Network meta-analysis of diagnostic test accuracy studies identifies and ranks the optimal diagnostic tests and thresholds for healthcare policy and decision making

Objective: Network meta-analyses have extensively been used to compare the effectiveness of multiple interventions for healthcare policy and decision-making. However, methods for evaluating the performance of multiple diagnostic tests are less established. In a decision-making context, we are often interested in comparing and ranking the performance of multiple diagnostic tests, at varying levels of test thresholds, in one simultaneous analysis. Study design and setting: Motivated by an example of cognitive impairment diagnosis following stroke, we synthesized data from 13 studies assessing the efficiency of two diagnostic tests: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), at two test thresholds: MMSE <25/30 and <27/30, and MoCA <22/30 and <26/30. Using Markov Chain Monte Carlo (MCMC) methods, we fitted a bivariate network meta-analysis model incorporating constraints on increasing test threshold, and accounting for the correlations between multiple test accuracy measures from the same study. Results: We developed and successfully fitted a model comparing multiple tests/threshold combinations while imposing threshold constraints. Using this model, we found that MoCA at threshold <26/30 appeared to have the best true positive rate, whilst MMSE at threshold <25/30 appeared to have the best true negative rate. Conclusion: The combined analysis of multiple tests at multiple thresholds allowed for more rigorous comparisons between competing diagnostics tests for decision making

The histone chaperones Nap1 and Vps75 bind histones H3 and H4 in a tetrameric conformation

Histone chaperones physically interact with histones to direct proper assembly and disassembly of nucleosomes regulating diverse nuclear processes such as DNA replication, promoter remodeling, transcription elongation, DNA damage, and histone variant exchange. Currently, the best-characterized chaperone-histone interaction is that between the ubiquitous chaperone Asf1 and a dimer of H3 and H4. Nucleosome assembly proteins (Nap proteins) represent a distinct class of histone chaperone. Using pulsed electron double resonance (PELDOR) measurements and protein crosslinking, we show that two members of this class, Nap1 and Vps75, bind histones in the tetrameric conformation also observed when they are sequestered within the nucleosome. Furthermore, H3 and H4 trapped in their tetrameric state can be used as substrates in nucleosome assembly and chaperone-mediated lysine acetylation. This alternate mode of histone interaction provides a potential means of maintaining the integrity of the histone tetramer during cycles of nucleosome reassembly

On the significance of new physics in b → sℓ+ℓ−b \to s\ell^+\ell^- decays

Motivated by deviations with respect to Standard Model predictions in decays, we evaluate the global significance of the new physics hypothesis in this system by including the look-elsewhere effect for the first time. We estimate the trial-factor with pseudo-experiments and find that it can be as large as seven. We calculate the global significance for the new physics hypothesis by considering the most general description of a non-standard amplitude of short-distance origin. Theoretical uncertainties are treated in a highly conservative way by absorbing the corresponding effects into a redefinition of the Standard Model amplitude. Using the most recent measurements of LHCb, ATLAS and CMS, we obtain the global significance to be 4.3 standard deviations

c-Src drives intestinal regeneration and transformation

The non‐receptor tyrosine kinase c‐Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult <i>Drosophila</i> and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage‐induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self‐renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non‐redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation <i>in vivo.</i&gt

Elite Scientists and the Global Brain Drain

There are signs – one is world university league tables – that people increasingly think globally when choosing the university in which they wish to work and study. This paper is an exploration of data on the international brain drain. We study highly-cited physicists, highly-cited bio-scientists, and assistant professors of economics. First, we demonstrate that talented researchers are being systematically funnelled into a small number of countries. Among young economists in the top American universities, for example, 75% did their undergraduate degree outside the United States. Second, the extent of the elite brain drain is considerable. Among the world’s top physicists, nearly half no longer work in the country in which they were born. Third, the USA and Switzerland are per capita the largest net-importers of elite scientists. Fourth, we estimate the migration ‘funnelling coefficient’ at approximately 0.2 (meaning that 20% of top researchers tend to leave their country at each professional stage). Fifth, and against our prior expectations, the productivity of top scientists, as measured by the Hirsch h-index, is similar between the elite movers and stayers. Thus it is apparently not true that it is disproportionately the very best people who emigrate. Sixth, there is extreme clustering of ISI Highly Cited Researchers into particular fields in different universities. Seventh, we debate the questions: are the brain drain and this kind of funnelling good or bad for the world, and how should universities and governments respond?

