Trauma-Informed Undergraduate Medical Education: A Pathway to Flourishing with Adversity by Enhancing Psychological Safety.

We describe the Life Experiences Curriculum (LEC), which attempts to integrate medical student well-being with trauma-informed medical education. The long-term goal of LEC is to help medical students flourish with adversity and trauma, where flourishing refers to having a sense of purpose that arises from awareness of one's strengths and limitations, shaped by life experiences. The short-term goal of LEC is to develop students' relational capacities, such as acceptance and awareness of self and others, while building and maintaining students' psychological safety. We describe the conceptual rationale for these goals and the curriculum's development, implementation, evaluation, and limitations. The curriculum extends over four years and involves a preclinical seminar and students' individual and group reflection sessions with LEC faculty. The seminar addresses the coexistence of trauma and flourishing across life experiences, as well as how safety in relationships is impaired by traumatic experiences and must be restored for healing and growth. The physician faculty have no role in student evaluation and co-lead all LEC activities. LEC is intended to provide students with new language for understanding the process of trauma and flourishing in both individuals and systems and to build and sustain students' relational capacities. There are ongoing efforts to re-imagine self-care as communal-care in which care and support are given and received in a community of students and faculty. Such a model may help build the relational capacities needed to deliver trauma-informed care and also promote flourishing with adversity in healers and in those seeking to be healed.

The Association of Childhood Parental Connection With Adult Flourishing and Depressive Symptoms.

OBJECTIVES: To determine whether a common measure of childhood emotional neglect, scored instead as a continuous measure of increasing parental connection, is associated with adult flourishing and depressive symptoms, and to compare the magnitude of these 2 associations. METHODS: We pooled cross-sectional survey data from the Midlife in the United States study, collected from 2 national cohorts (2004-2006 and 2011-2014) of English-speaking, US adults, aged 25 to 74 years. Using the 5-item emotional neglect subscale of the Childhood Trauma Questionnaire, a score of increasing childhood parental connection was created by not reverse-scoring responses. The adult outcomes were standardized scores of flourishing, from Ryff's Psychological Well-Being Scale, and depressive symptoms, from the Center for Epidemiologic Studies Depression Scale. RESULTS: Data were available for 2079 of 2118 participants (98.2%). The mean (SD) age was 53.1 (12.6) years and 54.6% were female. After adjusting for covariates (age, gender, race and ethnicity, marital status, chronic disease, socioeconomic disadvantage), the adult flourishing score was 0.74 (95% confidence interval 0.63-0.86) SD units higher in those in the highest quartile of childhood parental connection compared with the lowest, whereas the depressive symptoms score was lower by a similar magnitude (-0.65 [95% confidence interval -0.77 to -0.54] SD units). CONCLUSIONS: When emotional neglect is reframed as parental connection, it has associations with adult flourishing and depressive symptoms that are of similar magnitude but opposite direction. Clinicians and researchers should consider the more positive and aspirational frame of parental connection and its potential contribution to life course flourishing.

The Association Between Early Childhood Education Professionals' Perception of Workplace Spirituality and Their Intention to Stay in Their Current Program.

Turnover in the US early childhood education (ECE) workforce is associated with worse outcomes for children. Greater workplace spirituality, or the perception of meaningful work, sense of community, and alignment with organizational values, is associated with reduced turnover. However, this association has not been examined in ECE professionals. We administered an online survey to 265 ECE professionals in Pennsylvania (US) in the spring of 2021. Respondents were asked about their intention to stay in their current program, if given the option to leave. Workplace spirituality was measured with a 21-item scale assessing the dimensions of meaningful work, sense of community, and alignment with organizational values. The survey was completed by 246 (92.8%), and data were analyzed for 232 respondents. Of these, 94.8% were female, 54.4% were non-Hispanic White, and 70.7% had a bachelor's or graduate degree. The prevalence of intention to stay was 33.2%. After adjusting for all covariates, including gender, age, race/ethnicity, education, job position, workplace stress, and economic hardships, the prevalence (95% confidence interval [CI]) of intention to stay increased across tertiles of workplace spirituality from low to medium to high: 16.4% (7.9%, 24.9%) to 38.6% (28.4%, 48.8%) to 43.7% (32.1%, 55.3%), respectively. ECE professionals who perceived greater workplace spirituality were more likely to report they intended to stay in their current program. Turnover in the ECE workforce could potentially be reduced through efforts to increase a sense of meaning and community at work and to align the values of ECE programs with those who work in them. Supplementary Information: The online version contains supplementary material available at 10.1007/s10643-023-01506-7.

The Association Between Work as a Calling and Turnover Among Early Childhood Education Professionals.

