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In UK males, prostate cancer is the most common cancer, with over 47,500 diagnosed annually. Radiotherapy is a highly effective curative treatment but can be limited by dose to surrounding normal-tissues such as the rectum. Radiation to the rectum can be reduced by increasing the distance between prostate and rectum with a hydrogel spacer. Despite National Institute of Health and Care Excellence guidance, spacers are not widely funded in the UK. Limited funding has necessitated patient prioritization, without any existing consensus on method.
Studies have shown generally homogenous results in reduction of rectal toxicity across assessed subgroups, but the requirement to prioritize remains. One way of addressing the appropriate use of beneficial health technologies is the inclusion of end-user experts in decision-making. The study aim was to identify consensus among radiation oncologists on patient prioritization for rectal hydrogel spacers.
We conducted a Delphi study where six leading clinical oncologists and one urologist from across the UK experienced in using rectal hydrogel spacers participated in two rounds of online questionnaires and two virtual advisory board meetings.
The experts estimated that 83 percent of patients who could potentially benefit from a spacer were denied access. Overall, ten points of consensus were reached. Key ones concerning patient-access were:
• Spacer use in eligible patients significantly reduces radiation dose to the rectum and toxicity-related adverse events.
• Increased benefit is expected in patients on anticoagulation, with diabetes and with inflammatory bowel disease.
• Increased benefit can be expected with ultra-hypofractionated radiotherapy, but radiotherapy modality is not a key consideration for patient selection.
• Patients should have the opportunity to actively participate in the discussion regarding the use of a spacer.
Currently, not all patients who would benefit can access funding for hydrogel spacers. Consensus in this study indicates that appropriate health policy and funding mechanisms are warranted for patients, to provide equitable access to technologies improving quality of life.
To summarize current evidence on patient and public involvement (PPI) in health technology assessment (HTA) in order to synthesize the barriers and facilitators, and to propose a framework to assess its impact.
We conducted an update of a systematic review published in 2011 considering the recent scientific literature (qualitative, quantitative, and mixed-methods studies). We searched papers published between March 2009 (end of the initial search) and December 2019 in five databases using specific search strategies. We identified other publications through citation tracking and contacting authors of previous related studies. Reviewers independently selected relevant studies based on prespecified inclusion and exclusion criteria. We extracted information using a pre-established grid.
We identified a total of 7872 publications from the main search strategy. Ultimately, thirty-one distinct new studies met the inclusion criteria, whereas seventeen studies were included in the previous systematic review. PPI is realized through two main strategies: (i) patients and public members participate directly in decision-making processes (participation) and (ii) patients or public perspectives are solicited to inform decisions (consultation or indirect participation). This review synthesizes the barriers and facilitators to PPI in HTA, and a framework to assess its impact is proposed.
The number of studies on patients or public involvement in HTA has dramatically increased in recent years. Findings from this updated systematic review show that PPI is done mostly through consultation and that direct involvement is less frequent. Several barriers to PPI in HTA exist, notably the lack of information to patients and public about HTA and the lack of guidance and policies to support PPI in HTA.
Cigarette smoking is strongly associated with major depressive disorder (MDD). However, any genetic etiology of such comorbidity and causal relations is poorly understood, especially at the genome-wide level.
In the present in silico research, we analyzed summary data from the genome-wide association study of the Psychiatric Genetic Consortium for MDD (n = 191 005) and UK Biobank for smoking (n = 337 030) by using various biostatistical methods including Bayesian colocalization analysis, LD score regression, variant effect size correlation analysis, and Mendelian randomization (MR).
By adopting a gene prioritization approach, we identified 43 genes shared by MDD and smoking, which were significantly enriched in membrane potential, gamma-aminobutyric acid receptor activity, and retrograde endocannabinoid signaling pathways, indicating that the comorbid mechanisms are involved in the neurotransmitter system. According to linkage disequilibrium score regression, we found a strong positive correlation between MDD and current smoking (rg = 0.365; p = 7.23 × 10−25) and a negative correlation between MDD and former smoking (rg = −0.298; p = 1.59 × 10−24). MR analysis suggested that genetic liability for depression increased smoking.
