A Case-Based, Longitudinal Curriculum in Pediatric Behavioral and Mental Health.

Introduction: Pediatric behavioral and mental health (BMH) disorders are increasingly common, but most pediatricians feel inadequately trained to manage them. We implemented a case-based, longitudinal curriculum in BMH within a pediatric residency program to prepare trainees to diagnose and manage these conditions. Methods: The pediatric residency program at Wright State University/Wright-Patterson Medical Center implemented a new BMH curriculum in 2020-2021. The curriculum consisted of five simulated cases involving depression, anxiety, attention deficit disorder with hyperactivity (ADHD), developmental delays, behavioral concerns, and autism. To reflect follow-up within a continuity clinic, cases included initial encounters and multiple follow-up visits. Faculty facilitators led residents in monthly small-group meetings over the academic year, with each session consisting of two to three simulated patient encounters. Residents completed pre-post surveys regarding their confidence in diagnosing and managing BMH conditions and pre- and posttests to evaluate the impact of the curriculum on knowledge gains. Results: All 47 pediatric residents participated in the curriculum; 38 (81%) completed pre-post surveys. Upon completion of the curriculum, residents reported significantly increased confidence in managing ADHD, treating depression, creating safety plans for suicidality, recognizing autism, and counseling patients and families on special education services. Knowledge-based pre- and posttests completed by 25 residents (53%) also demonstrated significant improvement (M = 92.4, SD = 10.9, pre vs. M = 99.3, SD = 6.6, post, p = .009). Discussion: This case-based, longitudinal curriculum in pediatric BMH simulating patient continuity improved residents' confidence and knowledge in diagnosing and managing common BMH conditions.

Interprofessional Education in Child and Adolescent Mental Health: A Scoping Review.

To identify elements of effective interprofessional education (IPE) within child and adolescent mental health (CAMH), we conducted a scoping literature review. A search of four databases revealed 32 studies that met inclusion criteria describing IPE interventions regarding CAMH. Studies included a range of medical, mental health, allied health, educational, and community professionals in clinical, school-based, and community-based settings. The majority of studies have focused on autism or general child mental health. Outcomes were generally positive but skewed toward attitudinal and knowledge-based measures. Practice-based interventions tended to support higher levels of educational outcomes, including behavioral, patient-level, or systems-level changes.

Defragmenting the Day: The Effect of Full-Day Continuity Clinics on Continuity of Care and Perceptions of Clinic.

PROBLEM: Traditional half-day continuity clinics within primary care residency programs require residents to split time between their assigned clinical rotation and continuity clinic, which can have detrimental effects on resident experiences and patient care within continuity clinics. Most previous efforts to separate inpatient and outpatient obligations have employed block scheduling models, which entail significant rearrangements to clinical rotations, team structures, and didactic education and have yielded mixed effects on continuity of care. A full-day continuity clinic schedule within a traditional, non-block rotation framework holds potential to de-conflict resident schedules without the logistical rearrangements required to adopt block scheduling models, but no literature has described the effect of such full-day continuity clinics on continuity of care or resident experiences within continuity clinic. INTERVENTION: A pediatric residency program implemented full-day continuity clinics within a traditional rotation framework. We examined the change in continuity for physician (PHY) measure in the six months prior to versus the six months following the switch, as well as changes in how often residents saw clinic patients in follow-up and personally followed up clinic laboratory and radiology results, which we term episodic follow-up. Resident and attending perceptions of full-day continuity clinics were measured using a survey administered 5-7 months after the switch. CONTEXT: The switch to full-day continuity clinics occurred in January 2018 within the Wright State University/Wright-Patterson Medical Center Pediatric Residency Program. The program has 46 residents who are assigned to one of two continuity clinic sites, each of which implemented the full-day continuity clinics simultaneously. OUTCOME: The PHY for residents at one clinic decreased slightly from 18.0% to 13.6% (p<.001) with full-day continuity clinics but was unchanged at another clinic [60.6% vs 59.5%, p=.86]. Measures of episodic follow-up were unchanged. Residents (32/46 = 77% responding) and attendings (6/8 = 75% responding) indicated full-day continuity clinics improved residents' balance of inpatient and outpatient obligations, preparation for clinic, continuity relationships with patients, and clinic satisfaction. LESSONS LEARNED: Full-day continuity clinics within a traditional rotation framework had mixed effects on continuity of care but improved residents' experiences within clinic. This model offers a viable alternative to block scheduling models for primary care residency programs wishing to defragment resident schedules.Supplemental data for this article is available online at https://doi.org/10.1080/10401334.2021.1879652.