Turnover of early childhood education (ECE) professionals negatively impacts program costs, staff morale, and relationships with children. We determined whether the presence of work as a calling was associated with less intention to leave the ECE field. From an online survey administered to 265 ECE professionals in Pennsylvania, a calling score based on the Calling and Vocation Questionnaire was used to create sample-defined tertiles of low (< 38), medium (38-44), and high (> 44) presence of calling. Those intending to leave the ECE field reported that, given the option, they would most likely "find a position or get training in a completely different field," or "stop work, stay home, or retire." Analysis was restricted to 194 respondents currently employed in ECE and under age 60, of whom 94.8% were female and 53.9% were non-Hispanic White. After adjusting for race/ethnicity and workplace stress, the prevalence (95% CI) of intention to leave decreased as calling increased, from low (28.6% [17.8%, 38.4%]) to medium (12.2% [4.3%, 20.1%]) to high (9.1% [1.5%, 16.6%]). The presence of call was associated with less intention to leave the ECE field. Identifying, building, and sustaining call among ECE professionals may decrease turnover.

Relational Health as a Pathway from Trauma to Flourishing in School Communities.

BACKGROUND: Because traumatic life experiences are common, teaching and learning can be difficult without recognizing how trauma can make people feel psychologically unsafe. Safety can be restored through healthy relationships. CONTRIBUTIONS TO THEORY: We present a framework for how relational health-the capacity to develop and maintain safe, stable, and nurturing relationships with others-may allow flourishing in school communities, even amidst past and ongoing adversity. We propose four key assets for relational health-awareness of self, acceptance of self, awareness of others, and acceptance of others. To support this framework, we developed a relational asset score using data from a survey of 214 early childhood education professionals and examined its association with meaningful work, purpose in life, work satisfaction, and intention to stay in one's program. IMPLICATIONS FOR SCHOOL HEALTH: School health requires relational health. Research should evaluate the associations between relational assets and the perceptions of safety and connection in school communities. Leadership can prioritize relational health by supporting staff in building and using their relational assets. CONCLUSIONS: School communities may be more likely to flourish, even amidst adversity, if all adults in the community prioritize relational health, which provides the psychological safety required for teaching and learning.

Family Connection and Flourishing Among Adolescents in 26 Countries.

OBJECTIVES: To determine whether higher levels of family connection are associated with a greater prevalence of flourishing in adolescence. METHODS: We analyzed cross-sectional data from the International Survey of Children's Well-Being collected in 26 countries between 2016 and 2019 from 11- to 13-year-olds. Family connection was based on a mean score of 5 items that asked about care, support, safety, respect, and participation using a Likert-type scale (range 0-4). Flourishing was based on a mean score of 6 items that asked about self-acceptance, purpose in life, positive relations with others, personal growth, environmental mastery, and autonomy using a Likert-type scale (range 0-10). A mean score of >8 was considered flourishing. RESULTS: The analysis involved 37 025 of 39 286 (94.2%) adolescents, after excluding those with missing data. The mean (SD) age was 11.9 (0.6) years and 51.4% were girls. The prevalence (95% confidence interval) of flourishing was 65.8% (65.3-66.3). Adolescents were distributed across 5 increasing levels of the family connection score: <2.5 (11.2%), 2.5 to <3.0 (8.8%), 3.0 to <3.5 (24.2%), 3.5 to <4.0 (25.1%), and 4.0 (30.7%). After controlling for covariates, including material resources and food sufficiency, the prevalence (95% confidence interval) of flourishing increased across the 5 levels of increasing family connection: 34.9% (33.3-36.5), 45.0% (43.2-46.8), 58.2% (57.2-59.3), 72.6% (71.6-73.5), and 84.3% (83.6-85.1), respectively. CONCLUSIONS: Among adolescents from 26 countries, greater family connection was associated with a higher prevalence of flourishing. Family connection may contribute to flourishing, not just the avoidance of negative outcomes.

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal.

CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long-lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53-dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.

The interaction of adverse childhood experiences and gender as risk factors for depression and anxiety disorders in US adults: a cross-sectional study.