These findings inform the concomitant conditions of MDD and smoking and support the use of self-medication with smoking to counteract depression.
We present a novel distributed-memory parallel implementation of the concurrent atomistic-continuum (CAC) method. Written mostly in Fortran 2008 and wrapped with a Python scripting interface, the CAC simulator in PyCAC runs in parallel using Message Passing Interface with a spatial decomposition algorithm. Built upon the underlying Fortran code, the Python interface provides a robust and versatile way for users to build system configurations, run CAC simulations, and analyze results. In this paper, following a brief introduction to the theoretical background of the CAC method, we discuss the serial algorithms of dynamic, quasistatic, and hybrid CAC, along with some programming techniques used in the code. We then illustrate the parallel algorithm, quantify the parallel scalability, and discuss some software specifications of PyCAC; more information can be found in the PyCAC user’s manual that is hosted on www.pycac.org.
Large quantities of irradiated graphite will arise from the decommissioning of the UK's Magnox power stations. Irradiated graphite contains 14C as well as other longer lived radionuclides (e.g. 36Cl). The potential use of magnetic sector secondary ion mass spectrometry (MS-SIMS) to examine the distribution of the 14C within trepanned graphite samples from a Magnox nuclear power station has been investigated. This work indicates that the methodology proposed has the potential to be used to analyse irradiated graphite samples with preliminary results highlighting a possible 14C enrichment in the carbonaceous deposit found on a channel wall sample. 14C concentrations in samples without this deposit were below the limits of detection of the instrument. The methodology used for these determinations ensured that possible mass interferences between 14C species and oxygen-bearing or nitrogen-bearing species were eliminated from the analysis. Future work will utilize the methodology proposed in this work on a larger number of samples.
Objectives: Careful characterization of how functional decline co-evolves with cognitive decline in older adults has yet to be well described. Most models of neurodegenerative disease postulate that cognitive decline predates and potentially leads to declines in everyday functional abilities; however, there is mounting evidence that subtle decline in instrumental activities of daily living (IADLs) may be detectable in older individuals who are still cognitively normal. Methods: The present study examines how the relationship between change in cognition and change in IADLs are best characterized among older adults who participated in the ACTIVE trial. Neuropsychological and IADL data were analyzed for 2802 older adults who were cognitively normal at study baseline and followed for up to 10 years. Results: Findings demonstrate that subtle, self-perceived difficulties in performing IADLs preceded and predicted subsequent declines on cognitive tests of memory, reasoning, and speed of processing. Conclusions: Findings are consistent with a growing body of literature suggesting that subjective changes in everyday abilities can be associated with more precipitous decline on objective cognitive measures and the development of mild cognitive impairment and dementia. (JINS, 2018, 24, 104–112)
Development of winter wheat (Triticum aestivum) synthetics started at CIMMYT-Mexico in 2004, when winter durum wheat (Triticum turgidum) germplasm from Ukraine and Romania was crossed with Aegilops tauschii accessions from the Caspian Sea region. Chromosomes were doubled after pollination and embryo rescue, but chromosome number and cytological validation was not performed. F2 populations were grown in Mexico and were shipped to Turkey in 2008. During 2009–2015, these populations were subjected to rigorous pedigree selection under dry, cold, disease-affected environments of the Central Anatolian Plateau. The wide segregation and partial sterility observed in 2009 gradually decreased and, by 2016, most of the F8 single spike progenies demonstrated good fertility and agronomic performance. Since 2013, lines have been selected from synthetic populations and evaluated at multiple sites. Superior lines were characterized for resistance to leaf, stripe and stem rust, plant height, and reaction to common bunt and soil-borne pathogens. Thousand kernel weight of many lines exceeded 50 g, compared with the check varieties that barely reached 40 g. Threshability of synthetic lines varied from 0 to 95%, demonstrating genetic variation for this important domestication trait. Screening against Hessian fly, sunny pest and Russian wheat aphid identified several resistant genotypes. Both durum and Aegilops parents affected synthetic wheat traits. Several studies are underway to reveal the genetic diversity of synthetic lines and the basis of resistance to diseases and insects. This synthetic germplasm represents a new winter bread wheat parental pool. It is available upon request to interested breeding/research programmes.
