Search

BACKGROUND: Prospective genetic evaluation of patients at our referral research hospital presents clinical research challenges. OBJECTIVE: This study sought not only a single-gene explanation for participants’ immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune-phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: We developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% ≥18 years, and had diverse immune presentations. Overall, 327/1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9/22, 40.9%). One-quarter of the molecular diagnoses (92/361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251/361 (69.5%) of these molecular diagnoses could translate into ≥1 management option. CONCLUSION: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

We are a student–educator writing collective that have come together outside the formal classroom to experiment with ‘writing differently’, imbued with a desire to enact collective resistance against ‘unnoticed’ and intentionally hidden aspects of the business school curriculum that condone, normalize and reproduce social injustice and inequalities. As students and educator located in the Department of Organizational Psychology at a UK-based business school, we see our non-traditional writing and inquiry through collective writing as a form of resistance against hegemonic scientific norms of knowledge production that dominate our discipline. We evoked Freire’s problem-posing education through a collective enactment of ‘responsibility learning-in-action’ by participating in regular ‘writing as resistance’ sessions, where we wrote around our lived experiences of the ‘unnoticed’ and intentionally hidden curriculum and responsibility learning in the same virtual space and time and then read aloud to one another. Our coming together through this practice (re)claims relationality and solidarity in the student–educator relationship, which is in itself a contribution to the topic of the intersections between responsibility learning and the hidden curriculum at business schools.

Background: Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases. Methods: We ascertained five individuals with monoallelic pathogenic variants in MORC2, previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy; and a rare form of spinal muscular atrophy. Results: One of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2-related disorder, four of whom had clinical features strongly suggestive of CS. Conclusions: Our findings indicate that some forms of MORC2-related disorder have phenotypic similarities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2-related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diagnostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders.

Additional file 6. Observer OPTIONMCC scores with and without use of patient preparatory tool (intervention group).

Additional file 4. Baseline characteristics informal caregivers.

Additional file 7. Observer OPTIONMCC scores for geriatricians, patients and informal caregivers (subgroup analysis of eight geriatricians).

Additional file 3. Adapted control preference scale.

Additional file 1. Patient preparatory tool.

Additional file 5. Evaluation of use of the patient preparatory tool in the intervention group (n = 108).

ObjectiveTo provide insight into professionals’ perceptions of and experiences with shared decision-making (SDM) in the treatment of symptomatic patients with severe aortic stenosis (AS).MethodsA semistructured interview study was performed in the heart centres of academic and large teaching hospitals in the Netherlands between June and December 2020. Cardiothoracic surgeons, interventional cardiologists, nurse practitioners and physician assistants (n=21) involved in the decision-making process for treatment of severe AS were interviewed. An inductive thematic analysis was used to identify, analyse and report patterns in the data.ResultsFour primary themes were generated: (1) the concept of SDM, (2) knowledge, (3) communication and interaction, and (4) implementation of SDM. Not all respondents considered patient participation as an element of SDM. They experienced a discrepancy between patients’ wishes and treatment options. Respondents explained that not knowing patient preferences for health improvement hinders SDM and complicating patient characteristics for patient participation were perceived. A shared responsibility for improving SDM was suggested for patients and all professionals involved in the decision-making process for severe AS.ConclusionsProfessionals struggle to make highly complex treatment decisions part of SDM and to embed patients’ expectations of treatment and patients’ preferences. Additionally, organisational constraints complicate the SDM process. To ensure sustainable high-quality care, professionals should increase their awareness of patient participation in SDM, and collaboration in the pathway for decision-making in severe AS is required to support the documentation and availability of information according to the principles of SDM.

High-resolution earthquake locations and structural inversions using body waves rely on precise delay-time measurements. Subsample accuracy can be realized for P waves using multichannel cross correlation (MCCC), as developed by VanDecar and Crosson (1990), which exploits redundancy in pairwise cross correlations to determine delays between similar waveforms in studies of mantle structure using teleseismic sources (common source and multiple stations) and regional studies of structure and seismicity (multiple sources and common station). For regional S waves, alignment is complicated by the additional degree of freedom in waveform polarity that is expressed for sources with different moment tensors. Here, we recast MCCC within a principal component framework and demonstrate the equivalence between maximizing waveform correlation and minimization of various singular value–based objective functions for P waves. The singular-value framework is more general and leads naturally to an MCCC linear system for S waves that possesses an order of magnitude greater redundancy than that for P waves. Robust L1 solution of the system provides an effective means of mitigating outliers at the expense of subsample precision. Residual time shifts associated with higher-order singular vectors are employed in an iterative adaptive alignment that achieves subsample resolution. We demonstrate application of the approach on a seismicity cluster within the northern Cascadia crustal fore-arc.

This study is a metrological investigation of eight superconducting gravimeters that have operated in the Strasbourg gravimetric Observatory. These superconducting gravimeters include an older compact C026 model, a new observatory type iOSG23 and six iGravs (6, 15, 29, 30, 31, 32). We first compare the amplitude calibration of the meters using measurements from FG5 #206 absolute gravimeter (AG). In a next step we compute the amplitude calibration of all the meters by time regression with respect to iOSG23 itself carefully calibrated by numerous AG experiments. The relative calibration values are much more precise than absolute calibration for each instrument and strongly reduce any tidal residual signal. We also compare the time lags of the various instruments with respect to iOSG23, either by time cross-correlation or tidal analysis for the longest records (about 1 year). The instrumental drift behavior of the iGravs and iOSG23 is then investigated and we examine the relationships observed between gravity and body temperature measurements. Finally, we compare the noise levels of all the instruments. A three-channel correlation analysis is used to separate the incoherent (instrumental) noise from the coherent (ambient) noise. The self-noise is then compared to a model of thermal noise (Brownian motion) using the known instrumental parameters of the damped harmonic oscillator. The self-noise of iGrav instruments is well-explained by the thermal noise model at seismic frequencies (between 10–3 and 10–2 Hz). As expected, the self-noise of iOSG23 with a heavier sphere is also lower than that of iGravs at such frequencies.

In 1976, a small group of lesbian feminists in Amsterdam named themselves after Jill Johnston’s Lesbian Nation: The Feminist Solution (1973) and imagined a separate lesbian society, free from heter...