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Non-specific symptoms-based pathways for diagnosing less common cancers in primary care: a service evaluation
No full textBackground: Although less common cancers account for almost half of all cancer diagnoses in England, their relative scarcity and complex presentation, often with non-specific symptoms, means that patients often experience multiple primary care consultations, long times to diagnosis, and poor clinical outcomes. An urgent referral pathway for non-specific symptoms, the Multidisciplinary Diagnostic Centre (MDC), may address this problem.
Aim To examine the less common cancers identified during the MDC pilots and consider whether such an approach improves the diagnosis of these cancers.
Design and setting A service evaluation of five MDC pilot projects in England from December 2016 to March 2019.
Method Data items were collected by pilot sites in near-real time, based mainly on the English cancer outcomes and services dataset, with additional project-specific items. Simple descriptive and comparative statistics were used, including χ2 tests for proportions and t-tests for means where appropriate.
Results From 5134 referrals, 378 cancers were diagnosed, of which 218 (58%) were less common. More than 30 different less common tumour types were diagnosed in this cohort. Of the MDC patients with less common cancers, 23% (n = 50) had ≥3 GP consultations before referral and, at programme level, a median time of 57 days was recorded from GP urgent referral to treatment for these tumour types.
Conclusion A non-specific symptomatic referral route diagnoses a broad range of less common cancers, and can support primary care case management for patients with symptoms of possible cancer that do not qualify for a site-specific urgent referral
SERCAP: is the perfect the enemy of the good?
No full textSingle Encounter Radical Cure and Prophylaxis (SERCAP) describes an ideal anti-malarial drug that cures all malaria in a single dose. This target product profile has dominated anti-malarial drug discovery and development over the past decade. The operational advantage of a single encounter has to be balanced against the need for a high dose, reliable absorption, little variability in pharmacokinetic properties, slow elimination (to ensure curative drug exposures in all patients) and a very low rate of vomiting. The demanding aspirational target may have hindered anti-malarial drug development. Aiming for three-day regimens, as in current anti-malarial treatments, would be better
Predicting evolution over multiple generations in deteriorating environments using evolutionarily explicit Integral Projection Models
No full textHuman impacts on the natural world often generate environmental trends that can have detrimental effects on distributions of phenotypic traits. We do not have a good understanding of how deteriorating environments might impact evolutionary trajectories across multiple generations, even though effects of environmental trends are often significant in the statistical quantitative genetic analyses of phenotypic trait data that are used to estimate additive genetic (co)variances. These environmental trends capture reaction norms, where the same (average) genotype expresses different phenotypic trait values in different environments. These environmental effects are not incorporated into the predictive models typically parameterised from statistical analyses to predict evolution, such as the breeder’s equation. We describe how these environmental effects can be incorporated into multi-generational, evolutionarily explicit, structured population models before exploring how these effects can influence evolutionary dynamics. The paper is primarily a description of the modelling approach, but we do also show how incorporation into models of the types of environmental trends that human activity has generated can have considerable impacts on the evolutionary dynamics that are predicted
Partial order games
No full textWe introduce a non-cooperative game model in which players’ decision nodes are par- tially ordered by a dependence relation, which directly captures informational dependencies in the game. In saying that a decision node v is dependent on decision nodes v1, . . . , vk, we mean that the information available to a strategy making a choice at v is precisely the choices that were made at v1, . . . , vk. Although partial order games are no more expressive than extensive form games of imper- fect information (we show that any partial order game can be reduced to a strategically equivalent extensive form game of imperfect information, though possibly at the cost of an exponential blowup in the size of the game), they provide a more natural and compact representation for many strategic settings of interest. After introducing the game model, we investigate the relationship to extensive form games of imperfect information, the problem of computing Nash equilibria, and conditions that enable backwards induction in this new model
Estimating the burden of the COVID-19 pandemic on mortality, life expectancy and lifespan inequality in England and Wales: a population-level analysis
No full textBackground Deaths directly linked to COVID-19 infection may be misclassified, and the pandemic may have indirectly affected other causes of death. To overcome these measurement challenges, we estimate the impact of the COVID-19 pandemic on mortality, life expectancy and lifespan inequality from week 10 of 2020, when the first COVID-19 death was registered, to week 47 ending 20 November 2020 in England and Wales through an analysis of excess mortality.
