"Make the Implicit Explicit": Measuring Perceptions of Gender Bias and Creating a Gender Bias Curriculum for Internal Medicine Residents.

BACKGROUND: Gender bias in clinical training has been well established; however, little is known about how perceptions differ between men and women. Furthermore, few curricular options have been developed to discuss gender bias. OBJECTIVE: To measure the prevalence of gender bias, examine qualitative differences between men and women, and create a gender bias curriculum for internal medicine residents. METHODS: We surveyed 114 residents (response rate of 53.5%) to identify the prevalence and types of gender bias experienced in training. We compared estimates between genders and organized qualitative results into shared themes. We then developed a curriculum to promote and normalize discussions of gender bias. RESULTS: Among surveyed residents, 61% reported personal experiences of gender bias during training, with 98% of women and 19% of men reporting experiences when stratified by gender. We identified two domains in which gender bias manifested: role misidentification and a difficult working environment. Residents identified action items that led to the development of a gender bias curriculum. The curriculum includes didactic conferences and training sessions, a microaggression response toolkit, dinners for men and women residents, participation in a WhatsApp support group, and participation in academic projects related to gender bias in training. CONCLUSION: We confirmed a wide prevalence of gender bias and developed a scalable curriculum for gender bias training. Future work should explore the long-term impacts of these interventions.

Fostering Meaning in Residency to Curb the Epidemic of Resident Burnout: Recommendations From Four Chief Medical Residents.

Burnout has become commonplace in residency training, affecting more than half of residents and having negative implications for both their well-being and their ability to care for patients. During the authors' year as chief medical residents at Brigham and Women's Hospital in 2017-2018, they became intimately familiar with the burnout epidemic in residency training. The authors argue that addressing resident burnout requires residency programs and teaching hospitals to focus not on the individual contributors to burnout but instead on fostering meaning within residency to help residents find purpose and professional satisfaction in their work. In this Perspective, they highlight 4 important elements of residency that provide meaning: patient care, intellectual engagement, respect, and community. Patient care, intellectual engagement, and community provide residents with a focus that is larger than themselves, while respect is necessary for a resident's sense of belonging. The authors provide examples from their own experiences and from the literature to suggest ways in which residency programs and teaching hospitals can strengthen each of these elements within residency and curb the epidemic of burnout.

Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy.

Several phosphorylation signaling pathways have been implicated in the pathogenesis of epilepsy arising from both genetic causes and acquired insults to the brain. Identification of dysfunctional signaling pathways in epilepsy may provide novel targets for antiepileptic therapies. We previously described a deficit in phosphorylation signaling mediated by p38 mitogen-activated protein kinase (p38 MAPK) that occurs in an animal model of temporal lobe epilepsy, and that produces neuronal hyperexcitability measured in vitro. We asked whether in vivo pharmacological manipulation of p38 MAPK activity would influence seizure frequency in chronically epileptic animals. Administration of a p38 MAPK inhibitor, SB203580, markedly worsened spontaneous seizure frequency, consistent with prior in vitro results. However, anisomycin, a non-specific p38 MAPK activator, significantly increased seizure frequency. We hypothesized that this unexpected result was due to activation of a related MAPK, c-Jun N-terminal kinase (JNK). Administration of JNK inhibitor SP600125 significantly decreased seizure frequency in a dose-dependent manner without causing overt behavioral abnormalities. Biochemical analysis showed increased JNK expression and activity in untreated epileptic animals. These results show for the first time that JNK is hyperactivated in an animal model of epilepsy, and that phosphorylation signaling mediated by JNK may represent a novel antiepileptic target.

Comparative efficacy of combination drug therapy in refractory epilepsy.

OBJECTIVE: We retrospectively examined treatment records of developmentally disabled adults with highly refractory epilepsy to determine whether any combinations of 8 of the most commonly used antiepileptic drugs (AEDs) possessed superior efficacy. METHODS: We obtained the treatment records from 148 developmentally disabled adults with refractory epilepsy cared for in 2 state-run institutions. These records charted monthly convulsive seizure occurrence and AED regimen over 30 years. We studied the effects of 8 commonly used AEDs alone and in combination on seizure frequency in within-patient comparisons. RESULTS: Out of the 32 most frequently used AED combinations, we found that only the combination of lamotrigine and valproate had superior efficacy, measured against both an aggregate measure of other AED regimens to which patients were exposed, and in head-to-head comparisons with other AED combinations. We also found that while use of 2 concurrent AEDs provided improved efficacy over monotherapy, use of 3 AEDs at a time provided no further benefit over two. CONCLUSIONS: These results suggest that at least one AED regimen provides significantly better efficacy in refractory convulsive epilepsy, and that AEDs should be used no more than 2 at a time. Limitations of the study include its retrospective design, lack of randomization, and small sample sizes for some drug combinations. Future prospective trials are needed in this challenging clinical population.

Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus.

Epilepsy is associated with loss of expression and function of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels. Previously, we showed that loss of HCN channel-mediated current (I(h)) occurred in the dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced status epilepticus (SE), accompanied by loss of HCN1 channel protein expression. However, the precise onset and mechanistic basis of HCN1 channel loss post-SE was unclear, particularly whether it preceded the onset of spontaneous recurrent seizures and could contribute to epileptogenesis or development of the epileptic state. Here, we found that loss of I(h) and HCN1 channel expression began within an hour after SE and involved sequential processes of dendritic HCN1 channel internalization, delayed loss of protein expression, and later downregulation of mRNA expression. We also found that an in vitro SE model reproduced the rapid loss of dendritic I(h), demonstrating that this phenomenon was not specific to in vivo SE. Together, these results show that HCN1 channelopathy begins rapidly and persists after SE, involves both transcriptional and nontranscriptional mechanisms, and may be an early contributor to epileptogenesis.

Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling.

The onset of spontaneous seizures in the pilocarpine model of epilepsy causes a hyperpolarized shift in the voltage-dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (Ih) in CA1 hippocampal pyramidal neuron dendrites, contributing to neuronal hyperexcitability and possibly to epileptogenesis. However, the specific mechanisms by which spontaneous seizures cause downregulation of HCN channel gating are yet unknown. We asked whether the seizure-dependent downregulation of HCN channel gating was due to altered phosphorylation signaling mediated by the phosphatase calcineurin (CaN) or the kinase p38 mitogen-activated protein kinase (p38 MAPK). We first found that CaN inhibition upregulated HCN channel gating and reduced neuronal excitability under normal conditions, showing that CaN is a strong modulator of HCN channels. We then found that an in vitro model of seizures (1 h in 0 Mg2+ and 50 microM bicuculline at 35-37 degrees C) reproduced the HCN channel gating change seen in vivo. Pharmacological inhibition of CaN or activation of p38 MAPK partially reversed the in vitro seizure-induced hyperpolarized shift in HCN channel gating, and the shift was fully reversed by the combination of CaN inhibition and p38 MAPK activation. We then demonstrated enhanced CaN activity as well as reduced p38 MAPK activity in vivo in the CA1 hippocampal area of chronically epileptic animals. Pharmacological reversal of these phosphorylation changes restored HCN channel gating downregulation and neuronal hyperexcitability in epileptic tissue to control levels. Together, these results suggest that alteration of two different phosphorylation pathways in epilepsy contributes to the downregulation of HCN channel gating, which consequently produces neuronal hyperexcitability and thus may be a target for novel antiepileptic therapies.