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Refereed/Peer-reviewed Pathogenic variants in DNMT3A are most commonly associated with Tatton-Brown-Rahman Syndrome (TBRS), but includes other phenotypes such as Heyn-Sproul-Jackson syndrome and acute myeloid leukemia (AML). We describe a patient presenting to the neuromuscular clinic with a de novo missense variant in DNMT3A where the striking clinical feature is that of a congenital myopathy with associated episodes of rhabdomyolysis, severe myalgias and chest pain along with phenotypic features associated with TBRS. Muscle biopsy showed minor myopathic features and cardiac investigations revealed mildly impaired bi-ventricular systolic function. We confirmed the DNA methylation profile matched haplo-insufficient TBRS cases, consistent with a loss of methyltransferase activity. Our report emphasizes the phenotypic overlap of patients with syndromic disorders presenting to neuromuscular clinics and limitations of gene panels in establishing a molecular diagnosis.

Refereed/Peer-reviewed Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.

Mutation detection is increasingly used for the management of hematological malignancies. Prior whole transcriptome and whole exome sequencing studies using total RNA and DNA identified diverse mu-tation types in cancer-related genes associated with treatment failure in patients with chronic myeloid leukemia. Variants included single-nucleotide variants and small insertions/deletions, plus fusion transcripts and partial or whole gene deletions. The hypothesis that all of these mutation types could be detected by a single cost-effective hybridization capture next-generation sequencing method using total RNA was assessed. A method was developed that targeted 130 genes relevant for myeloid and lymphoid leukemia. Retrospective samples with 121 precharacterized variants were tested using total RNA and/or DNA. Concordance of detection of precharacterized variants using RNA or DNA was 96%, whereas the enhanced sensitivity identified additional variants. Comparison between 24 matched DNA and RNA samples demonstrated 95.3% of 170 variants detectable using DNA were detected using RNA, including all but one variant predicted to activate nonsense-mediated decay. RNA identified an addi-tional 10 variants, including fusion transcripts. Furthermore, the true effect of splice variants on RNA splicing was only evident using RNA. In conclusion, capture sequencing using total RNA alone is suitable for detecting a range of variants relevant in chronic myeloid leukemia and may be more broadly applied to other hematological malignancies where diverse variant types define risk groups. Refereed/Peer-reviewed

BACKGROUND Electronic Health Records (EHRs) play an increasingly important role in the delivery of HIV care in low-and-middle-income countries. The data collected is used for direct clinical care, quality improvement activities, reporting and clinical research. Despite widespread EHR use for HIV care in East Africa, and countries like Nigeria, Mozambique and Haiti, challenges remain especially with achieving and maintaining high quality data. OBJECTIVE To determine factors influencing data quality in a large scale EHR deployment and potential strategies to improve quality. METHODS We carried out a data quality evaluation in 50 health facilities in Rwanda using the OpenMRS EHR systems for HIV care. The sites were part of a larger randomized controlled trial and half of the sites had an enhanced version of the EHR with clinical decision support alerts. Trained data collectors visited 50 health facilities to collect 28 variables from both paper charts and the EHR system using the ODK app. We measured the data completeness, timeliness, the degree of matching of paper and EHR data including use of concordance scores. Factors potentially effecting data quality were drawn from a previous survey of users in the 50 sites. RESULTS We randomly selected 3467 records, reviewed from the paper charts and EHR, collecting a total of 194,152 data items. Data completeness was above the 85% threshold for all variables except viral load (VL) results and second and third line drug regimens. Matching scores for data values were close to or above 85%, but lower for dates particularly for drug pickups and VL. Data concordance had a mean of 10.2/15 (68%) for the 15 variables. Site and user factors (years of EHR use, technology experience, EHR availability/uptime, intervention status) were tested for correlation with data quality measures. EHR system availability/uptime was positively correlated with concordance, and users experiences of technology was negatively correlated. The alerts for missing viral load results implemented in 11 intervention sites showed clear evidence of improving timeliness and completeness of initially low matching of VL results in the EHR and paper records (11.9% to 26.7%, P CONCLUSIONS The EHR records in the 50 health facilities generally had a high level of completeness. Matching results were within 3% of the 85% threshold or above for non-date variables, but lower for dates. Higher EHR stability and uptime was associated with better data quality. Alerts and reminders for entering VL were shown to have a strong effect in improving data quality. Overall, most data was considered fit for purpose, but more regular data quality assessments, training, mentoring and technical improvements in forms and data reports would be beneficial particularly for dates and key lab data. CLINICALTRIAL N/A

