The Chicagoland Free Clinics Consortium: A Model for Student-Run Free Clinic Collaboration.

BACKGROUND: While student-run free clinics (SRFCs) play an important role in care for underserved populations, few mechanisms exist to promote collaboration among regional SRFCs. AIMS: To address this gap, the Chicagoland Free Clinics Consortium (CFCC) was formed to (1) facilitate collaboration between Chicagoland SRFCs, (2) provide innovation grant funding, and (3) host an annual conference. SETTING AND PARTICIPANTS: In 2018, students from the Pritzker School of Medicine founded the CFCC and partnered with peers from area schools to implement programming. PROGRAM DESCRIPTION: Between 2018 and 2022, CFCC engaged 23 SRFCs representing all 6 Chicagoland schools, held 4 annual conferences, and distributed $15,423 in grants to 19 projects at 14 SRFC sites. PROGRAM EVALUATION: A total of 176 students from 5 schools attended the 4 conferences. In 2022, 82 unique participants were surveyed, and 66% (54/82) responded. Eighty percent (43/54) reported they were "more likely to collaborate with other Chicagoland free clinics." In 2022, all grant sites were surveyed and 84% (16/19) responded. Most (87%,14/16) agreed the grant "allowed them to implement a project that would not have otherwise been accomplished" and 21% (4/19) were inter-institutional collaborations. DISCUSSION: To our knowledge, CFCC is the first student-led organization to promote sustained collaboration across SRFCs in a metropolitan area.

Eliminating Explicit and Implicit Biases in Health Care: Evidence and Research Needs.

Health care providers hold negative explicit and implicit biases against marginalized groups of people such as racial and ethnic minoritized populations. These biases permeate the health care system and affect patients via patient-clinician communication, clinical decision making, and institutionalized practices. Addressing bias remains a fundamental professional responsibility of those accountable for the health and wellness of our populations. Current interventions include instruction on the existence and harmful role of bias in perpetuating health disparities, as well as skills training for the management of bias. These interventions can raise awareness of provider bias and engage health care providers in establishing egalitarian goals for care delivery, but these changes are not sustained, and the interventions have not demonstrated change in behavior in the clinical or learning environment. Unfortunately, the efficacy of these interventions may be hampered by health care providers' work and learning environments, which are rife with discriminatory practices that sustain the very biases US health care professions are seeking to diminish. We offer a conceptual model demonstrating that provider-level implicit bias interventions should be accompanied by interventions that systemically change structures inside and outside the health care system if the country is to succeed in influencing biases and reducing health inequities.

Impact of the Early Phase of the COVID-19 Pandemic on Medical Student Well-Being: a Multisite Survey.

BACKGROUND: The COVID-19 pandemic drastically impacted medical student experiences. Little is known about the impact of the pandemic on student well-being and protective factors for burnout. OBJECTIVE: Assess US medical student burnout, stress, and loneliness during the initial phase of the pandemic, compare results to pre-pandemic data, and identify risk factors for distress and protective factors to inform support interventions. DESIGN: Cross-sectional survey of medical students conducted between May and July 2020. PARTICIPANTS: 3826 students from 22 medical schools. MAIN MEASURES: Burnout (MBI-HSS), stress (PSS-10), loneliness (UCLA scale), and student experiences. Compared burnout and stress to pre-pandemic studies (2010-2020). KEY RESULTS: Of 12,389 students, 3826 responded (31%). Compared to pre-pandemic studies, burnout was lower (50% vs. 52%, P = 0.03) while mean stress was higher (18.9 vs. 16.0, P < 0.001). Half (1609/3247) reported high (≥ 6/9) loneliness scores. Significant differences were found in burnout and stress by class year (P = 0.002 and P < 0.001) and race (P = 0.004 and P < 0.001), with the highest levels in second- and third-year students and Black, Asian, or other racial minority students. Students experiencing financial strain or racism had higher burnout and stress (P < 0.001 for all). Respondents with COVID-19 diagnoses in themselves or family members had higher stress (P < 0.001). Nearly half (1756/3569) volunteered during the pandemic, with volunteers reporting lower burnout [48% (782/1639) vs. 52% (853/1656), P = 0.03]. CONCLUSIONS: While stress was higher compared to pre-pandemic data, burnout was significantly lower. Higher burnout and stress among Black, Asian, and other racial minority students and those who experienced financial strain, racism, or COVID-19 diagnoses likely reflect underlying racial and socioeconomic inequalities exacerbated by the pandemic and concurrent national racial injustice events. Volunteer engagement may be protective against burnout. Schools should proactively support vulnerable students during periods of stress.

mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain.

