The Role of Moral Distress on Physician Burnout during COVID-19.

The purpose of this study was to explore the role of moral distress on physician burnout during COVID-19. Physicians in the US were interviewed between February and March 2021; 479 responded to our survey. The results indicated that moral distress was a key mediator in explaining the relationship between perceived organizational support, medical specialization, emotional labor, and coping with burnout. Results did not support increased burnout among female physicians, and contracting COVID-19 likewise did not play a role in burnout. Our findings suggest that physician burnout can be mitigated by increasing perceived organizational support; likewise, physicians who engaged in deep emotional labor and problem-focused coping tended to fare better when it came to feelings of moral distress and subsequent burnout.

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors.

The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma.

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799-808. ©2016 AACR.

Who is most vulnerable to social rejection? The toxic combination of low self-esteem and lack of negative emotion differentiation on neural responses to rejection.

People have a fundamental need to belong that, when satisfied, is associated with mental and physical well-being. The current investigation examined what happens when the need to belong is thwarted-and how individual differences in self-esteem and emotion differentiation modulate neural responses to social rejection. We hypothesized that low self-esteem would predict heightened activation in distress-related neural responses during a social rejection manipulation, but that this relationship would be moderated by negative emotion differentiation-defined as adeptness at using discrete negative emotion categories to capture one's felt experience. Combining daily diary and neuroimaging methodologies, the current study showed that low self-esteem and low negative emotion differentiation represented a toxic combination that was associated with stronger activation during social rejection (versus social inclusion) in the dorsal anterior cingulate cortex and anterior insula-two regions previously shown to index social distress. In contrast, individuals with greater negative emotion differentiation did not show stronger activation in these regions, regardless of their level of self-esteem; fitting with prior evidence that negative emotion differentiation confers equanimity in emotionally upsetting situations.

Justice for the average Joe: the role of envy and the mentalizing network in the deservingness of others' misfortunes.

The misfortunes of enviable individuals are met by observers with pleasure whereas those of "average", non-enviable individuals elicit pain. These responses are mirrored in deservingness judgments, as enviable individuals' misfortunes are perceived as deserved and those of non-enviable individuals perceived as undeserved. However, the neural underpinnings of these deservingness disparities remain unknown. To explore this phenomenon, we utilized fMRI to test the hypotheses that (A) non-enviable targets' misfortunes would be associated with activation of brain regions that mediate empathic responding (pain matrix, mentalizing network) and not for enviable targets and (B) that activation of those regions would predict decreases in deservingness judgments. Supporting our first hypothesis, the misfortunes of non-enviable targets (as opposed to good fortunes) were associated with activation of the mentalizing network: medial prefrontal cortex, posterior cingulate cortex, temporal-parietal junction, and anterior temporal lobes. Supporting our second hypothesis, dorsomedial prefrontal cortex activation from this contrast was negatively correlated with subsequent reports of how much the non-enviable target deserved his/her misfortune. These findings suggest that non-enviable individuals' misfortunes are perceived as unjust due, in part, to the recruitment of the mentalizing network.

Do neural responses to rejection depend on attachment style? An fMRI study.

Social bonds fulfill the basic human need to belong. Being rejected thwarts this basic need, putting bonds with others at risk. Attachment theory suggests that people satisfy their need to belong through different means. Whereas anxious attachment is associated with craving acceptance and showing vigilance to cues that signal possible rejection, avoidant attachment is associated with discomfort with closeness and using avoidant strategies to regulate one's relationships. Given these different styles by which people satisfy their need to belong (that can operate simultaneously within the same individual), responses to social rejection may differ according to these individual differences in attachment anxiety and avoidance. To test this hypothesis, we used neuroimaging techniques to examine how the degree to which people display each of the two attachment dimensions (anxiety and avoidance) uniquely correlated with their neural activity during a simulated experience of social exclusion. Anxious attachment related to heightened activity in the dorsal anterior cingulate cortex (dACC) and anterior insula, regions previously associated with rejection-related distress. In contrast, avoidant attachment related to less activity in these regions. Findings are discussed in terms of the strategies that individuals with varying attachment styles might use to promote maintenance of social bonds.

Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels.

