Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

John Punch, Scotist Holy War, and the Irish Catholic Revolutionary Tradition in the Seventeenth Century

During the 1640s, the Irish Franciscan theologian John Punch taught his theology students in Rome that war against Protestants was made just by their religion alone. Jesuits like Luis de Molina identified the holy war tradition in which Punch stood as a Scotist one, and insisted that the Scotists had confused the natural and supernatural spheres. Among Irishmen, Punch was unusual. The main Irish Catholic revolutionary tradition employed Jesuit and Thomist theory. They argued that the Stuarts had lost the right to rule Ireland for natural reasons, not supernatural ones; because the Stuarts were tyrants, not because they were Protestants.

John Maxwell

Biography of General Sir John Maxwell

Violation of Bell inequalities in larger Hilbert spaces: robustness and challenges

We explore the challenges posed by the violation of Bell-like inequalities by d-dimensional systems exposed to imperfect state-preparation and measurement settings. We address, in particular, the limit of high-dimensional systems, naturally arising when exploring the quantum-to-classical transition. We show that, although suitable Bell inequalities can be violated, in principle, for any dimension of given subsystems, it is in practice increasingly challenging to detect such violations, even if the system is prepared in a maximally entangled state. We characterize the effects of random perturbations on the state or on the measurement settings, also quantifying the efforts needed to certify the possible violations in case of complete ignorance on the system state at hand.

John Thompson: Seeing through China

In 1848, Karl Marx predicted that a flow of cheap commodities would be the heavy artillery which would batter down all Chinese walls and open up the country to the west (Marx, 1978, p. 477). The Scottish photographer John Thomson (1837-1921) was both chronicler of and participant in the early moments of this process. Thomson was a commercial photographer who first arrived in the Far East in 1862. He earned the moniker of 'China' in a decade-long stay during which he photographed what he considered to be the key aspects of its culture and landscape. In this body of work, Illustrations of China and its People (first published in 1874) is perhaps the most comprehensive. It explores, through two hundred photographs and accompanying texts, a series of phenomena from the macro-scale of landscape, infrastructure and industry to the smaller scales of streetscapes, domestic spaces, individual portraits, and other details of everyday life. Despite his own description of the volumes as encyclopedic, Illustrations is geographically quite limited. Thomson's explorations into the hinterland proceed up the country’s principal rivers from those coastal ports which had already been wrested into western hands during the Opium Wars (of the 1840s) and subsequently opened up to trade. This is perhaps one of the reasons why Illustrations has been described as an explicitly colonial text, a guide-book for the prospective settler whose content offered the strategic knowledge of land, culture and natural resources necessary if the territorial advantages of the coastal periphery were to extended to the interior (Jeffrey, 1981, p. 64). It can also be argued, however, that Thomson’s volume offered justification for a potential colonial presence. Faced with a civilization whose history was as sophisticated as the west, it depicts a culture that is static and moribund, its addiction to traditional values an impediment to progress. While this is perhaps most explicit in the texts of Illustrations of China, it can also be seen in the images whose uniform chemical rendering also serves to make an essentially diverse culture seem homogenous. Yet it is these images that distinguish Illustrations from previous attempts to collate China’s culture and landscape. Here, the mechanical precision of his camera captures a reality that often subverts the colonial narrative, confounding stereotypes as Thomson’s mass-produced images allow another China to emerge.

Do Children still need to Escape Childhood? A Reassessment of John Holt and his Vision for Children's Rights

The work of children’s liberationists have been long been critiqued for pushing the parameters of rights discourse too far; specifically, by suggesting that there are no significant differences between children and adults, including their ability for self-determination. John Holt’s 1974 text Escape from Childhood is one such work which was deemed highly controversial for its time. This article uses Holt’s Escape from Childhood as an overarching framework against which to examine the current state of play on children’s rights as explicated through the UN Convention on the Rights of the Child. It suggests that whilst Holt has often been critiqued for being too radical, in the context of current children’s rights discourse Holt’s visioning is not as radical as it might first appear.

Hanna, John Connor (1871-1947)

Profile and biography entry of John Connor Hanna, early film censor

Closed circuit rebreathing to achieve inert gas wash-in for multiple breath wash-out

Multiple breath wash-out (MBW) testing requires prior wash-in of inert tracer gas. Wash-in efficiency can be enhanced by a rebreathing tracer in a closed circuit. Previous attempts to deploy this did not account for the impact of CO2 accumulation on patients and were unsuccessful. We hypothesised that an effective rebreathe wash-in could be delivered and it would not alter wash-out parameters. Computer modelling was used to assess the impact of the rebreathe method on wash-in efficiency. Clinical testing of open and closed circuit wash-in–wash-out was performed in healthy controls and adult patients with cystic fibrosis (CF) using a circuit with an effective CO2 scrubber and a refined wash-in protocol. Wash-in efficiency was enhanced by rebreathing. There was no difference in mean lung clearance index between the two wash-in methods for controls (6.5 versus 6.4; p=0.2, n=12) or patients with CF (10.9 versus 10.8; p=0.2, n=19). Test time was reduced by rebreathe wash-in (156 versus 230 s for CF patients, p<0.001) and both methods were well tolerated. End wash-in CO2 was maintained below 2% in most cases. Rebreathe–wash-in is a promising development that, when correctly deployed, reduces wash-in time and facilitates portable MBW testing. For mild CF, wash-out outcomes are equivalent to an open circuit.