The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.

Dysregulation of the unfolded protein response (UPR) in the dorsolateral prefrontal cortex in elderly patients with schizophrenia.

Abnormalities in protein localization, function, and posttranslational modifications are targets of schizophrenia (SCZ) research. As a major contributor to the synthesis, folding, trafficking, and modification of proteins, the endoplasmic reticulum (ER) is well-positioned to sense cellular stress. The unfolded protein response (UPR) is an evolutionarily conserved adaptive reaction to environmental and pathological perturbation in ER function. The UPR is a highly orchestrated and complex cellular response, which is mediated through the ER chaperone protein, BiP, three known ER transmembrane stress sensors, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), inositol requiring enzyme 1α (IRE1α), and their downstream effectors. In this study, we measured protein expression and phosphorylation states of UPR sensor pathway proteins in the dorsolateral prefrontal cortex (DLPFC) of 22 matched pairs of elderly SCZ and comparison subjects. We observed increased protein expression of BiP, decreased PERK, and decreased phosphorylation of IRE1α. We also observed decreased p-JNK2 and increased sXBP1, downstream targets of the IRE1α arm of the UPR. The disconnect between decreased p-IRE1α and increased sXBP1 protein expression led us to measure sXbp1 mRNA. We observed increased expression of the ratio of sXbp1/uXbp1 transcripts, suggesting that splicing of Xbp1 mRNA by IRE1α is increased and drives upregulation of sXBP1 protein expression. These findings suggest an abnormal pattern of UPR activity in SCZ, with specific dysregulation of the IRE1α arm. Dysfunction of this system may lead to abnormal responses to cellular stressors and contribute to protein processing abnormalities previously observed in SCZ.

Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity.

While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser-capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed overrepresented groups of gene sets in schizophrenia, particularly in immunity and synapse-related pathways, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected other pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, postsynaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. Considering the effects of antipsychotic treatment on gene expression, we applied a novel bioinformatics approach to compare our differential expression gene profiles with 51 antipsychotic treatment datasets, demonstrating that our results were not influenced by antipsychotic treatment. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.

Differential genetic associations and expression of PAPST1/SLC35B2 in bipolar disorder and schizophrenia.

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system.

Intracellular compartment-specific proteasome dysfunction in postmortem cortex in schizophrenia subjects.

Protein homeostasis is an emerging component of schizophrenia (SZ) pathophysiology. Proteomic alterations in SZ are well-documented and changes in transcript expression are frequently not associated with changes in protein expression in SZ brain. The underlying mechanism driving these changes remains unknown, though altered expression of ubiquitin proteasome system (UPS) components have implicated protein degradation. Previous studies have been limited to protein and transcript expression, however, and do not directly test the function of the proteasome. To address this gap in knowledge, we measured enzymatic activity associated with the proteasome (chymotrypsin-, trypsin-, and caspase-like) in the superior temporal gyrus (STG) of 25 SZ and 25 comparison subjects using flourogenic substrates. As localization regulates which cellular processes the proteasome contributes to, we measured proteasome activity and subunit expression in fractions enriched for nucleus, cytosolic, and membrane compartments. SZ subjects had decreased trypsin-like activity in total homogenate. This finding was specific to the nucleus-enriched fraction and was not associated with changes in proteasome subunit expression. Interestingly, both chymotrypsin-like activity and protein expression of 19S RP subunits, which facilitate ubiquitin-dependent degradation, were decreased in the cytosol-enriched fraction of SZ subjects. Intracellular compartment-specific proteasome dysfunction implicates dysregulation of protein expression both through altered ubiquitin-dependent degradation of cytosolic proteins and regulation of protein synthesis due to degradation of transcription factors and transcription machinery in the nucleus. Together, these findings implicate proteasome dysfunction in SZ, which likely has a broad impact on the proteomic landscape and cellular function in the pathophysiology of this illness.

Accounting for complexity in medical education: a model of adaptive behaviour in medicine.