Methods We estimated age and sex-specific excess mortality risk and deaths above a baseline adjusted for seasonality with a systematic comparison of four different models using data from the Office for National Statistics. We additionally provide estimates of life expectancy at birth and lifespan inequality defined as the SD in age at death.
Results There have been 57 419 (95% prediction interval: 54 197, 60 752) excess deaths in the first 47 weeks of 2020, 55% of which occurred in men. Excess deaths increased sharply with age and men experienced elevated risks of death in all age groups. Life expectancy at birth dropped 0.9 and 1.2 years for women and men relative to the 2019 levels, respectively. Lifespan inequality also fell over the same period by 5 months for both sexes.
Conclusion Quantifying excess deaths and their impact on life expectancy at birth provide a more comprehensive picture of the burden of COVID-19 on mortality. Whether mortality will return to—or even fall below—the baseline level remains to be seen as the pandemic continues to unfold and diverse interventions are put in place
Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial
No full textBackground
Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings.
Methods
We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com, ISRCTN11643110.
Findings
41 344 children were vaccinated in April–May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI −12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed.
Interpretation
Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses.
Funding
The study was funded by the Bill & Melinda Gates Foundation
Preparing narrow velocity distributions for quantum memories in room-temperature alkali-metal vapors
No full textQuantum memories are a crucial technology for enabling large-scale quantum networks through synchronization of probabilistic operations. Such networks impose strict requirements on quantum memory, such as storage time, retrieval efficiency, bandwidth, and scalability. On- and off-resonant ladder protocols on warm atomic vapor platforms are promising candidates, combining efficient high-bandwidth operation with low-noise on-demand retrieval. However, their storage time is severely limited by motion-induced dephasing caused by the broad velocity distribution of atoms composing the vapor. In this paper, we demonstrate velocity selective optical pumping to overcome this decoherence mechanism. This will increase the achievable memory storage time of vapor memories. This technique can also be used for preparing arbitrarily shaped absorption profiles, for instance, preparing an atomic frequency comb absorption feature
Unresponsive or just asleep? Do local slow waves in the perilesional cortex have a function?
No full textTarget 2035-update on the quest for a probe for every protein
No full textTwenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome
Patient and informal carer experience of hip fracture: a qualitative study using interviews and observation in acute orthopaedic trauma
No full textObjectives The time taken for older people to recover from hip fracture can be extensive. The aim of this study was to gain an understanding of patient and informal carer experience of recovery in the early stage, while in acute care.
Design A phenomenological (lived experience) approach was used to guide the design of the study. Interviews and observation took place between March 2016 and December 2016 in acute care.
Setting Trauma wards in a National Health Service Foundation Trust in the South West of England.
Participants A purposive sample of 25 patients were interviewed and observation taking 52 hours was undertaken with 13 patients and 12 staff. 11 patients had memory loss, 2 patients chose to take part in an interview and observation. The age range was 63–91 years (median 83), 10 were men. A purposive sample of 25 informal carers were also interviewed, the age range was 42–95 years (mean 64), 11 were men.
Results The results identified how participants moved forward together after injury by sharing the journey. This was conveyed through three themes: (1) sustaining relationships while experiencing strong emotions and actively helping, (2) becoming aware of uncertainty about the future and working through possible outcomes, (3) being changed, visibly looking different, not being able to walk, and enduring indignity and pain.
Conclusion This study identified the experience of patients and informal carers as they shared the journey during a challenging life transition. Strategies that support well-being and enable successful negotiation of the emotional and practical challenges of acute care may help with longer term recovery. Research should focus on developing interventions that promote well-being during this transition to help provide the foundation for patients and carers to live fulfilled lives