MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance

(Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens

Developing and piloting a well-being program for hospital-based physicians

Background: Demanding working conditions in medical practice pressurise the well-being of physicians across all career stages, likely harming patients and healthcare systems. Structural solutions to harmful working conditions are necessary as well as interventions to support physicians in contemporary practice. We report on developing and piloting a team-based program for physicians to improve their working conditions and well-being. Approach: Program development steps involved: a preparatory phase, needs assessment, and program design. The program consisted of (1) a feedback tool addressing working conditions and well-being, and an intervention including (2a) a facilitated team dialogue and (2b) a team training on communication and collaborative job crafting. In the program’s pilot, 377 physicians from 48 teams in 14 Dutch hospitals used the feedback tool. Four teams participated in the team dialogue. Two teams performed the team training. Evaluation: Physicians indicated that the program was a useful format to gain insight into their working conditions and well-being, and possibly to improve their well-being collaboratively. Reflection: We provide seven critical reflections on developing and piloting our program, accompanied by recommendations for developing well-being interventions. Our development approach, program components, and recommendations may support physicians and other healthcare professionals in demanding work environments

The relationship between physicians' selfkindness and professional fulfillment and the mediating role of personal resilience and work-home interference: A cross-sectional study

Background Professional fulfillment is crucial for physicians' well-being and optimal patient care. Highly demanding work environments, perfectionism and self-critical attitudes jeopardize physicians' professional fulfillment. Objective To explore to what extent a kinder attitude towards the self, i.e. self-kindness, was associated with physicians' professional fulfillment and whether this relationship was mediated by personal resilience and work-home interference. Methods In 2020, cardiologists (n = 374) in the Netherlands participated in a web-based survey. Selfkindness was measured by the self-kindness subscale of the Self-Compassion Scale, personal resilience by the Brief Resilience Scale, work-home interference by the negative Work-Home Interference subscale of the Survey Work-Home Interaction-Nijmegen, and professional fulfillment by the corresponding subscale of the Professional Fulfillment Index. Using Hayes' SPSS macro PROCESS v3.5, the authors tested the parallel mediation model. Results Self-kindness was not directly associated with professional fulfillment (direct effect = .042, p = .36, 95% CI: -0.048, 0.132). Self-kindness was indirectly related to professional fulfillment through individual resilience (indirect effect = .049, 95% CI: .020, 0.086) and work-home interference (indirect effect = .057, 95% CI: .023, 096). Conclusions This study suggests that improving physicians' self-kindness may enhance professional fulfillment through personal resilience and work-home interference. Our findings may stimulate and remind physicians to be kind towards themselves as it may benefit them and their patients

Developing and piloting a well-being program for hospital-based physicians

Background: Demanding working conditions in medical practice pressurise the well-being of physicians across all career stages, likely harming patients and healthcare systems. Structural solutions to harmful working conditions are necessary as well as interventions to support physicians in contemporary practice. We report on developing and piloting a team-based program for physicians to improve their working conditions and well-being. Approach: Program development steps involved: a preparatory phase, needs assessment, and program design. The program consisted of (1) a 

Doctors’ alertness, contentedness and calmness before and after night shifts: a latent profile analysis

Abstract Background While night shifts are crucial for patient care, they threaten doctors’ well-being and performance. Knowledge of how the impact of night shifts differs for doctors is needed to attenuate the adverse effects of night shifts. This study aimed to obtain more precise insight into doctors’ feelings surrounding night shift by: identifying profiles based on doctors’ alertness, contentedness and calmness scores before and after night shifts (research question (RQ) 1); assessing how doctors’ pre- and post-shift profiles change (RQ2); and determining associations of doctors’ demographics and shift circumstances with alertness, contentedness and calmness change (RQ3). Methods Latent Profile Analysis using doctors’ pre- and post-shift self-rated alertness, contentedness and calmness scores was employed to identify pre- and post-shift profiles (RQ1). A cross-tabulation revealed pre- and post-shift profile changes (RQ2). Multiple regressions determined associations of demographics (i.e. age, sex, specialty) and night shift circumstances (i.e. hours worked pre-call, hours awake pre-call, shift duration, number of consecutive shifts, total hours of sleep) with alertness, contentedness and calmness change (RQ3). Results In total, 211 doctors participated with a mean age of 39.8 ± 10 years; 47.4% was male. The participants included consultants (46.4%) and trainees (53.6%) of the specialties surgery (64.5%) and obstetrics/gynaecology (35.5%). Three pre-shift (Indifferent, Ready, Engaged) and four post-shift profiles (Lethargic, Tired but satisfied, Excited, Mindful) were found. Most doctors changed from Ready to Tired but satisfied, with alertness reducing most. Age, specialty, sleep, shift duration and the number of consecutive shifts associated with alertness, contentedness and calmness changes. Conclusions The results provided nuanced insight into doctors’ feelings before and after night shifts. Future research may assess whether specific subgroups benefit from tailored interventions

