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Extending fecal immunochemical tests for hemoglobin (FITs) to primary care patients with high-risk symptoms suggestive of colorectal cancer (CRC) could reduce colonoscopy waiting lists, enabling earlier treatment. Higher FIT thresholds could decrease referrals but increase missed disease compared with lower thresholds. We aimed to systematically review and synthesize test accuracy data across thresholds for use in a cost-effectiveness analysis.
Methods
Searches across ten sources were conducted (December 2022). Included were diagnostic accuracy studies of HM-JACKarc, OC-Sensor, FOB Gold, QuikRead go, NS-Prime, and four Immunodiagnostik (IDK) tests in patients presenting to, or referred from, primary care with symptoms suggestive of CRC using any reference standard. Risk of bias was assessed with QUADAS-2. Syntheses of sensitivity and specificity at all reported thresholds were planned for each test to provide summary estimates at all possible thresholds within the observed range. Sensitivity analyses investigating population type and reference standard, and subgroup analyses by patient characteristics (e.g., anemia, age, sex, ethnicity) were conducted.
Results
HM-JACKarc (n=16 studies) sensitivity ranged from 95.9 percent (95 percent credible interval [95% CrI]: 92.7, 97.9) to 46.3 percent (95% CrI: 37.4, 54.9) and specificity from 65.1 percent (95% CrI: 55.6, 74.8) to 97.7 percent (95% CrI: 94.7, 99.2) (thresholds 2 and 400 μg hemoglobin/g feces [μg/g], respectively). OC-Sensor (n=11) sensitivity ranged from 94.2 percent (95% CrI: 91.2, 96.7) to 54.2 percent (95% CrI: 48.4, 60.2) and specificity from 62.7 percent (95% CrI: 47.4, 77.2) to 97.3 percent (95% CrI: 92.9, 99.3) (thresholds 4 and 200 μg/g, respectively). FOB Gold (n=3) sensitivity ranged from 91.4 percent (95% CrI: 71.6, 99.6) to 73.9 percent (95% CrI: 53.8, 91.2) and specificity from 78.1 percent (95% CrI: 70.0, 86.0) to 96.4 percent (95% CrI: 92.6, 98.9) (thresholds 2 and 150 μg/g, respectively). There were limited or no data on the other tests.
Conclusions
Sensitivity and specificity were synthesized for three tests only, since data for the remaining tests were extremely limited or absent. Even at the lowest threshold, none of the tests had perfect sensitivity. Future studies should further investigate comparative accuracy and the impact of patient characteristics, patient recruitment criteria, and the reference standard on estimates of diagnostic test accuracy.
Approximately 42,000 new cases of colorectal cancer (CRC) are diagnosed annually in the United Kingdom with 16,800 deaths. Evidence suggests that quantitative fecal immunochemical tests (FIT) are a good predictor of CRC risk in symptomatic patients presenting to primary care. We aimed to assess the cost-effectiveness of FIT in this setting, considering capacity constraints and waiting times for subsequent colonoscopy.
Methods
We compared two diagnostic FIT strategies, at various thresholds, in the model: (i) FIT for all patients and (ii) current practice where only low-risk patients received FIT. Patients with positive FIT scores and high-risk patients in current practice received colonoscopy. Diagnostic accuracy evidence from published literature, standard UK cost sources, and other sources were used to estimate health outcomes and costs. Waiting times before colonoscopy were assumed proportional to the numbers referred, with the impact of delayed colonoscopy taken from published models. Savings per quality-adjusted life years (QALYs) lost and incremental net monetary benefit (INMB) were used. Uncertainty was evaluated.
Results
Model results suggested that, compared to current practice, FIT generated a positive INMB for the majority of thresholds assessed (GBP200 [USD254] to GBP350 [USD445] per patient at a willingness to pay of GBP20,000 [USD25,474] per QALY gained). A reduction in the number of patients sent to colonoscopy led to cost savings. However, these thresholds were associated with slight QALY losses due to a small proportion of false negative results associated with significantly delayed diagnosis, which outweighed the benefits associated with quicker times to colonoscopy for those with positive FIT results. Savings of over GBP100,000 (USD127,374) per QALY lost were generated. Conclusions were robust to the sensitivity analyses undertaken.
Conclusions
With capacity constraints explicitly represented in the economic modeling, offering FIT to all patients presenting to primary care with symptoms suggestive of CRC was cost effective when compared to current practice. However, the optimal threshold could not be robustly determined due to limited diagnostic accuracy data, parameter uncertainty, and limitations in the model structure; additional primary research could reduce uncertainty.
Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.
Methods
We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.
Results
The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).
Conclusion
The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.