“Couch-to-5k or Couch to Ouch to Couch!?” Who Takes Part in Beginner Runner Programmes in the UK and Is Non-Completion Linked to Musculoskeletal Injury?

Physical activity has mental and physical health benefits, however globally, three-quarters of the population do not meet physical activity guidelines. The Couch-to-5k is a beginner runners pro-gramme aimed at increasing physical activity. However, this programme lacks an evidence-base and it is unclear who is attracted to the programme, plus running has a high rate of musculoskel-etal (MSK) injuries. The aims of this study were to identify the characteristics of people taking part, the incidence of MSK injuries and to explore the experiences of people who dropped out of a modified 9-week Couch-to-5k programme. 110 runners (average age was 47.1±13.7 years) partic-ipated in the study which involved completion of questionnaires (running experience and foot-wear information, quality of life (EQ-5D-5L), physical activity level (IPAQ-short form), MSK inju-ry history and knee condition (SNAPPS and KOOS-PS)) at the start, middle and end of the pro-gramme collecting socio-demographics (age, gender, social economic status, relationship status, education level), body mass index, running experience , footwear information, quality of life, physical activity levels, MSK injuries and knee condition. Fifteen drop-outs were interviewed to explore experiences of the programme. Runners were mainly females (81.8%) with an average age 47.1-year-olds, average body mass index of 28.1kg.m2, mainly from high socio-economic lev-els, married and educated to degree level. 64% of the sample had previous running experience and were classified as active. Half the sample self-reported pain / discomfort and 37.2% reported anxiety / depression at the start of the programme via the EQ-5D-5L scale. Self-reported health scores increased (p = 0.047) between baseline (73.1±18.8 out of 100) and at the midpoint (81.2±11.6) but were no significant differences between any other time points (end point 79.7±17.5, p>0.05). Twenty-one injuries were reported during the programme (19%). Previous in-jury increased the risk of new injury (OR 7.56 95% CI 2.06 to 27.75). Only 27.3% completed the programme. Three themes emerged from interviews; MSK injury, negative emotions linked to non-completion and design of the programme. The Couch-to-5k may not attract diverse inactive populations, future work with larger sample sizes is needed to substantiate this finding. Drop-ping out was linked to MSK injury and progressive design, future programmes should consider including injury prevention advice and more flexible designs

The DL Advocate: Playing the devil's advocate with hidden systematic uncertainties

We propose a new method based on machine learning to play the devil's advocate and investigate the impact of unknown systematic effects in a quantitative way. This method proceeds by reversing the measurement process and using the physics results to interpret systematic effects under the Standard Model hypothesis. We explore this idea with two alternative approaches, one relies on a combination of gradient descent and optimisation techniques, the other employs reinforcement learning. We illustrate the potentiality of the presented method by considering two examples, firstly the case of a branching fraction measurement of a particle decay and secondly the determination of the $P_{5}^{'}$ angular observable in $B^0 \to K^{*0} \mu^+ \mu^-$ decays. We find that for the former, the size of a hypothetical hidden systematic uncertainty strongly depends on the kinematic overlap between the signal and normalisation channel, while the latter is very robust against possible mismodellings of the efficiency.Comment: 21 pages, 7 figure

Hunting for B+→K+τ+τ−B^+\to K^+ \tau^+\tau^- imprints on the B+→K+μ+μ−B^+ \to K^+ \mu^+\mu^- dimuon spectrum

We investigate the possibility of indirectly constraining the $B^{+}\to K^{+}\tau^+\tau^-$ decay rate using precise data on the $B^{+}\to K^{+}\mu^+\mu^-$ dimuon spectrum. To this end, we estimate the distortion of the spectrum induced by the $B^{+}\to K^{+}\tau^+\tau^-\to K^{+} \mu^+\mu^-$ re-scattering process, and propose a method to simultaneously constrain this (non-standard) contribution and the long-distance effects associated to hadronic intermediate states. The latter are constrained using the analytic properties of the amplitude combined with data and perturbative calculations. Finally, we estimate the sensitivity expected at the LHCb experiment with present and future datasets. We find that constraints on the branching fraction of $O(10^{-3})$, competitive with current direct bounds, can be achieved with the current dataset, while bounds of $O(10^{-4})$ could be obtained with the LHCb upgrade-II luminosity.Comment: 13 pages, 3 figures, 1 table, v2: more references, less typo