Whose Patient Is This? A Scoping Review of Patient Ownership.

PURPOSE: The scope of physicians' responsibility toward patients is becoming increasingly complicated to delimit as interdisciplinary care delivery and degrees of subspecialization increase. Patients can easily be lost across multiple transitions involved in care. Preparing learners to engage in safe and responsible patient care requires that we be clear about parameters of patient ownership. This scoping review (1) explores and synthesizes definitions of patient ownership and (2) describes the factors that influence patient ownership. METHOD: Searching PubMed, Embase, and PsycINFO, the authors sought out publications of any format (i.e., original research papers, review articles, commentaries, editorials, and author discussions) that (1) addressed patient ownership directly or a closely related concept that explicitly affected patient ownership, (2) included medical care providers (attending/faculty physicians, medical residents, and/or medical students), and (3) were published in English. The authors analyzed findings to construct common themes and categorize findings. RESULTS: Of 411 papers screened, 82 met our inclusion criteria. Twenty-three papers defined patient ownership in highly variable ways. Common themes across definitions included responsibility for patient care, personally carrying out patient care tasks, knowledge of patients' medical information, independent decision making, and putting patients' needs above one's own. Factors influencing patient ownership were (1) logistical concerns, (2) personal attributes, and (3) socially or organizationally constructed expectations. CONCLUSIONS: A new definition of patient ownership is proposed encompassing findings from the review, while also respecting the shift from individual to a team-based patient care, and without removing the centrality of an individual provider's commitment to patients.

Extracellular calcium sensing promotes human B-cell activation and function.

Calcium is a second messenger for many signaling pathways in B cells, but its role as a receptor ligand has not been well characterized. However, pulses of free calcium were found to cause the rapid release of internal calcium stores in normal human B cells. This response appeared to be mediated by a cell surface protein with receptor properties as it could be blocked by pretreatment with trypsin and with kinase and phospholipase Cgamma inhibitors. The calcium receptor on B cells was not the conventional calcium-sensing receptor (CaSR) since B cells did not express CaSR and calcium-induced responses could not be blocked by specific CaSR inhibitors. B-cell responses to extracellular calcium activated phosphoinositide-3 kinase/AKT, calcineurin, extracellular signal regulated kinase, p38 mitogen-activated protein kinase, protein kinase C, Ca(2+)/calmodulin kinase II, and nuclear factor-kappaB signaling pathways, and resulted in transcription of the early response gene, CD83. This extracellular calcium sensor enhanced B-cell responses to Toll-like receptor, B-cell receptor, and cytokine receptor agonists. These findings suggest a means by which B cells prepare to engage in immune responses by responding to calcium fluctuations in their environment.

Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity.