Hereditary platelet disorders (HPDs) are a group of blood disorders with variable severity and clinical impact. Although phenotypically there is much overlap, known genetic causes are many, prompting the curation of multigene panels for clinical use, which are being deployed in increasingly large-scale populations to uncover missing heritability more efficiently. For some of these disorders, in particular RUNX1, ETV6, and ANKRD26, pathogenic germ line variants in these genes also come with a risk of developing hematological malignancy (HM). Although they may initially present as similarly mild-moderate thrombocytopenia, each of these 3 disorders have distinct penetrance of HM and a different range of somatic alterations associated with malignancy development. As our ability to diagnose HPDs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients and how to optimize management and surveillance of patients and carriers who have not developed malignancy. The volume of genetic information now being generated has created new challenges in how to accurately assess and report identified variants. The answers to all these questions involve international initiatives on rare diseases to better understand the biology of these disorders and design appropriate models and therapies for preclinical testing and clinical trials. Partnered with this are continued technological developments, including the rapid sharing of genetic variant information and automated integration with variant classification relevant data, such as high-throughput functional data. Collective progress in this area will drive timely diagnosis and, in time, leukemia preventive therapeutic interventions.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

BACKGROUND Symptom checkers (SCs) are diagnostic decision support apps for patients, used by tens of millions of people annually. They are designed to provide diagnosis and triage advice and assist users in seeking the appropriate level of care. Little evidence is available on their diagnostic and triage accuracy with direct use by patients for urgent conditions. OBJECTIVE To determine the diagnostic and triage accuracy and usability of a symptom checker in use by for patients presenting to an emergency department METHODS We recruited a convenience sample of English-speaking patients presenting for care in an urban emergency department. Each consenting patient used a leading SC from Ada Health prior to ED evaluation. Diagnostic accuracy was evaluated, comparing (1) the SC’s diagnoses and (2) those of 3 independent emergency physicians viewing the patient-entered symptom data, to (3) the final diagnoses from the ED evaluation. The Ada diagnoses and triage were also critiqued by the independent physicians. Patients completed a usability survey based on the Technology Acceptance Model. RESULTS Forty participants (80% of those approached, mean age 40.1 years (range 18 – 76); 65% female, 68% White, 48% Hispanic or Latino, completed the SC assessment and usability survey. Sensitivity for at least one of the ED final diagnoses by Ada (based on it’s top 5 diagnoses) was 70.0% (95% CI 54% – 86%) close to the mean sensitivity for the 3 physicians (on their top 3 diagnoses) of 68.9%. The physicians rated Ada triage decisions as 62% fully agree, and 24% safe but too cautious. It was rated unsafe and too risky in 22% by at least one physician, 14% by two and 5% by all 3, although none of the under-triaged patients suffered an adverse event in the ED. Some cases only had symptoms recorded for their ED diagnosis, limiting analysis. Usability was rated highly, participants agreed or strongly agreed a mean of 84.6% with the 7 TAM usability questions, although “satisfaction” and “enjoyment” were rated low. CONCLUSIONS This study provides preliminary evidence that a SC can provide acceptable usability and diagnostic accuracy for patients with a variety of urgent conditions. 14% of SC triage recommendations were deemed unsafe and too risky by at least 2 physicians based on the symptoms recorded. Larger studies are needed of diagnosis and triage performance with direct patient use in different clinical environments.

This article begins by exploring – and insisting upon – the difference between a ‘fiscal-military state’ and a ‘fiscal state’, concepts often amalgamated by historians. It then explores how the idea of a fiscal-military state in 18th-century Britain has evolved since the term’s invention in 1988, paying particular attention to its impact upon Ireland and Scotland and on relations between central and local government. It goes on to suggest that the concept might profitably be applied to the Austrian Habsburg Monarchy during its Heldenzeit (‘Age of Heroes’) between the 1670s and 1720 and, more generally, during the long 18th century, when many financial and administrative innovations resembling those in Britain were introduced due to the impact of regular and large-scale warfare, above all the development of a system of structured borrowing supported by public bodies and by fiscal innovations.

Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a definite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the definite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

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.

GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 465 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 231 of these confirmed to be familial and 22 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome (MDS) is the first diagnosis in 75% of these cases with acute myeloid leukemia (AML) in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing and expression. In this review, we provide the first expert curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings.