Photocrosslinkable biomaterials are promising for tissue engineering applications due to their capacity to be injected and form hydrogels in situ in a minimally invasive manner. Our group recently reported on the development of photocrosslinked alginate hydrogels with controlled biodegradation rates, mechanical properties, and cell adhesive properties. In this study, we present an affinity-based growth factor delivery system by incorporating heparin into photocrosslinkable alginate hydrogels (HP-ALG), which allows for controlled, prolonged release of therapeutic proteins. Heparin modification had minimal effect on the biodegradation profiles, swelling ratios, and elastic moduli of the hydrogels in media. The release profiles of growth factors from this affinity-based platform were sustained for 3weeks with no initial burst release, and the released growth factors retained their biological activity. Implantation of bone morphogenetic protein-2 (BMP-2)-loaded photocrosslinked alginate hydrogels induced moderate bone formation around the implant periphery. Importantly, BMP-2-loaded photocrosslinked HP-ALG hydrogels induced significantly more osteogenesis than BMP-2-loaded photocrosslinked unmodified alginate hydrogels, with 1.9-fold greater peripheral bone formation and 1.3-fold greater calcium content in the BMP-2-loaded photocrosslinked HP-ALG hydrogels compared to the BMP-2-loaded photocrosslinked unmodified alginate hydrogels after 8weeks implantation. This sustained and controllable growth factor delivery system, with independently controllable physical and cell adhesive properties, may provide a powerful modality for a variety of therapeutic applications.

Acetaminophen reduces social pain: behavioral and neural evidence.

Pain, whether caused by physical injury or social rejection, is an inevitable part of life. These two types of pain-physical and social-may rely on some of the same behavioral and neural mechanisms that register pain-related affect. To the extent that these pain processes overlap, acetaminophen, a physical pain suppressant that acts through central (rather than peripheral) neural mechanisms, may also reduce behavioral and neural responses to social rejection. In two experiments, participants took acetaminophen or placebo daily for 3 weeks. Doses of acetaminophen reduced reports of social pain on a daily basis (Experiment 1). We used functional magnetic resonance imaging to measure participants' brain activity (Experiment 2), and found that acetaminophen reduced neural responses to social rejection in brain regions previously associated with distress caused by social pain and the affective component of physical pain (dorsal anterior cingulate cortex, anterior insula). Thus, acetaminophen reduces behavioral and neural responses associated with the pain of social rejection, demonstrating substantial overlap between social and physical pain.

Biodegradable, photocrosslinked alginate hydrogels with independently tailorable physical properties and cell adhesivity.

Biocompatible polymers capable of photopolymerization are of immense interest for tissue engineering applications as they can be injected in a minimally invasive manner into a defect site and, then upon application of ultraviolet light, rapidly form hydrogels in situ. Cell adhesion interactions with a biomaterial are known to be important in regulating cell behaviors such as proliferation and differentiation. Therefore, we have covalently modified photocrosslinkable alginate with cell adhesion ligands containing the Arg-Gly-Asp amino acid sequence to form biodegradable, photocrosslinked alginate hydrogels with controlled cell adhesivity. This unique polymer system allows for independent modulation of the physical and biochemical signaling environment presented to cells. The physical properties of the hydrogels such as elastic moduli, swelling ratios, and degradation profiles were similar at the same crosslinking density regardless of the presence of adhesion ligands. Chondrocytes seeded on the surface of the adhesion ligand-modified hydrogels were able to attach and spread, whereas those seeded on unmodified hydrogels exhibited minimal adherence. Importantly, the adhesion-ligand-modified hydrogels enhanced the proliferation and chondrogenic differentiated function of encapsulated chondrocytes as demonstrated by increased DNA content and production of glycosaminoglycans compared to unmodified control hydrogels. This new photocrosslinkable, biodegradable biomaterial system in which the soluble (e.g., growth factors) and insoluble (e.g., cell adhesion ligands) biochemical signaling environment and the biomaterial physical properties (e.g., the elastic moduli) can be independently controlled may be a powerful tool for elucidating the individual and combined effects of these parameters on cell function for cartilage tissue engineering and other regenerative medicine applications.

Relativistic origins of emotional reactions to events happening to others and to ourselves.

The purpose of the present study was to show that people's emotional reactions to both good and bad events happening to others can be influenced by how their own experiences compare with these events. Female undergraduate students took a test of intellectual ability and received false feedback suggesting that they had done well or poorly. Later, they viewed written feedback apparently given to another participant suggesting that she had performed well or poorly. Finally, participants gave their emotional reactions to their own performance as well as the performance of the other participant. Results showed that participants' relative performance influenced how happy they felt for the high performing other participant and how sad they felt for the low performing other participant. Participants' self-focused emotions of pride and shame were also affected by the relative performance of the other participant.