Each year, tobacco use causes over 6 million deaths and is responsible for hundreds of billions of dollars in health care and economic costs in the world (WHO, 2011). If current trends continue, tobacco is expected to kill over 1 billion people in the 21st century, making it one of the single greatest causes of preventable death and disease in history (WHO, 2011). Long-term abstinence from tobacco use dramatically improves individuals’ health, reduces the incidence of tobacco-related disease, and is clearly responsible for saving lives (Anthonisen et al., 2005). Most tobacco users express a desire to achieve long-term abstinence from tobacco use and make numerous unsuccessful quit attempts over the course of many years (Borland, Partos, Yong, Cummings, & Hyland, 2012; CDC, 2011). Evidence-based treatments for tobacco use and dependence greatly improve the chances that quit attempts result in long-term abstinence (Chambless & Hollon, 1998; Chambless et al., 1998; Compas, Haaga, Keefe, Leitenberg, & Williams, 1998; Fiore et al., 2008; Zwar et al., 2004). Increasing the availability of high-quality evidence-based treatment for tobacco use and dependence will make it more likely that tobacco users use evidence-based treatments and that quit attempts translate into long-term abstinence. The professionalisation of treatment for tobacco dependence by the development of a rigorous, unified Tobacco Treatment Specialist (TTS) certification process will increase the availability of high-quality evidence-based treatment for tobacco use and dependence for all tobacco users.
Predictions of marine ice-sheet behaviour require models able to simulate grounding-line migration. We present results of an intercomparison experiment for plan-view marine ice-sheet models. Verification is effected by comparison with approximate analytical solutions for flux across the grounding line using simplified geometrical configurations (no lateral variations, no buttressing effects from lateral drag). Perturbation experiments specifying spatial variation in basal sliding parameters permitted the evolution of curved grounding lines, generating buttressing effects. The experiments showed regions of compression and extensional flow across the grounding line, thereby invalidating the boundary layer theory. Steady-state grounding-line positions were found to be dependent on the level of physical model approximation. Resolving grounding lines requires inclusion of membrane stresses, a sufficiently small grid size (<500 m), or subgrid interpolation of the grounding line. The latter still requires nominal grid sizes of <5 km. For larger grid spacings, appropriate parameterizations for ice flux may be imposed at the grounding line, but the short-time transient behaviour is then incorrect and different from models that do not incorporate grounding-line parameterizations. The numerical error associated with predicting grounding-line motion can be reduced significantly below the errors associated with parameter ignorance and uncertainties in future scenarios.
Clozapine remains the most effective antipsychotic for management of schizophrenia, one of the most challenging mental disorders. Yet, this medication is underutilized due to the frequent blood draws associated with monitoring adverse side effects and maintaining effective drug levels in the body. Lab-on-a-chip (LOC)-based diagnostics at the point-of-care could decrease the burden on patients and doctors, enable personalized medicine, and improve treatment outcomes. Towards that goal, we present the development of an electrochemically active biomaterial probe to facilitate monitoring of clozapine as part of patient’s treatment regimen. The probe consists of the naturally derived polymer chitosan modified with catechol to provide a redox capacitor system, allowing for significant amplification. We demonstrate a 3- fold increase of the electrochemical signal generated by clozapine with the catechol-modified chitosan system over bare gold electrodes. The improved signal-to-noise ratio and overall performance of the bio-amplifier yield a detection limit below 1 μM, thus sufficient for the clinically relevant range of 1–3 μM. We further characterize the robustness of the biomaterial system with respect to re-use and storage, and demonstrate retention of its amplification characteristics when implemented on an electrochemical microchip. Our results align well with the clinical requirements and represent a critical first step in developing a point-of-care device for improved and personalized schizophrenia treatment.
