The spectral shift function and spectral flow

This paper extends Krein's spectral shift function theory to the setting of semifinite spectral triples. We define the spectral shift function under these hypotheses via Birman-Solomyak spectral averaging formula and show that it computes spectral flow.Comment: 47 page

Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencer and a novel computational pipeline—NanoSV. We demonstrate that nanopore long reads are superior to short reads with regard to detection of de novo chromothripsis rearrangements. The long reads also enable efficient phasing of genetic variations, which we leveraged to determine the parental origin of all de novo chromothripsis breakpoints and to resolve the structure of these complex rearrangements. Additionally, genome-wide surveillance of inherited SVs reveals novel variants, missed in short-read data sets, a large proportion of which are retrotransposon insertions. We provide a first exploration of patient genome sequencing with a nanopore sequencer and demonstrate the value of long-read sequencing in mapping and phasing of SVs for both clinical and research applications

Breaking point: the genesis and impact of structural variation in tumours

Somatic structural variants undoubtedly play important roles in driving tumourigenesis. This is evident despite the substantial technical challenges that remain in accurately detecting structural variants and their breakpoints in tumours and in spite of our incomplete understanding of the impact of structural variants on cellular function. Developments in these areas of research contribute to the ongoing discovery of structural variation with a clear impact on the evolution of the tumour and on the clinical importance to the patient. Recent large whole genome sequencing studies have reinforced our impression of each tumour as a unique combination of mutations but paradoxically have also discovered similar genome-wide patterns of single-nucleotide and structural variation between tumours. Statistical methods have been developed to deconvolute mutation patterns, or signatures, that recur across samples, providing information about the mutagens and repair processes that may be active in a given tumour. These signatures can guide treatment by, for example, highlighting vulnerabilities in a particular tumour to a particular chemotherapy. Thus, although the complete reconstruction of the full evolutionary trajectory of a tumour genome remains currently out of reach, valuable data are already emerging to improve the treatment of cancer

Implementing coaching programmes for healthcare professionals-A review of the barriers and facilitators

Background: The European Union faces severe and worsening personnel shortages in healthcare. Coaching has emerged as a human-centred strategy to enhance sustainable employment and retention. While the number of efficacy studies on coaching continues to grow, knowledge about the barriers and facilitators to implementing coaching interventions among healthcare professionals (HCPs) remains scarce. Objectives: This systematic review aimed to describe common barriers and facilitators to the implementation of coaching interventions for HCPs. Methods: In April 2023, five databases were searched for eligible articles. Barriers and facilitators were systematically identified and mapped onto the constructs of the Consolidated Framework for Implementation Research (CFIR). Directed content analysis yielded thematic areas and a reporting frequency. Results: A total of thirty (n = 30) studies were included in this review, representing twenty-five (n = 25) distinct coaching programmes. Implementation determinants were clustered under two CFIR domains: the Inner Setting (8 facilitators, 5 barriers) and Implementation Process (6 facilitators, 1 barrier). Barriers included (i) limited organisational capacity, (ii) lack of psychological safety, (iii) competing work demands, and (iv) insufficient leadership buy-in, while facilitators were the (i) allocation of protected time for participants and coaches, (ii) promotion through opinion leaders, (iii) embeddedness in existing Continuous Professional Development programmes, and (iv) programme co-creation. Conclusion: The findings of this study provide practical insights to guide the future implementation of coaching interventions at an organisational level. In particular, the identified barriers and facilitators suggest, for optimal efficacy and sustainment, coaching interventions must be implemented within a safe, supportive organisational climate.</p

Physician exhaustion and work engagement during the COVID-19 pandemic: A longitudinal survey into the role of resources and support interventions