BACKGROUND: Exposure to adverse childhood experiences (ACEs) and being female are distinct risk factors for having a major depressive episode (MDE) or an anxiety disorder (AD) in adulthood, but it is unclear whether these two risk factors are synergistic. The purpose of this study was to determine whether exposure to ACEs and being female are more than additive (synergistic) in their association with MDE and AD in US adults. METHODS: We pooled cross-sectional survey data in the Midlife in the United States study from two nationally-representative cohorts of English-speaking US adults. Data from the first cohort were collected in 2004-2006 and from the second in 2011-2014. Data from both cohorts included the 12-month prevalence of MDE and AD (generalized anxiety disorder or panic disorder) assessed with the Composite International Diagnostic Interview Short Form, gender (here termed female and male), and the count of five categories of exposure to ACEs: physical, sexual, or emotional abuse; household alcohol or substance abuse; and parental separation or divorce. RESULTS: Of the 5834 survey respondents, 4344 (74.5%) with complete data on ACEs were included in the analysis. Mean (SD) age was 54.1 (13.8) years and 53.9% were female. The prevalences of MDE, AD, and exposure to 3-5 categories of ACEs were 13.7, 10.0, and 12.5%, respectively. After adjusting for covariates (age, race, and current and childhood socioeconomic disadvantage), for those with both risk factors (female and 3-5 ACEs) the prevalence of MDE was 26.9%. This was 10.2% (95% CI: 1.8, 18.5%) higher than the expected prevalence based on the additive associations of the two risk factors. The adjusted prevalence of AD among females with 3-5 ACEs was 21.9%, which was 11.4% (95% CI: 4.0, 18.9%) higher than the expected prevalence. CONCLUSIONS: For both MDE and AD, there was synergy between the two risk factors of exposure to ACEs and being female. Identification and treatment of MDE and AD may benefit from understanding the mechanisms involved in the synergistic interaction of gender with ACEs.

Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways.

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein-protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein-protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways.

Newly Identified Gross Human Anatomy: Eight Paired Vestigial Breast Mounds Run along the Embryological Mammary Ridges in Lean Adults.

Although isolated accessory breasts have been reported in many locations on the torso, we noted that lean men presenting for liposuction had mounds of fullness in a curvilinear array (axilla to groin) consistent with the configuration of the embryological mammary ridge. We hypothesized that grid mapping and pinch testing would elucidate the pattern of fullness and its relation to the "milk line." METHODS: Twenty lean participants (10 men, 10 women) each underwent standardized photography and grid mapping of anterior torsos. We then pinch-tested each for subcutaneous fullness in 250 standardized loci. We used plotted pinch values and OLS regression models to determine if focal fullness corresponded to published configurations of the embryologic mammary ridge. RESULTS: We identified a pattern of paired mounds in all participants running bilaterally in curved linear arrays from axillae to groin in the exact form of milk lines. Regression models applied to the male and female pinch data indicated that focal thickness matched mammary ridge configurations in all subjects (P = 0.023 for men, <0.001 for women). Fatty fullness never appeared elsewhere on the anterior torsos. CONCLUSIONS: The linear pattern of paired focal fat mounds present on the anterior torsos is consistent with the paths of embryological mammary ridges, suggesting these focal fat pads are of breast origin. The consistent mounds are distinct from general subcutaneous fullness and therefore represent a new finding of gross human anatomy. We recommend further research to define differential physiology of distinct subpopulations of yellow fat and clinical implications.

Diabetes distress and glycaemic control in young adults with type 1 diabetes: Associations by use of insulin pumps and continuous glucose monitors.

AIMS: We determined whether high diabetes distress (DD) in young adults with type 1 diabetes was associated with higher glycated haemoglobin (HbA1c ) levels and whether this association was similar among those who were and were not using diabetes devices (insulin pumps and/or continuous glucose monitors [CGMs]). METHODS: In 2017, an online survey was completed by 423 of 743 (57%) young adults (19-31 years) with type 1 diabetes receiving care at a specialty clinic in New York City. HbA1c level was the primary outcome measure, and high DD (Diabetes Distress Scale score ≥3) was the primary exposure. Associations were adjusted for sociodemographic covariates. RESULTS: Of the 419 respondents with complete DD data, 59% were female and 69% were non-Hispanic white. Both devices (pump and CGM) were used by 35%, either device by 42% and neither device by 24%. The mean (SD) HbA1c was 64 (19) mmol/mol (8.0 [1.7] %) and 24% had high DD. The adjusted mean (95% confidence interval) HbA1c was 10 (6, 14) mmol/mol (0.9 [0.5, 1.2] %) greater in those with high DD than in those without it. This HbA1c difference associated with high DD was similar regardless of device use: 9 (3, 15) mmol/mol (0.8 [0.3, 1.4] %) greater among those using both devices; and 9 (-0.9, 18) mmol/mol (0.8 [-0.1, 1.7] %) greater among those using neither device. CONCLUSIONS: High DD in young adults requires more attention because it is associated with higher HbA1c levels, even among those using insulin pumps and CGMs.

Childhood Family Connection and Adult Flourishing: Associations Across Levels of Childhood Adversity.

