt forms, co-crystals, hydrates and solvates are also amenable to study in HT crystallization systems. The impact of form diversity encompasses issues of stability and bioavailability, as well as development considerations such as process definition, formulation design, patent protection and regulatory control. This review highlights the opportunities and challenges of HT crystallization technologies as they apply to pharmaceutical research and development.
To describe a collaborative approach for developing an electronic health record (EHR) phenotyping algorithm for drug-induced liver injury (DILI).
We analyzed types and causes of differences in DILI ...case definitions provided by two institutions-Columbia University and Mayo Clinic; harmonized two EHR phenotyping algorithms; and assessed the performance, measured by sensitivity, specificity, positive predictive value, and negative predictive value, of the resulting algorithm at three institutions except that sensitivity was measured only at Columbia University.
Although these sites had the same case definition, their phenotyping methods differed by selection of liver injury diagnoses, inclusion of drugs cited in DILI cases, laboratory tests assessed, laboratory thresholds for liver injury, exclusion criteria, and approaches to validating phenotypes. We reached consensus on a DILI phenotyping algorithm and implemented it at three institutions. The algorithm was adapted locally to account for differences in populations and data access. Implementations collectively yielded 117 algorithm-selected cases and 23 confirmed true positive cases.
Phenotyping for rare conditions benefits significantly from pooling data across institutions. Despite the heterogeneity of EHRs and varied algorithm implementations, we demonstrated the portability of this algorithm across three institutions. The performance of this algorithm for identifying DILI was comparable with other computerized approaches to identify adverse drug events.
Phenotyping algorithms developed for rare and complex conditions are likely to require adaptive implementation at multiple institutions. Better approaches are also needed to share algorithms. Early agreement on goals, data sources, and validation methods may improve the portability of the algorithms.
Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the ...consequences of transheterozygosity are poorly understood.
From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.
The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.
Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide ...association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
This paper relates evidence obtained from an in-depth study involving detailed questioning of over 250 executives, during the period from 2000-2006, into the successes and challenges that those ...involved in KTP were experiencing. The analysis subsequently uncovered four fundamental themes (the 4 ‘C’s of KTP) that will provide effective guidance to any future KTP, and more importantly, those responsible for them. The four themes outlined were Confusion, (what is KTP all about?), Convergence (how does the KTP fit with organizational or business strategy?), Commitment (how much time, effort and resources do we put to the KTP?) and finally Culture, how does KTP activity fit with and ultimately change the culture of the organisation?
Many commentators of the time would agree with Eliot in viewing the essential European batde as diat between Christianity and paganism, though they might define these terms, and their applicability ...to England and Germany respectively, rather differendy. ...a widelyadvertised account of the situation in Germany under the title T he New Racial Paganism, by the Catholic writer Mario Bendiscioli, bases its discussion on elements Eliot almost completely ignores, such as fascist ideals of racial purity and die fundamental status of 'blood'.16 Bendiscioli gives many details of the more seemingly 'religious' rites of the new paganism, including solstice rituals (p. 29), 'sun and fire-worship' (p. 8), the revival of Norse mythology (pp. 1 5ff.) and die attempt 'to resuscitate in its full vigour' the primitive ideal of 'the pure Nordic man, hitherto buried beneath the contaminating overgrowths of Latin and "Syriaco-Semitic" accretions' (p. 33). ...in not giving his own peasants any such status in FourQuartetsEliotis reserving both die terms 'blood' and 'soil' for a more significant context; thus the term 'significant soil' figures at the end of 'The Dry Salvages' as that which is in proximity to the 'yew-tree', that is, within the church-yard of die Christian communion. Jason Harding has righdy pointed out, in answer to accusations by Anthony JuHus, or to Christopher Hitchens's claim diat the Criterion 'was at best loftily indifferent to the rise of fascism', that EHot's journal did feature correspondents in the 1930s who documented 'die rising tide of Nazi anti-inteUectuaHsm, including die persecution of Jewish writers'.28 Nevertheless, Harding is by no means persuasive that EHot's fundamental concern with our society rather than Germany does not show a curious comparative inattentiveness, and the fact that his book nowhere discusses Idea emphasises this. ...he quotes what he caUs the 'passionate observation' of the Rev. Edward Quinn, whose article on 'Christian PoHtics' was pubHshed in die Criterion in July 1938: 'the racial theories of National-SociaHsm are opposed to die universal aims of Christianity and, leading to immoral legislation, are ultimately in contradiction with Divine law'. When EHot does attend to differences between the nations in Idea, these are 'of minor importance' when seen from the standpoint of Christian teleology, that is, 'in the long run' (p. 44). ...the charge of 'Germanization' could only have been ultimately made by someone looking down on the world, like Chaucer's Troilus, from a transcendental height where the nations coalesce into one 'Htel spot of erthe', and the detaüs of difference vanish.30 For Eliot, 'paganism ' is a pseudo-religious system in which God is replaced by the State as the (enforced) object of veneration . .
Precision health's more individualized molecular approach will enrich our understanding of disease etiology and patient outcomes. Universal implementation of precision health will not be feasible, ...however, until there is much greater automation of processes related to genomic data transmission, transformation, and interpretation. In this paper, we describe a framework for genomic data flow developed by the Clinical Informatics Work Group of the NIH National Human Genome Research Institute (NHGRI) IGNITE Network consortium. We subsequently report the results of a genomic data flow survey administered to sites funded by NIH-NHGRI for large scale genomic medicine implementations. Finally, we discuss insights and challenges identified through these survey results as they relate to both the current and a desirable future state of genomic data flow.
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