Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms.

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2(MT)) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower- to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1(MT) and IDH2(MT) are ancestral in up to 14/74 (19%) vs 34/99 (34%; P=0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2(MT) was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1(MT) cases were associated with a worse prognosis than subclonal IDH1(MT) cases, whereas the position of IDH2(MT) within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1(MT) cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2(MT) cases. Our data demonstrate important clinical and biological differences between IDH1(MT) and IDH2(MT) myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2(MT) inhibitors of IDH1/2(MT) patients.

The context of discrimination: workplace conditions, institutional environments, and sex and race discrimination charges.

This article explores the organizational conditions under which discrimination charges occur. Drawing on structural and organizational theories of the workplace, the authors demonstrate how organizational conditions affect workers' and regulatory agents' understandings of unlawful discrimination. Using a national sample of work establishments, matched to discrimination-charge data obtained from the Equal Employment Opportunity Commission (EEOC), the authors examine how characteristics of the workplace and institutional environment affect variation in the incidence of workers' charges of sex and race discrimination and in the subset of discrimination claims that are verified by EEOC investigators. The findings indicate that workplace conditions, including size, composition, and minority management, affect workers' charges as well as verified claims; the latter are also affected by institutional factors, such as affirmative action requirements, subsidiary status, and industrial sector. These results suggest that internal workplace conditions affect both workers' and regulatory agents' interpretations of potentially discriminatory experiences, while institutional conditions matter only for regulatory agents' interpretations of those events.

Surgery for large-angle congenital esotropia. Two vs three and four horizontal muscles.

Large-angle congenital esotropia is usually managed surgically by either of two fundamentally different approaches: (1) the uniform approach, in which surgery is restricted to two extraocular muscles (bimedial recessions or monocular recession-resection), or (2) the selective approach, in which bimedial recessions are combined with resections of one or both lateral rectus muscles. We compared surgical results of the two types of surgery during a ten-year period for 107 patients, of whom 57 underwent bimedial recessions, two had monocular recession-resections, and 48 received three- or four-muscle surgery. The average follow-up time was 2.6 years. The percentage of good surgical results (orthophoria +/- 10 PD) in the selective group was 64.5%, compared with 37.3% in the uniform group. Only three of the 48 patients in the selective group required a second procedure, compared with 17 of 59 patients in the uniform group.