This chapter aims to begin the process of exploring the impact of COVID-19 on drug trends and markets in the United Kingdom (UK). It is too early to say what the full impact will be and what the legacy will be for alcohol and other drugs use. What we can assume, however, is that if national lockdowns and reduced opportunities for social drug and alcohol use have not impacted in any significant way on harmful consumption, then the trends witnessed over recent years will likely be continued and even magnified under the conditions of the pandemic. In this chapter, we start to piece together some of the key changes impacting on drug markets in the UK (with a particular focus on England) by triangulating data from a range of sources and interspersing this with some theoretical insights. We do this by considering emerging drug trends in relation to COVID-19, looking for points of continuity and change in the issues that preoccupied drug policy and practice over previous years. In doing so, we take a lead from the interim findings of the Releasesponsored survey, published in Drugs in the time of COVID (Aldrdige et al, 2021), but we seek to embellish the key findings from this report by drawing on a range of other sources and targeted surveys and other research. We also pursue separate lines of investigation where necessary.
Overall, we consider the impact of the pandemic on supply, but focusing more on changes in drug availability. We look at how drug distribution has been impacted by the responses to the pandemic (as well as specific responses to the drug issue). Moving on, we consider the impact of the pandemic on alcohol, noting some overlaps with the issues around other drugs. Finally, we explore the impact of the pandemic on drug harms. This is, at this stage, more speculative as the longer-term harms associated with the pandemic and drug use will only become apparent in time.
COVID-19 has altered life in ways that were once unimaginable. Over the course of the pandemic, there have been unprecedented restrictions placed on daily life, meaning that digital delivery has come to the fore of all kinds of activity, whether it be education and learning in schools, colleges and universities, the delivery of a range of public services or hospitality.
The history of maize in Central America and surrounding areas has implications for the slow transition from hunting and gathering to agriculture. The spread of early forms of domesticated maize from southern Mexico across Mesoamerica and into South America has been dated to about 8,700–6,500 years ago on the basis of a handful of studies relying primarily on the analysis of pollen, phytoliths, or starch grains. Recent genomic data from southern Belize have been used to identify Archaic period south-to-north population movements from lower Central America, suggesting this migration pattern as a mechanism that introduced genetically improved maize races from South America. Gradually, maize productivity increased to the point that it was suitable for use as a staple crop. Here we present a summary of paleoecological data that support the late and uneven entry of maize into the Maya area relative to other regions of Central America and identify the Pacific coastal margin as the probable route by which maize spread southward into Panama and South America. We consider some implications of the early appearance of maize for Late Archaic populations in these areas; for example, with respect to the establishment of sedentary village life.
Little is known about the early history of the chicken (Gallus gallus domesticus), including the timing and circumstances of its introduction into new cultural environments. To evaluate its spatio-temporal spread across Eurasia and north-west Africa, the authors radiocarbon dated 23 chicken bones from presumed early contexts. Three-quarters returned dates later than those suggested by stratigraphy, indicating the importance of direct dating. The results indicate that chickens did not arrive in Europe until the first millennium BC. Moreover, a consistent time-lag between the introduction of chickens and their consumption by humans suggests that these animals were initially regarded as exotica and only several centuries later recognised as a source of ‘food’.
Timothy Aelurus was the episcopal successor in Alexandria to the luminaries Cyril (412–444) and Dioscorus (444–451). The sobriquet “Aelurus” has been variously interpreted as “the Cat” or “the Weasel,” and it was purportedly bestowed by enemies on account of his ascetical emaciation. A monk in his youth, he was ordained presbyter by Cyril and was in the entourage of Dioscorus at the second Council of Ephesus in 449. After the latter’s deposition at the Council of Chalcedon in 451, Proterius, a Chalcedonian, was installed as bishop of Alexandria. Timothy, however, remained loyal to Dioscorus. When news of Emperor Marcian’s death (on January 26, 457) reached Alexandria in early February, this sparked the anti-Chalcedonian faction to find at long last a replacement for Dioscorus. They chose Timothy, who was consecrated as a rival bishop on March 16, 457, possibly by only two bishops and thus irregularly (since three bishops were required for a canonical ordination as bishop).
• Multiple pregnancy, with profound associated hazards, is an avoidable iatrogenic consequence of IVF • Adverse outcomes associated with twin pregnancy are costly both to individuals and society • With improved cryopreservation capability, similar birth rates, with less risks associated, are maintained with SET based practice • Adequate state funding and sound regulatory reporting of outcomes, support SET based practice • Clinical practice must take account of our moral obligations to society as well as to the individual
An authoritative account of the causes of infertility that fully explores the clinical assessment of patients and covers the decision-making behind treatment options. The content follows the MRCOG syllabus as well as delving deeper into subjects covered by the RCOG Advanced Training Skills Modules (ATSMs), leaving readers well prepared for their examinations. Written by nationally recognised leaders in the field, this volume concisely reviews contemporary clinical practice. Using an aetiology-based approach, chapters discuss ovulatory dysfunction, endometriosis, male infertility, uterine/tubal factors and unexplained infertility. The increasing use of third-party reproduction and surrogacy is explored, along with the psychosocial aspects of this type of treatment. Ethical dilemmas surrounding reproductive medicine and their management are covered in depth. With an emphasis on practical approaches to the delivery and organisation of clinical and laboratory services, readers learn how to ensure the support and care they offer is of the highest quality.
This chapter seeks to give an overview of the place of Quality Management (QM) in contemporary fertility practice. It provides the reader with an understanding of the terminology used in QM and explores the definition of quality and success in fertility care. An examination of process modelling in the organisation of services is outlined and an analysis in practical terms as to how QM is applied in practice is provided, covering key issues such as document control, organisational structure and the role of the quality manager. Audit as a tool for improving quality is a fundamental tool and its use within a clinical governance framework including risk management/assessment, and other key responsibilities is detailed. Measuring what we do, analysing performance and setting targets to improve should be fundamental to how we approach our work in contemporary clinical practice.
This chapter discusses the epidemiology of infertility and the importance of the initial assessment of the infertile individual. Profound changes in society over the last two decades challenge previously agreed on norms in our understanding of the nature of parenthood and family. Defining infertility in a contemporary context has thus also changed as the profile of those seeking advice has evolved. Nevertheless it remains essential that efficient mechanisms for referral and investigation are established for those involved in the planning of fertility services. These must involve good liaison between primary care providers and medical, nursing and diagnostic laboratory staff in specialist centres. Adherence to agreed on protocols will facilitate appropriate and timely investigation along standardised paths, thereby minimising risk of delay and repetition of tests which those seeking assistance find particularly demoralising. Once a diagnosis is reached it should be possible to offer people with infertility an accurate prognosis and the opportunity to consider the issues relevant to treatment choices for their particular situation.
The evidence of funerary archaeology, historical sources and poetry has been used to define a ‘heroic warrior ethos’ across Northern Europe during the first millennium AD. In northern Britain, burials of later prehistoric to early medieval date are limited, as are historical and literary sources. There is, however, a rich sculptural corpus, to which a newly discovered monolith with an image of a warrior can now be added. Comparative analysis reveals a materialisation of a martial ideology on carved stone monuments, probably associated with elite cemeteries, highlighting a regional expression of the warrior ethos in late Roman and post-Roman Europe.
As part of a multifactorial approach to address weak incentives for innovative antimicrobial drug development, market entry rewards (MERs) are an emerging solution. Recently, the Duke-Margolis Center for Health Policy released the Priority Antimicrobial Value and Entry (PAVE) Award proposal, which combines a MER with payment reforms, transitioning from volume-based to “value-based” payments for antimicrobials. Here, the PAVE Award and similar MERs are reviewed, focusing on further refinement and avenues for implementation.
Shallow ice cores were obtained from widely distributed sites across the West Antarctic ice sheet, as part of the United States portion of the International Trans-Antarctic Scientific Expedition (US ITASE) program. The US ITASE cores have been dated by annual-layer counting, primarily through the identification of summer peaks in non-sea-salt sulfate (nssSO42–) concentration. Absolute dating accuracy of better than 2 years and relative dating accuracy better than 1 year is demonstrated by the identification of multiple volcanic marker horizons in each of the cores, Tambora, Indonesia (1815), being the most prominent. Independent validation is provided by the tracing of isochronal layers from site to site using high-frequency ice-penetrating radar observations, and by the timing of mid-winter warming events in stable-isotope ratios, which demonstrate significantly better than 1 year accuracy in the last 20 years. Dating precision to ±1 month is demonstrated by the occurrence of summer nitrate peaks and stable-isotope ratios in phase with nssSO42–, and winter-time sea-salt peaks out of phase, with phase variation of <1 month. Dating precision and accuracy are uniform with depth, for at least the last 100 years.
The new research here covers a number of aspects of the politics and culture of fourteenth-century England, including religious culture and institutions as illustrated in the cult of Thomas of Lancaster, preaching to women in the later fourteenth century, and in the Church's response to a royal fundraising campaign. There are detailed examinations of prominent and less prominent individuals - Bishop Thomas Hatfield, Agnes Maltravers, and Lord Thomas Despenser - together with investigations of broader policy issues, particularly the dispensation of justice in the reign of Richard II. Finally, the intersection of environmental, political, and economic issues is approached from two very different perspectives, the development of royal landscapes and of the late medieval coal industry.
Contributors: JOHN T. MCQUILLEN, AMANDA RICHARDSON, A. K. MCHARDY, CHRISTIAN D. LIDDY, J.S. BOTHWELL, BETH ALLISON BARR, DIANE MARTIN, HELEN LACEY, JOHN LELAND, MARTYN LAWRENCE, ULRIKE GRASSNICK,MARK ARVANIGIAN
J.S. HAMILTON is Professor and Chair of History at Baylor University.