The innate ability of B lymphoma cells to escape control by tumor-reactive T cells must be overcome to develop effective immunotherapies for these diseases. Because signals from both the innate and adaptive immune systems direct the acquisition of strong immunogenicity by professional APCs, the effects of IL-2 and the TLR-7 agonist, S28690, on the immunogenic properties of chronic lymphocytic leukemia (CLL) B cells were studied. IL-2 with S28690 caused CLL cells to proliferate and increased their expression of B7-family members, production of TNF-alpha and IL-10, and levels of tyrosine-phosphorylated STAT-1 and STAT-3 proteins. S28690 increased CD25 expression on CLL cells and sensitized them to IL-2 signaling. However, IL-2 did not change TLR-7 expression or signaling in CLL cells. The ability to stimulate T cell proliferation required additional activation of protein kinase C, which inhibited tumor cell proliferation, "switched off" IL-10 production, and caused essentially all CLL cells (regardless of clinical stage) to acquire a CD83(high)CD80(high)CD86(high)CD54(high) surface phenotype marked by the activation of STAT-1 without STAT-3. These findings suggest that TLR-7 "licenses" human B cells to respond to cytokines of the adaptive immune system (such as IL-2) and provide a strategy to increase the immunogenicity of lymphoma cells for therapeutic purposes.

A phase I/II trial of oxidized autologous tumor vaccines during the "watch and wait" phase of chronic lymphocytic leukemia.

Based on their activity in patients with advanced stage chronic lymphocytic leukemia (CLL), a phase I/II study was designed to evaluate the feasibility, safety, and efficacy of autologous vaccines made from oxidized tumor cells in patients with earlier stage CLL, and to determine an optimal schedule of injections. Eighteen patients (at risk for disease progression and with white blood cell counts between 15 and 100 x 10(6) cells/ml) were injected intramuscularly with 10 ml of oxidized autologous blood (composed mainly of CLL cells) either 12 times over 6 weeks (group 1), 12 times over 16 days (group 2), or 4 times over 6 weeks (group 3). Fourteen out of eighteen patients had Rai stage 0-II disease, while 4/18 had stage III-IV disease but did not require conventional treatment. Partial clinical responses, associated with enhanced anti-tumor T cell activity in vitro, were observed in 5/18 patients of whom three were in group 2. Stable disease was observed in six patients while disease progression appeared not to be affected in the remaining patients. Toxicity was minimal. Vaccination with oxidized autologous tumor cells appears worthy of further investigation and may be a potential alternative to a "watch and wait" strategy for selected CLL patients.

Effect of serum and antioxidants on the immunogenicity of protein kinase C-activated chronic lymphocytic leukemia cells.

Since the intrinsically poor immunogenicity of chronic lymphocytic leukemia (CLL) cells might be a key factor in allowing them to avoid immune control mechanisms, the development of methods to enhance CLL cell immunogenicity might lead to improved disease control. The ability of CLL cells to stimulate T cells was increased significantly by the protein kinase C (PKC) agonist phorbol myristic acetate (PMA). However, under serum-free conditions, PMA-activated CLL cells died within 48 hours. Antioxidants, such as 2-mercaptoethanol (2-ME), or fetal calf serum could prevent the death of these cells but caused them to enter distinct states of differentiation. In the presence of 2-ME, PMA-activated CLL cells extended dendritic-like protrusions and exhibited increased T-cell stimulatory capacity. In the presence of serum, PMA-activated CLL cells developed fewer dendrites, made less IL-10 and more IL-12 p40 mRNA transcripts, and showed an increased capacity to induce IFN-gamma production by T cells. The effects of serum on the promotion of type 1 immune responses by phorbol ester-activated CLL cells were dominant and correlated with activation of the NF-kappaB signaling pathway. Other PKC agonists, such as Bryostatin-1 and a synthetic Bryostatin analog (Picolog), had similar effects on CLL cells. The observation that CLL cells can acquire features of dendritic cells that promote type 1 immunity may find clinical application in immunotherapeutic strategies for this disease.

Effect of IL-2R beta-binding cytokines on costimulatory properties of chronic lymphocytic leukaemia cells: implications for immunotherapy.

