Surfacing undiagnosed disease: consideration, counting and coding.

The diagnostic odyssey for people living with rare diseases (PLWRD) is often prolonged for myriad reasons including an initial failure to consider rare disease and challenges to systemically and systematically identifying and tracking undiagnosed diseases across the diagnostic journey. This often results in isolation, uncertainty, a delay to targeted treatments and increase in risk of complications with significant consequences for patient and family wellbeing. This article aims to highlight key time points to consider a rare disease diagnosis along with elements to consider in the potential operational classification for undiagnosed rare diseases during the diagnostic odyssey. We discuss the need to create a coding framework that traverses all stages of the diagnostic odyssey for PLWRD along with the potential benefits this will have to PLWRD and the wider community.

Antimicrobial Prescribing in the Emergency Department; Who Is Calling the Shots?

Objective: Inappropriate antimicrobial prescribing in the emergency department (ED) can lead to poor outcomes. It is unknown how often the prescribing clinician is guided by others, and whether prescriber factors affect appropriateness of prescribing. This study aims to describe decision making, confidence in, and appropriateness of antimicrobial prescribing in the ED. Methods: Descriptive study in two Australian EDs using both questionnaire and medical record review. Participants were clinicians who prescribed antimicrobials to patients in the ED. Outcomes of interest were level of decision-making (self or directed), confidence in indication for prescribing and appropriateness (5-point Likert scale, 5 most confident). Appropriateness assessment of the prescribing event was by blinded review using the National Antibiotic Prescribing Survey appropriateness assessment tool. All analyses were descriptive. Results: Data on 88 prescribers were included, with 61% making prescribing decisions themselves. The 39% directed by other clinicians were primarily guided by more senior ED and surgical subspecialty clinicians. Confidence that antibiotics were indicated (Likert score: 4.20, 4.35 and 4.35) and appropriate (Likert score: 4.07, 4.23 and 4.29) was similar for juniors, mid-level and senior prescribers, respectively. Eighty-five percent of prescriptions were assessed as appropriate, with no differences in appropriateness by seniority, decision-making or confidence. Conclusions: Over one-third of prescribing was guided by senior ED clinicians or based on specialty advice, primarily surgical specialties. Prescriber confidence was high regardless of seniority or decision-maker. Overall appropriateness of prescribing was good, but with room for improvement. Future qualitative research may provide further insight into the intricacies of prescribing decision-making.

Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2.

Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way-by combining data from seven countries on four continents-we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons.