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usc Refereed/Peer-reviewed Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.

The Hong-Ou-Mandel effect provides a mechanism to determine the distinguishability of a photon pair by measuring the bunching rates of two photons interfering at a beam splitter. Of particular interest is the distinguishability in time, which can be used to probe a time delay. Photon detectors themselves give some timing information, however, while that resolution may dwarf that of an interferometric technique, typical analyses reduce the interference to a binary event, neglecting temporal information in the detector. By modeling detectors with number and temporal resolution we demonstrate a greater precision than coincidence rates or temporal data alone afford. Moreover, the additional information can allow simultaneous estimation of a time delay alongside calibration parameters, opening up the possibility of calibration-free protocols and approaching the precision of the quantum Cram\'er-Rao bound.

Recent decades have seen a welcome revival of scholarly interest in the Seven Years War (1756—63). This has not been accompanied, however, by sufficient appreciation of the burdens imposed by the fighting and the enormous impact of these upon the states which were at war. Drawing upon the abundant recent scholarship, this article argues that the adoption of an international and comparative perspective, together with an extension of the time frame within which consequences are assessed, makes clear that the Seven Years War was decisive for the European ancien régime. It drove governments to adopt new policies and to introduce fundamental reforms, and in some states stimulated opposition to established political authority.

Interpretations of England's Glorious Revolution of 1688–1689 fall into two categories. The first views the opposition to James II as a national movement—establishing English religious freedom and political liberty under the auspices of a parliamentary monarchy significantly different from the continental kingdoms in which absolutism held sway. The second posits an international conspiracy involving only a small minority of England's peerage and gentry and culminating in the invasion of William III, Dutch Stadtholder and eventual English king, who wanted to deploy British resources in the struggle against French power. Scholars have recently combined the two positions to form a composite interpretation. Pincus' 1688, however, sets out to overthrow almost every piece of this established picture and to substitute the interpretation emblazoned in his subtitle; 1688 was nothing less than “The First Modern Revolution.”

Divisions between Marxist and non-Marxist historians have fuelled debate of late medieval and early modern popular protest over the past fifty years. Yet, an underlying consensus has arisen with two broad forms of popular revolt, a ‘pre-modern’ (encompassing the Middle Ages to as late as the mid-nineteenth century) and a ‘modern’ one. Supposedly, high bread prices sparked the former, women filled their ranks, the leaders came from the elites and not the rank-and-file of peasants or artisans, their ideologies were primitive and backward looking, and these revolts ended in repression, not revolution. With modernity the characteristics changed. This chapter challenges this ‘pre-modern’/’modern’ divide, arguing that late medieval popular revolts differed profoundly from those of the early modern period across all of these characteristics. The changes depended on a growing gap in power between rulers and the ruled that had begun in places by the closing decades of the fourteenth century.