Weak immunogenicity of chronic lymphocytic leukaemia (CLL) cells may contribute to disease progression and inhibit the effectiveness of immunotherapies, such as vaccines. Agents that can enhance the antigen presenting capabilities of CLL cells might then help to improve the clinical results of immunotherapies. This study investigated the effects of the common gamma chain-binding cytokines, interleukin (IL)-2 and IL-15, on costimulatory properties of primary CLL cells from 51 patients. IL-2 improved the ability of CLL cells to stimulate T cell proliferation and increased the expression of costimulatory molecules (particularly CD80) in a dose-dependent fashion, especially in CLL cells with weak expression of CD38. CD80 and CD86 induction by IL-2 were positively regulated through the mitogen-activated protein kinase pathway, while CD86 expression was negatively regulated through Janus kinase pathways. However, further activation with protein kinase C agonists was required for IL-2 activated CLL cells to stimulate autologous T cells sufficiently to clear bystander CLL cells from mixed lymphocyte responses. IL-15 had similar effects on the costimulatory properties of CLL cells. These results suggest a role for IL-2, or IL-15, in immunotherapeutic strategies for CLL.

Amplification of virus-induced antimelanoma T-cell reactivity by high-dose interferon-alpha2b: implications for cancer vaccines.

PURPOSE: The therapeutic effectiveness of cancer vaccines, composed of tumor antigens that are also self-antigens, may be limited by the normal mechanisms that preserve immunological tolerance. Consistent with this notion, we found that vaccination of melanoma patients with recombinant viral vaccines expressing gp100 (a melanoma antigen also expressed by normal melanocytes) produced only transient increases in noncytotoxic T cells specific for immunodominant gp100 epitopes. To improve the therapeutic effects of these vaccines, IFN-alpha2b (IFN-alpha) was administered to some high-risk patients. EXPERIMENTAL DESIGN: 7 HLA-A*0201(+) patients were injected with high doses of IFN-alpha (20 MU/m(2) x 20 doses) at various times after completing the vaccination protocol. Clinical toxicity and responses were documented, and the effects on gp100-reactive T cells were measured by IFN-gamma enzyme-linked immunospot assays, tetramers of HLA-A*0201 and gp100 epitopes, and cellular cytotoxicity assays. RESULTS: In patients who had previously responded to vaccination, high doses of IFN-alpha recalled gp100-reactive T cells with the ability to kill gp100-expressing tumor targets in vitro. Concomitant with the reappearance of these cytotoxic T cells, tumor regression was observed in the two patients with clinically evident metastatic disease. CONCLUSIONS: The finding that high-dose IFN recalls previously activated tumor-reactive T cells with potent killing ability suggests a strategy to maintain antitumor responses initiated by cancer vaccines.

Chronic lymphocytic leukemia-reactive T cells during disease progression and after autologous tumor cell vaccines.

PURPOSE: Tumor-reactive T cells were measured in patients with chronic lymphocytic leukemia (CLL) because vaccines that increase the activity of these cells might lead to better disease control. EXPERIMENTAL DESIGN: Proliferation and ELISPOT assays (for T cells producing IFN-gamma after stimulation by CD40-activated CLL cells) were used to determine the prevalence of tumor-reactive T cells in 25 CLL patients at various stages of disease progression. The effects of vaccines, composed of autologous-oxidized tumor cells, on both the clinical course and tumor-reactive T-cell numbers were then determined in 2 patients. RESULTS: CLL-reactive T cells were found at frequencies of > or =10(-3) in 6 of 11 patients. Significant proliferation was found in 15 of 25 patients and correlated with clinical stage. The inability to measure CLL-reactive T cells in the remaining patients was not uniformly a result of generalized T-cell dysfunction or defective antigen presentation by CD40-activated CLL cells. CLL-reactive T-cell frequencies increased in response to vaccination with oxidized autologous tumor cells in a patient with preexisting CLL-reactive T cells but not in a patient where tumor-reactive T cells were undetectable in the ELISPOT assay. CONCLUSIONS: Tumor-reactive T cells exist in some CLL patients (mainly during earlier stages of disease) and may potentially mediate therapeutic responses if their numbers and activation states can be sufficiently increased by tumor vaccines.