Clonality, antigen recognition, and suppression of CD8+ T cells differentially affect prognosis of breast cancer subtypes

Purpose: In breast cancer, response rates to immune therapies are generally low and differ significantly across molecular subtypes, urging a better understanding of immunogenicity and immune evasion. Experimental Design: We interrogated large gene-expression data sets including 867 node-negative, treatment-naïve breast cancer patients (microarray data) and 347 breast cancer patients (whole-genome sequencing and transcriptome data) according to parameters of T cells as well as immune microenvironment in relation to patient survival. Results: We developed a 109-immune gene signature that captures abundance of CD8 tumor-infiltrating lymphocytes (TIL) and is prognostic in basal-like, her2, and luminal B breast cancer, but not in luminal A or normal-like breast cancer. Basal-like and her2 are characterized by highest CD8 TIL abundance, highest T-cell clonality, highest frequencies of memory T cells, and highest antigenicity, yet only the former shows highest expression level of immune and metabolic checkpoints and highest frequency of myeloid suppressor cells. Also, luminal B shows a high antigenicity and T-cell clonality, yet a low abundance of CD8 TILs. In contrast, luminal A and normal-like both show a low antigenicity, and notably, a low and high abundance of CD8 TILs, respectively, which associates with T-cell influx parameters, such as expression of adhesion molecules. Conclusions: Collectively, our data argue that not only CD8 T-cell presence itself, but rather T-cell clonality, T-cell subset distribution, coinhibition, and antigen presentation reflect occurrence of a CD8 T-cell response in breast cancer subtypes, which have been aborted by distinct T-cell-suppressive mechanisms, providing a rationale for subtype-specific combination immune therapies

Variability of residents’ ratings of faculty’s teaching performance measured by five- and seven-point response scales

Abstract Background Medical faculty’s teaching performance is often measured using residents’ feedback, collected by questionnaires. Researchers extensively studied the psychometric qualities of resulting ratings. However, these studies rarely consider the number of response categories and its consequences for residents’ ratings of faculty’s teaching performance. We compared the variability of residents’ ratings measured by five- and seven-point response scales. Methods This retrospective study used teaching performance data from Dutch anaesthesiology residency training programs. Questionnaires with five- and seven-point response scales from the extensively studied System for Evaluation of Teaching Qualities (SETQ) collected the ratings. We inspected ratings’ variability by comparing standard deviations, interquartile ranges, and frequency (percentage) distributions. Relevant statistical tests were used to test differences in frequency distributions and teaching performance scores. Results We examined 3379 residents’ ratings and 480 aggregated faculty scores. Residents used the additional response categories provided by the seven-point scale – especially those differentiating between positive performances. Residents’ ratings and aggregated faculty scores showed a more even distribution on the seven-point scale compared to the five-point scale. Also, the seven-point scale showed a smaller ceiling effect. After rescaling, the mean scores and (most) standard deviations of ratings from both scales were comparable. Conclusions Ratings from the seven-point scale were more evenly distributed and could potentially yield more nuanced, specific and user-friendly feedback. Still, both scales measured (almost) similar teaching performance outcomes. In teaching performance practice, residents and faculty members should discuss whether response scales fit their preferences and goals

Variability of residents’ ratings of faculty’s teaching performance measured by five- and seven-point response scales

Abstract Background Medical faculty’s teaching performance is often measured using residents’ feedback, collected by questionnaires. Researchers extensively studied the psychometric qualities of resulting ratings. However, these studies rarely consider the number of response categories and its consequences for residents’ ratings of faculty’s teaching performance. We compared the variability of residents’ ratings measured by five- and seven-point response scales. Methods This retrospective study used teaching performance data from Dutch anaesthesiology residency training programs. Questionnaires with five- and seven-point response scales from the extensively studied System for Evaluation of Teaching Qualities (SETQ) collected the ratings. We inspected ratings’ variability by comparing standard deviations, interquartile ranges, and frequency (percentage) distributions. Relevant statistical tests were used to test differences in frequency distributions and teaching performance scores. Results We examined 3379 residents’ ratings and 480 aggregated faculty scores. Residents used the additional response categories provided by the seven-point scale – especially those differentiating between positive performances. Residents’ ratings and aggregated faculty scores showed a more even distribution on the seven-point scale compared to the five-point scale. Also, the seven-point scale showed a smaller ceiling effect. After rescaling, the mean scores and (most) standard deviations of ratings from both scales were comparable. Conclusions Ratings from the seven-point scale were more evenly distributed and could potentially yield more nuanced, specific and user-friendly feedback. Still, both scales measured (almost) similar teaching performance outcomes. In teaching performance practice, residents and faculty members should discuss whether response scales fit their preferences and goals