OBJECTIVE: To investigate whether higher levels of childhood family connection were associated with greater adult flourishing and if this association was present across levels of adverse childhood experiences (ACEs) and childhood socioeconomic disadvantage (SED). METHODS: We pooled cross-sectional data from telephone and mailed surveys in the Midlife in the United States study that were collected from 2 nationally representative cohorts (2004-06 and 2011-14) of English-speaking, US adults, aged 25 to 74 years. Adult flourishing z score, standardized to the study population, was created from Ryff's 42-item Psychological Well-being Scale and quartiles of childhood family connection from a 7-item scale assessing parental attention, affection, and communication during childhood. RESULTS: Data were analyzed for the 4199 (72.0% of 5834) participants with complete data. The mean age of participants was 53.9 years and 85.4% were White. After adjusting for covariates, including adult chronic disease, ACEs, and childhood and current SED, mean (95% CI) flourishing z scores increased from the lowest to highest quartiles of family connection: -0.41 (-0.49, -0.33), -0.18 (-0.25, -0.12), -0.01 (-0.07, 0.06), and 0.25 (0.18, 0.32), respectively. For each 1 SD increase in the family connection score, there was a 0.25 (95% CI, 0.20, 0.29) unit increase in the adjusted flourishing z score. This positive association was also present across levels of ACEs and childhood SED. CONCLUSIONS: Greater childhood family connection was associated with greater flourishing in US adults across levels of childhood adversity. Supporting family connection in childhood may influence flourishing decades later, even with early adversity.

The role of the angle of the fibularis longus tendon in foot arch support.

INTRODUCTION: Understanding the contribution of the fibularis longus tendon to the support of the midfoot arches has potential therapeutic applications. This cadaveric study sought to quantify this support across both the transverse arch and medial longitudinal arch and to establish whether a correlation exists between this support and the angle at which the tendon enters the sole. MATERIALS AND METHODS: Markers placed in 11 dissected cadaveric foot specimens defined the arch boundaries. Incremental weights up to 150 N were applied to the fibularis longus tendon to simulate progressive muscle contraction, and associated changes in the transverse and medial longitudinal arch boundaries were recorded. RESULTS: A force of 150 N reduced the transverse arch distance by 4.6 (1.7) mm (mean [SD]) and medial longitudinal arch distance by 6.8 (1.4) mm. The angle of the fibularis longus tendon on the sole correlated well with changes in the transverse arch distance (slope ± s.e. = 0.56 ± 0.13 mm/degree, Pearson r = .83, p = .002) but only weakly with the medial longitudinal arch (0.18 ± 0.18 mm/degree, r = .32, p = .33). CONCLUSIONS: The results of this preliminary study raise the possibility that physical therapies targeting the fibularis longus tendon may be valuable in the management of midfoot arch collapse. The correlation observed with the transverse arch suggests the possibility that surgical modification of the angle of the fibularis longus tendon on the sole may benefit patients with transverse arch collapse.

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73.

MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.

Viewpoint: do antipsychotics protect against early death? A critical view.

In the past 15 years, researchers utilizing prescription databases to assess medication usage have concluded that antipsychotics reduce mortality in patients diagnosed with schizophrenia and other psychotic disorders. These findings stand in contrast to studies in non-psychiatric patients that have found that antipsychotics, because of their adverse effects on physical health, increase the risk of early death. A critical review of the evidence reveals that the worry remains. There is reason to conclude that antipsychotics contribute to the 'mortality gap' between the seriously mentally ill and the general population and that the database studies are plagued with methodological and reporting issues. Most importantly, the database studies tell of mortality rates within a drug-centered paradigm of care, which confounds any comparison of mortality risks when patients are on or off antipsychotics.

The GTPase Rab27b regulates the release, autophagic clearance, and toxicity of α-synuclein.

α-Synuclein (αsyn) is the primary component of proteinaceous aggregates termed Lewy bodies that pathologically define synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). αsyn is hypothesized to spread through the brain in a prion-like fashion by misfolded protein forming a template for aggregation of endogenous αsyn. The cell-to-cell release and uptake of αsyn are considered important processes for its prion-like spread. Rab27b is one of several GTPases essential to the endosomal-lysosomal pathway and is implicated in protein secretion and clearance, but its role in αsyn spread has yet to be characterized. In this study, we used a paracrine αsyn in vitro neuronal model to test the impact of Rab27b on αsyn release, clearance, and toxicity. shRNA-mediated knockdown (KD) of Rab27b increased αsyn-mediated paracrine toxicity. Rab27b reduced αsyn release primarily through nonexosomal pathways, but the αsyn released after Rab27b KD was of higher-molecular-weight species, as determined by size-exclusion chromatography. Rab27b KD increased intracellular levels of insoluble αsyn and led to an accumulation of endogenous light chain 3 (LC3)-positive puncta. Rab27b KD also decreased LC3 turnover after treatment with an autophagosome-lysosome fusion inhibitor, chloroquine, indicating that Rab27b KD induces a defect in autophagic flux. Rab27b protein levels were increased in brain lysates obtained from postmortem tissues of individuals with PD and DLB compared with healthy controls. These data indicate a role for Rab27b in the release, clearance, and toxicity of αsyn and, ultimately, in the pathogenesis of synucleinopathies.