When a photon interferes with itself while traversing a Mach-Zehnder inteferometer, the output port where it emerges is influenced by the phase difference between the interferometer arms. This allows for highly precise estimation of the path length difference (delay) but is extremely sensitive to phase noise. By contrast, a delay between the arms of the two-photon Hong-Ou-Mandel interferometer directly affects the relative indistinguishability of the photon pair, affecting the rate of recorded coincidences. This likewise allows for delay estimation; notably less precise but with the advantage of being less sensitive to perturbations of the photons' phase. Focusing on two-photon input states, we here investigate to what degree of noise Mach-Zehnder interferometry retains its edge over Hong-Ou-Mandel interferometry. We also explore the competing benefits of different two-photon inputs for a Mach-Zehnder interferometer, and under what parameter regimes each input performs best., Comment: 19 pages, 10 figures

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.

Few institutions have possessed as enduring importancein Europe's history as the Holy Roman Empire. Dating its foundation to Charlemagne's coronation in 800, it survived for a millennium, being dissolved only in 1806 in the face of the overwhelming threat from Napoleonic imperialism. Its geographical extent was equally remarkable: at its peak, imperial territory stretched eastward from the North Sea as far as Poland, and southward from the shores of the Baltic deep into the Italian Peninsula. Around 1800, shortly before its nemesis, the Empire was Europe's second largest polity, with a territorial area of around 687,000 square kilometers. It was eclipsed only by Russia, which during the later-seventeenth and eighteenth century had expanded spectacularly. Its population too was impressive: with around twenty-nine million inhabitants, its only rivals were France and Russia. Claiming descent from ancient Rome, the Empire long embodied the idea of a unified Christendom, while its defensive role against Ottoman expansion from the late fifteenth century onward sustained its religious mission even after the Protestant Reformation. Yet it is often squeezed out of accounts of Europe's past, an exclusion which is particularly evident for the early modern centuries.

Olivier Chaline, with Ivo Cerman, eds., Les Schwarzenberg: Une famille dans l'histoire de l'Europe, XVIe–XXIe siecles (Panazol: Lavauzelle, 2012), 395 pp. €38.Jean Berenger, ed., Prince Ferdinand S...

This chapter explores the development, primarily in Anglophone and Western European historical scholarship, and aims to explain both the current interest and the distinctive approach which became established in many national historiographies at that time and continues until the present day. A connection between contemporary developments and scholarly fashion was evident. The continental European nobility lost much of its political and social power, together with a large part of its extensive landholding, between, very approximately, the 1880s and 1945. An identical development occurred a generation later in England, where the final demise of the landed classes only took place after the Second World War. Indeed, before the 1960s, if there was a field of European history where the social elite was both subjected to intensive study and integrated into an overall explanation of political change, it was Ancient History. On the European continent abundant research has been and continues to be published.

This study sought to examine the effectiveness of a live case methodology for individuals engaged in executive development. In particular, the research examined whether ‘hard’ skills such as strategy could be developed by using a case study approach that is traditionally known for improving transferable or ‘soft’ skills. A three-day live case study was undertaken by 19 participants as part of an executive development programme on strategy. Through completion of both pre and post case study questionnaires, change scores on knowledge and understanding of a range of both ‘hard’ (strategy related) and ‘soft’ (transferable skills) skills and confidence to perform these skills effectively was calculated. The results clearly demonstrated that the use of the live case study was an excellent method for improving knowledge and understanding of strategy. However, the more surprising result was that with middle and senior managers on an executive education programme, the live case study did not significantly improve knowledge, understanding or confidence for transferable skills. The findings are discussed in relation to the current literature on the benefits of live cases, and the specific characteristics of the executive development cohort.

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.”

The introduction of printing by moveable type and the development of engraving and other intaglio processes from the mid-fifteenth century transformed the ways in which books and documents were published. Manuscripts had enjoyed European-wide circulation, but the print-led increase in the volume of publication, the accuracy and redesign of textual replication, its social penetration and the rapidity of its circulation encouraged new modes of social interaction and new methods in the construction and dissemination of knowledge. The printing revolution challenged political and religious authority, resulting in new attempts at intellectual censorship and the restraint of publication. Resurgent interest in historical bibliography has inspired dozens of studies of an early modern ?print culture?. The novelty and effectiveness of the transmission of print, however, were tempered by technological and transport constraints that suggest fitful and uneven development, but one that was pan-European and essentially transnational in its character and significance.