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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex–disparate GVHD model of lethally irradiated BALB/c mice given T cell–depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ–transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplantation and subsequent epidermal allografting from the bone marrow transplant donor. Epidermal allografting of these patients has decreased wound surface area for up to 3 years after treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes coexpressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered proinflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing profibrotic gene POSTN, which may have implications in the development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights into and targets for future RDEB studies and treatments.

Suicidality is known to be elevated among people with an eating disorder. The aim of the current study was to examine whether any of three specific behavioral facets of eating disorders (i.e., purging, binge eating, restricting) would be the strongest predictors of suicidal ideation, controlling for one another, in longitudinal analyses from admission to discharge. We hypothesized that purging, above and beyond restricting or binge eating, would be the most important predictor of suicidal ideation.In the present study, patients with an eating disorder (N = 936), the majority of whom met criteria for a current DSM-5 diagnosis of Anorexia Nervosa (n = 560), completed the Eating Pathology Symptoms Inventory (EPSI) and the Beck Depression Inventory II-Item 9 suicidal ideation index, at admission and again at discharge. The settings were eating disorder treatment facilities offering inpatient, residential, partial hospitalization program (PHP), and intensive outpatient (IOP) levels of care. We pitted EPSI purging, EPSI restriction, and EPSI binge eating against one another in a regression framework predicting discharge suicidal ideation controlling for suicidal ideation at admission.EPSI Purging significantly predicted both presence/absence of suicidal ideation (β = .22, t = 2.48, p = .01; OR = 1.25, 95% CI [1.05, 1.49]) and intensity of suicidal ideation (β = .04, t = 2.31, p = .02) at discharge, whereas neither EPSI Restricting nor EPSI Binge Eating did (p .30).Study results suggest that purging may have particular relevance in estimating suicide risk in patients with an eating disorder.

Background: Recent reimbursement cuts for hospitals with higher 30-day heart failure (HF)-related readmission rates call for means of reducing those readmissions. Objective: To determine if pharmacist-initiated education increases HF knowledge and assess if an increase in HF knowledge decreases HF readmission. Methods: This was a prospective interventional study. Participants were ≥18 years old admitted through the emergency department of a 322-bed community hospital with a diagnosis and/or past medical history of HF. Terminal/palliative care patients, patients residing in an assisted-living environment, or patients with a mental illness that deemed them incapable of participating were excluded. Forty-eight patients received pharmacist-initiated HF education on HF pathophysiology and its pharmacologic and nonpharmacologic treatment. Medication assistance and ancillary services were consulted when necessary. Patients’ knowledge of HF was assessed using the same questionnaire prior to education and through a follow-up phone call within 7 days postdischarge. Results: Posteducation HF knowledge scores were 13.7 points higher than preeducation scores ( P < .05). Twenty-five patients (52%) had HF as a primary discharge diagnosis. Of those patients, 9 (36%) were readmitted within 30 days for any cause. Only 3 patients (12%) had a HF-related diagnosis at readmission. There was a statistical difference in the level of knowledge but that was not translated into a statistical difference in readmission rates. Conclusion: Patients’ HF knowledge scores increased after pharmacist education. Improvements in HF knowledge could not be correlated with readmission rates. However, the majority of HF patients in this study did not have a HF-related diagnosis at the time of readmission.

BACKGROUND Previous studies show some patients with functional gastrointestinal disorders (disorders of gut-brain interaction) may be at risk for or already have an eating disorder (ED). Avoidant/restrictive food intake disorder (ARFID) (ED not primarily motivated by body shape/weight concerns) may be particularly relevant but previous studies have been unable to fully apply diagnostic criteria. This study aimed to determine the frequency and nature of the full spectrum of ED symptoms, among adults with disorders of gut-brain interaction. METHODS Adults with disorders of gut-brain interaction (n = 99, 77.1% female, ages 18-82 years) from academic medical center gastroenterology clinics completed a modified ARFID Canadian Paediatric Surveillance Program Questionnaire, the ED Examination Questionnaire (EDE-Q), and other self-report measures of depression, generalized anxiety, and pain interference. KEY RESULTS Of the 93 participants who completed the measures, 37 (39.8%) had ARFID symptoms and 12 (12.9%) had clinically significant shape/weight-motivated ED symptoms (EDE-Q-Global ≥4.0). Exploratory comparisons among ARFID, shape/weight-motivated ED, and no-ED groups revealed that ARFID symptom presence was associated with lower body mass index (BMI), and shape/weight-motivated ED presence was associated with higher depression, anxiety, and pain interference. However, the majority (86%) of patients with ARFID symptoms had a BMI >18.5 kg/m2 . CONCLUSIONS & INFERENCES The full spectrum of ED symptoms was frequent among patients with disorders of gut-brain interaction, particularly ARFID symptoms. Further research is needed to understand risk and maintenance factors to inform prevention and intervention efforts.