CONTEXT: Medicine is practised in complex systems. Physicians engage in clinical and operational problems that are dynamic and lack full transparency. As a consequence, the behaviour of medical systems and diseases is often unpredictable. Medical science has equipped physicians with powerful tools to favourably impact health, but a reductionist approach alone is insufficient to optimally address the complex challenges posed by illness and public health. Concepts from complexity science, such as continuous quality improvement and teamwork, strive to fill the gap between biomedical knowledge and the realities of practice. However, the superficial treatment of these systems-thinking concepts in medical education has distorted their implementation and undermined their impact. 'Systems thinking' has been conflated with 'systematic thinking'; concepts which are adaptive in nature are being taught as standardised, reductionist tools. METHODS: Using concepts from complexity science, the history of science and psychology, this problem is outlined and a theoretical model of professional development is proposed. RESULTS: This model proposes that complex problem solving and adaptive behaviour, not technical expertise, are distinguishing features of professionalism. DISCUSSION: The impact of this model on our understanding of physician autonomy, professionalism, teamwork and continuous quality improvement is discussed. This model has significant implications for the structure and content of medical education. Strategies for enhancing medical training, including interventions in recruitment, the curriculum and evaluation, are reviewed. Such adjustments would prepare trainees to more effectively utilise biomedical knowledge and tools in the complex high-stakes reality of medical practice.

Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide.

OBJECTIVES: In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls. METHOD: We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls. RESULTS: Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p < 0.01) and GRIN2C mRNA (laminae I-VI; -27%, p < 0.05) were lower in the anterior cingulate cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral prefrontal cortex (-19%, p < 0.01). In major depressive disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower (-35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex. CONCLUSION: These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine.

Enhancing the Graduate Medical Education Clinical Learning Environment Through Community of Practice Forums.

ABSTRACT: An optimal clinical learning environment (CLE) is associated with improved learning and patient care outcomes. Significant concerns exist about the state of the CLE in graduate medical education (GME). Research suggests GME programming falls short in interpersonal aspects of training that promote trainee engagement and psychological safety. Furthermore, published educational interventions in the CLE lack adequate theoretical backing to inform a rational approach to interventions in the CLE that could address these important problems.The authors apply the 2002 work of Etienne Wenger on communities of practice (COP) to address these GME CLE concerns. To distinguish this COP intervention from earlier theoretical work on COPs, the authors refer to this management concept as "COP forums." COP forums favorably influence the GME CLE through effects that complement experiential learning in patient care. COP forums support trainee psychological safety, mentorship from near peers, and opportunities to innovate-effects that can serve as a counterbalance to the time pressures, hierarchy, and compliance culture often experienced in the clinical environment. Deliverables of COP forums, including practice innovation and trainee self-efficacy, can favorably impact organization-wide performance and engagement.This article describes the historical position of COP forums in the evolution of COP theory and outlines the basic structure and function of COP forums. It contrasts COP forums to other COP-related concepts to explain their relevance to the GME CLE. Examples of innovative GME COP forums illustrate the structure and function of these interventions. Finally, the authors call for more research on the impact of COP forums on the GME CLE. To avoid confusion, such scholarship must account for the ongoing evolution of the larger COP framework and target specific dimensions of the theory most pertinent to the medical education research question at hand.

Application in Parallel to U.S. Residency Training Programs in Multiple Specialties: Trends and Differences by Applicant Educational Background, 2009-2021.

PURPOSE: The medical education community is pursuing reforms addressing unsustainable growth in the number of residency applications per applicant and application costs. Little research has examined the prevalence or contributions of parallel applications (application to residency in multiple specialties) to this growth. METHOD: A retrospective analysis of Electronic Residency Application Service® data provided by the Association of American Medical Colleges was conducted. The percentage of applicants applying to ≥1 specialty, mean number of specialties applied, number of submitted applications, and percentage of applicants to each specialty who were parallel applying were determined. MD, DO, and international (U.S. international medical graduate [IMG] and IMG) applicants were included. RESULTS: The sample contained 586,246 applicant records from 459,704 unique applicants. The percentage of applicants who parallel applied decreased from 41.3% to 35.4% between 2009 and 2021. DO applicants were the only group for whom the percentage parallel applying increased (30.6% vs. 32.1%). IMG (60.4% vs. 49.1%) or USIMG applicants (69.6% vs. 63.1%) were groups with the greatest percentage of applicants parallel applying each year (2009-2021). The mean number of specialties applied to when parallel applying also decreased from 2.96 in 2009 to 2.79 in 2021, overall. Between 2009 and 2021, mean number of applications increased for all applicant types amongst both single-specialty applicant and parallel-applying applicants. Among applicants who were single-specialty applying, mean number of applications grew from 38.6 in 2009 to 74.6 in 2021 and from 95.2 to 149.8 for parallel-applying applicants. CONCLUSIONS: All applicant groups experienced decreases in percentages parallel applying except for DO applicants. Parallel application appears to be common and slowly declining, and does not appear to significantly contribute to increasing numbers of applications per candidate. Efforts to control the growth of applications per applicant should continue to focus on applicants' numbers of applications submitted to each specialty.