The process of re-emergence of Dendroctonus frontalis parent adults was investigated using emergence traps placed systematically along the bole of infested loblolly pine, Pinus taeda. Daily collections of the traps showed the re-emergence pattern by height through time. Re-emergence/100 cm2 (Y) was described as a function of time (X) by the model Y = C(18X)B−1 exp (−A(18X)B) + ɛε for intervals along the infested bole. Peak re-emergence occurred shortly after peak attack density and continued 16–20 days. Highest re-emergence density occurred at the midportion of the infested bole and tapered to the ends. The same model was used to describe re-emergence as an average process for the entire tree. For convenience in evaluating expected re-emergence totals over a time span, the cumulative form of the model was fit to the data. The proportion of re-emergence was studied using bark samples taken at the beginning and end of the process and was found to be 97% of the attacking adult population. An empirical distribution function was developed and the probability of re-emergence described using the function Y = ABCXB−1 exp (−AXB) + ɛε, where Y = the probability of re-emergence at a time X in days given that a beetle was present on day 1 of the process. The cumulative form of this model was also provided.
Using laboratory bioassays parent adults were tested and found to respond to the attractant mixture of frontalin, trans-verbenol, and loblolly pine turpentine.
Re-emergence may play several functions in the population dynamics of D. frontalis: conditioning host trees through mass colonization; establishing brood populations through multiple re-emergence, thereby efficiently allocating egg populations; identifying new hosts and aggregating populations through pheromone production; and maintenance of continuity in pheromone production at the active portion of the infestation, thereby identifying the location of trees under colonization. The prolonged re-emergence period was suggested to be of survival value to the insect in that local short term disasters would affect only a small proportion of the re-emerging population. The number of re-emergences and proportions of re-emergence were suggested to be related to oviposition per parent adult and hence attack density.
Language exerts hidden power, like the moon on the tides.
Rita Mae Brown
In this chapter we will consider three hypotheses regarding the clause structure of English using the analytical methods and modeling techniques described in Chapter 7. Two of these hypotheses – the DP and IP hypotheses – represent recent proposals within the “Minimalist” tradition of Generative Grammar (Chomsky 1995, Radford 1997). These hypotheses provide helpful insights for the English language professional in that they highlight the importance of Determiners in the nominal system and Inflection in the verbal system. Determiners “anchor” noun phrases in pragmatic space while Inflection “anchors” verb phrases in time and reality (see Chapter 15). The third hypothesis – the GP hypothesis – while not central to an understanding of the overall syntactic character of English, is a logical consequence of the theoretical principles introduced in Chapter 7, and is helpful in understanding the meaning and use of genitive noun phrases.
The DP hypothesis
To this point we have been using the terms NP and DP without giving much evidence for why it is necessary to posit these two distinct phrasal categories, or how to tell one from the other. In this section I would like to provide evidence, using the tests for constituency described in Chapter 7, to show that DP is in fact an important phrasal category in English grammar. These facts are important to English language professionals for a couple of reasons.
The harmony between thought and reality is to be found in the grammar of the language … Uttering a word is like striking a note on the keyboard of the imagination.
Ludwig Wittgenstein (1981)
Language gives form to thought. Thought itself is hidden, internal, intangible, whereas language seems to be external, physical, exposed for all the world to see and hear. But is it really? Certainly the noises we make when we communicate using spoken language are “external” in that they are physical modifications of the mind–external environment in the form of complex sound waves moving through air. But the noises themselves are not the essence of our language. We often think in language without overt expression. When we write, we say we are writing “in a language,” even though the medium is visible marks (or pixels) rather than noises. Signed languages used by the deaf are still languages, though they don't rely on sounds at all. The forms of language are certainly not random, like the sound of water tumbling over rocks in a stream. Regardless of the form it takes, language is governed by complex underlying patterns. If there were no consistent patterns, people would not be able to communicate with one another, and, after all, language is all about communication. It is the harmony between underlying patterns and external expression that is the essence of language.