Background   Physicians increasingly show symptoms of burnout due to the high job demands they face, posing a risk for the quality and safety of care. Job and personal resources as well as support interventions may function as protective factors when demands are high, specifically in times of crisis such as the COVID-19 pandemic. Based on the Job Demands-Resources theory, this longitudinal study investigated how monthly fluctuations in job demands and job and personal resources relate to exhaustion and work engagement and how support interventions are associated with these outcomes over time.  Methods   A longitudinal survey consisting of eight monthly measures in the period 2020–2021, completed by medical specialists and residents in the Netherlands. We used validated questionnaires to assess job demands (i.e., workload), job resources (e.g., job control), personal resources (e.g., psychological capital), emotional exhaustion, and work engagement. Additionally, we measured the use of specific support interventions (e.g., professional support). Multilevel modeling and longitudinal growth curve modeling were used to analyze the data.  Results   378 medical specialists and residents were included in the analysis (response rate: 79.08%). Workload was associated with exhaustion (γ = .383, p < .001). All job resources, as well as the personal resources psychological capital and self-judgement were associated with work engagement (γs ranging from -.093 to .345, all ps < .05). Job control and psychological capital attenuated the workload-exhaustion relationship while positive feedback and peer support strengthened it (all ps < .05). The use of professional support interventions (from a mental health expert or coach) was related to higher work engagement (estimate = .168, p = .032) over time. Participation in organized supportive group meetings was associated with higher exhaustion over time (estimate = .274, p = .006).  Conclusions   Job and personal resources can safeguard work engagement and mitigate the risk of emotional exhaustion. Professional support programs are associated with higher work engagement over time, whereas organized group support meetings are associated with higher exhaustion. Our results stress the importance of professional individual-level interventions to counteract a loss of work engagement in times of crisis

Physician exhaustion and work engagement during the COVID-19 pandemic: A longitudinal survey into the role of resources and support interventions

Background   Physicians increasingly show symptoms of burnout due to the high job demands they face, posing a risk for the quality and safety of care. Job and personal resources as well as support interventions may function as protective factors when demands are high, specifically in times of crisis such as the COVID-19 pandemic. Based on the Job Demands-Resources theory, this longitudinal study investigated how monthly fluctuations in job demands and job and personal resources relate to exhaustion and work engagement and how support interventions are associated with these outcomes over time.  Methods   A longitudinal survey consisting of eight monthly measures in the period 2020–2021, completed by medical specialists and residents in the Netherlands. We used validated questionnaires to assess job demands (i.e., workload), job resources (e.g., job control), personal resources (e.g., psychological capital), emotional exhaustion, and work engagement. Additionally, we measured the use of specific support interventions (e.g., professional support). Multilevel modeling and longitudinal growth curve modeling were used to analyze the data.  Results   378 medical specialists and residents were included in the analysis (response rate: 79.08%). Workload was associated with exhaustion (γ = .383, p < .001). All job resources, as well as the personal resources psychological capital and self-judgement were associated with work engagement (γs ranging from -.093 to .345, all ps < .05). Job control and psychological capital attenuated the workload-exhaustion relationship while positive feedback and peer support strengthened it (all ps < .05). The use of professional support interventions (from a mental health expert or coach) was related to higher work engagement (estimate = .168, p = .032) over time. Participation in organized supportive group meetings was associated with higher exhaustion over time (estimate = .274, p = .006).  Conclusions   Job and personal resources can safeguard work engagement and mitigate the risk of emotional exhaustion. Professional support programs are associated with higher work engagement over time, whereas organized group support meetings are associated with higher exhaustion. Our results stress the importance of professional individual-level interventions to counteract a loss of work engagement in times of crisis

Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells

Up to 80% of human cancers, in particular solid tumors, contain cells with abnormal chromosomal numbers, or aneuploidy, which is often linked with marked chromosomal instability. Whereas in some tumors the aneuploidy occurs by missegregation of one or a few chromosomes, aneuploidy can also arise during proliferation of inherently unstable tetraploid cells generated by whole genome doubling from diploid cells. Recent findings from cancer genome sequencing projects suggest that nearly 40% of tumors underwent whole genome doubling at some point of tumorigenesis, yet its contribution to cancer phenotypes and benefits for malignant growth remain unclear. Here, we investigated the consequences of a whole genome doubling in both cancerous and non-transformed p53 positive human cells. SNP array analysis and multicolor karyotyping revealed that induced whole-genome doubling led to variable aneuploidy. We found that chromosomal instability (CIN) is a frequent, but not a default outcome of whole genome doubling. The CIN phenotypes were accompanied by increased tolerance to mitotic errors that was mediated by suppression of the p53 signaling. Additionally, the expression of pro-apoptotic factors, such as iASPP and cIAP2, was downregulated. Furthermore, we found that whole genome doubling promotes resistance to a broad spectrum of chemotherapeutic drugs and stimulates anchorage-independent growth even in non-transformed p53-positive human cells. Taken together, whole genome doubling provides multifaceted benefits for malignant growth. Our findings provide new insight why genome-doubling promotes tumorigenesis and correlates with poor survival in cancer