Supplementing cross-cover communication with the patient acuity rating.

BACKGROUND: Patient hand-offs at physician shift changes have limited ability to convey the primary team's longitudinal insight. The Patient Acuity Rating (PAR) is a previously validated, 7-point scale that quantifies physician judgment of patient stability, where a higher score indicates a greater risk of clinical deterioration. Its impact on cross-covering physician understanding of patients is not known. OBJECTIVE: To determine PAR contribution to sign-outs. DESIGN: Cross-sectional survey. SUBJECTS: Intern physicians at a university teaching hospital. INTERVENTIONS: Subjects were surveyed using randomly chosen, de-identified patient sign-outs, previously assigned PAR scores by their primary teams. For each sign-out, subjects assigned a PAR score, then responded to hypothetical cross-cover scenarios before and after being informed of the primary team's PAR. MAIN MEASURE: Changes in intern assessment of the scenario before and after being informed of the primary team's PAR were measured. In addition, responses between novice and experienced interns were compared. KEY RESULTS: Between May and July 2008, 23 of 39 (59 %) experienced interns and 25 of 42 (60 %) novice interns responded to 480 patient scenarios from ten distinct sign-outs. The mean PAR score assigned by subjects was 4.2 ± 1.6 vs. 3.8 ± 1.8 by the primary teams (p < 0.001). After viewing the primary team's PAR score, interns changed their level of concern in 47.9 % of cases, their assessment of the importance of immediate bedside evaluation in 48.7 % of cases, and confidence in their assessment in 43.2 % of cases. For all three assessments, novice interns changed their responses more frequently than experienced interns (p = 0.03, 0.009, and <0.001, respectively). Overall interns reported the PAR score to be theoretically helpful in 70.8 % of the cases, but this was more pronounced in novice interns (81.2 % vs 59.6 %, p < 0.001). CONCLUSIONS: The PAR adds valuable information to sign-outs that could impact cross-cover decision-making and potentially benefit patients. However, correct training in its use may be required to avoid unintended consequences.

Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy.

PURPOSE: Increased interictal concentrations of extracellular hippocampal glutamate have been implicated in the pathophysiology of temporal lobe epilepsy (TLE). Recent studies suggest that perturbations of the glutamate metabolizing enzymes glutamine synthetase (GS) and phosphate activated glutaminase (PAG) may underlie the glutamate excess in TLE. However, the molecular mechanism of the enzyme perturbations remains unclear. A better understanding of the regulatory mechanisms of GS and PAG could facilitate the discovery of novel therapeutics for TLE. METHODS: We used in situ hybridization on histologic sections to assess the distribution and quantity of messenger RNA (mRNA) for GS and PAG in subfields of hippocampal formations from the following: (1) patients with TLE and concomitant hippocampal sclerosis, (2) patients with TLE and no hippocampal sclerosis, and (3) nonepilepsy autopsy subjects. KEY FINDINGS: GS mRNA was increased by ~50% in the CA3 in TLE patients without hippocampal sclerosis versus in TLE patients with sclerosis and in nonepilepsy subjects. PAG mRNA was increased by >100% in the subiculum in both TLE patient categories versus in nonepilepsy subjects. PAG mRNA was also increased in the CA1, CA2, CA3, and dentate hilus in TLE without hippocampal sclerosis versus in TLE with sclerosis. Finally, PAG mRNA was increased in the dentate gyrus in TLE with sclerosis versus in nonepilepsy subjects, and also increased in the hilus in TLE without sclerosis versus in TLE with sclerosis. SIGNIFICANCE: These findings demonstrate complex changes in the expression of mRNAs for GS and PAG in the hippocampal formation in TLE, and raise the possibility that both transcriptional and posttranscriptional mechanisms may underlie the regulation of GS and PAG proteins in the epileptic brain.