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To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

The U.S. High-Luminosity LHC Accelerator Upgrade Project, in collaboration with CERN, is developing Nb 3 Sn quadrupole magnets (MQXFA) to be installed at the interaction region of the LHC. The project will deliver 20 MQXFA magnets in 10 cold masses. These magnets need to meet the stringent requirements on field quality at the nominal operating current. Compared to the mature NbTi accelerator magnet technology, achieving excellent field quality can be challenging for Nb 3 Sn magnets. To help track, understand, and allow effective correction of geometric field errors, field quality measurements at room temperature during the MQXFA assembly stage was planned for the project. The measurements also intend to evaluate the magnetic axis and twist angle along the magnet aperture. We report the first measurement on a prototype MQXFA magnet using a recently developed measurement system. The magnetic axis and twist angle met the acceptance criteria. Further development needs for the room-temperature measurements were discussed. We expect that statistics obtained from such measurements throughout the project will provide insight into future applications of high-performance Nb 3 Sn accelerator magnets.

Despite the effective clinical use of steroids for the treatment of Diamond Blackfan anemia (DBA), the mechanisms through which glucocorticoids regulate human erythropoiesis remain poorly understood. We report that the sensitivity of erythroid differentiation to dexamethasone is dependent on the developmental origin of human [CD34.sup.+] progenitor cells, specifically increasing the expansion of [CD34.sup.+] progenitors from peripheral blood (PB) but not cord blood (CB). Dexamethasone treatment of erythroid-differentiated PB, but not CB, [CD34.sup.+] progenitors resulted in the expansion of a newly defined [CD34.sup.+][CD36.sup.+] [CD71.sup.hi] [CD105.sup.med] immature colony-forming unit-erythroid (CFU-E) population. Furthermore, proteomics analyses revealed the induction of distinct proteins in dexamethasone-treated PB and CB erythroid progenitors. Dexamethasone treatment of PB progenitors resulted in the specific upregulation of [p57.sup.Kip2], a Cip/Kip cyclin-dependent kinase inhibitor, and we identified this induction as critical; shRNA-mediated downregulation of [p57.sup.Kip2], but not the related [p57.sup.Kip1], significantly attenuated the impact of dexamethasone on erythroid differentiation and inhibited the expansion of the immature CFU-E subset. Notably, in the context of DBA, we found that steroid resistance was associated with dysregulated [p57.sup.Kip2] expression. Altogether, these data identify a unique glucocorticoid-responsive human erythroid progenitor and provide new insights into glucocorticoid-based therapeutic strategies for the treatment of patients with DBA., Introduction Diamond Blackfan anemia (DBA) is an inherited bone marrow (BM) failure syndrome with an incidence of 5 to 10 cases per million live births and is characterized by red [...]

As Delaware has developed its doctrine with respect to controlling shareholders, its view of their relationship to directors has evolved. This evolution has produced some pronounced inconsistencies with respect to [...]

I am honored to have been asked to deliver the Griswold Lecture this year. I know that it is customary at these presentations to say a few words honoring Dean [...]

ObjectiveTo evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomographic scans with fludeoxyglucose F 18 (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and patients with Alzheimer disease (AD).DesignTwelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere-frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex, and posterior cingulate cortex. Results were compared with neuropathological diagnoses.SettingAcademic medical centers.PatientsForty-five patients with pathologically confirmed FTLD (n=14) or AD (n=31).ResultsRaters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27 of 31 patients [87%]) than in patients with FTLD (7 of 14 patients [50%]) (P=.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 scans lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.ConclusionsTemporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism but rather must take into account the relative hypometabolism of all brain regions.

BackgroundThe clinical diagnosis of dementing diseases largely depends on the subjective interpretation of patient symptoms. Consensus panels are frequently used in research to determine diagnoses when definitive pathologic findings are unavailable. Nevertheless, research on group decision making indicates that many factors can adversely affect panel performance.ObjectiveTo determine conditions that improve consensus panel diagnosis.DesignComparison of neuropathologic diagnoses with individual and consensus panel diagnoses based on clinical scenarios only, fludeoxyglucose F 18 positron emission tomography images only, and scenarios plus images.SettingExpert and trainee individual and consensus panel deliberations using a modified Delphi method in a pilot research study of the diagnostic utility of fludeoxyglucose F 18 positron emission tomography.PatientsForty-five patients with pathologically confirmed Alzheimer disease or frontotemporal dementia.Main outcome measuresStatistical measures of diagnostic accuracy, agreement, and confidence for individual raters and panelists before and after consensus deliberations.ResultsThe consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive rather than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules.ConclusionsUsing a modified Delphi protocol to arrive at a consensus diagnosis is a reasonable substitute for pathologic information. This protocol improves diagnostic accuracy and certainty when panelist judgments differ and is easily adapted to other research and clinical settings while avoiding the potential pitfalls of group decision making.

Ever since the rise of the great corporations in the late nineteenth and early twentieth centuries, commenters have debated whether firms should be run solely to benefit investors, or whether instead they should be run to benefit society as a whole. Both sides have claimed their preferred policies are necessary to maintain a capitalist system of private enterprise distinct from state institutions. What we can learn from the current iteration of the debate--now rebranded as "environmental, social, governance" or "ESG" investing--is that efforts to disentangle corporate governance from the regulatory state are futile; governmental regulation has an inevitable role in structuring the corporate form. [ABSTRACT FROM AUTHOR]