Patients with personality disorders can be challenging to care for in emergency settings. Their poor coping, unstable affect, impulsivity, and interpersonal dysfunction can present unique challenges for health-care professionals. Having a personality disorder negatively affects medical outcomes and increases health-care utilization. In most cases, a personality disorder is suspected when a patient’s behavior is unusual, results in conflict, or elicits a strong emotional reaction from providers. Making a formal diagnosis of a personality disorder can be complicated and time-consuming and is generally beyond the scope of emergency care. However, identification of features commonly seen in individuals with personality disorders is helpful for patient care. Even individuals who do not meet full diagnostic criteria may have significant impairment and can benefit from the interventions described in this chapter.

Background Prior studies have described the career paths of physician-scientist candidates after graduation, but the factors that influence career choices at the candidate stage remain unclear. Additionally, previous work has focused on MD/PhDs, despite many physician-scientists being MDs. This study sought to identify career sector intentions, important factors in career selection, and experienced and predicted obstacles to career success that influence the career choices of MD candidates, MD candidates with research-intense career intentions (MD-RI), and MD/PhD candidates. Methods A 70-question survey was administered to students at 5 academic medical centers with Medical Scientist Training Programs (MSTPs) and Clinical and Translational Science Awards (CTSA) from the NIH. Data were analyzed using bivariate or multivariate analyses. Results More MD/PhD and MD-RI candidates anticipated or had experienced obstacles related to balancing academic and family responsibilities and to balancing clinical, research, and education responsibilities, whereas more MD candidates indicated experienced and predicted obstacles related to loan repayment. MD/PhD candidates expressed higher interest in basic and translational research compared to MD-RI candidates, who indicated more interest in clinical research. Overall, MD-RI candidates displayed a profile distinct from both MD/PhD and MD candidates. Conclusions MD/PhD and MD-RI candidates experience obstacles that influence their intentions to pursue academic medical careers from the earliest training stage, obstacles which differ from those of their MD peers. The differences between the aspirations of and challenges facing MD, MD-RI and MD/PhD candidates present opportunities for training programs to target curricula and support services to ensure the career development of successful physician-scientists. Electronic supplementary material The online version of this article (doi:10.1186/s12909-017-0954-8) contains supplementary material, which is available to authorized users.

Personality disorders are pervasive patterns of maladaptive behaviors, thoughts, and emotions that often go unrecognized and can wreak havoc in the patient's interpersonal life. These inflexible patterns of managing the world can be disruptive when an individual is admitted to the hospital, causing distress for both the patient who lacks the skills to deal with the expectations of the hospital environment and the treatment team who can feel ill equipped to manage such behavior. Having a personality disorder has implications for an individual's healthcare outcomes; those with a personality disorder have a life expectancy nearly 2 decades shorter than the general population for a multitude of reasons, among them trouble interacting with the healthcare system. Although a diagnosis of a specific personality disorder may be difficult to make on an acute care unit, identification of dysfunctional personality structures can provide opportunity for better management of an individual patient's medical and psychological needs. This review focuses on the identification of these individuals in the acute care setting and provides an overview of evidence-based behavioral and pharmacological interventions. Journal of Hospital Medicine 2015;11:873-878. © 2015 Society of Hospital Medicine.

The ability to exert self-control in the face of appetitive, alluring cues is a critical component of healthy development. The development of behavioral measures that use disease-relevant stimuli can greatly improve our understanding of cue-specific impairments in self-control. To produce such a tool relevant to the study of eating and weight disorders, we modified the traditional go/no-go task to include food and non-food targets. To confirm that performance on this new task was consistent with other go/no-go tasks, it was given to 147 healthy, normal weight volunteers between the ages of 5 and 30. High-resolution photos of food or toys were used as the target and nontarget stimuli. Consistent with expectations, overall improvements in accuracy were seen from childhood to adulthood. Participants responded more quickly and made more commission errors to food cues compared to nonfood cues (F(1,140)=21.76, P

Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.

Protein cysteine thiols can be divided into four groups based on their reactivities: those that form permanent structural disulfide bonds, those that coordinate with metals, those that remain in the reduced state, and those that are susceptible to reversible oxidation. Physicochemical parameters of oxidation-susceptible protein thiols were organized into a database named the Balanced Oxidation Susceptible Cysteine Thiol Database (BALOSCTdb). BALOSCTdb contains 161 cysteine thiols that undergo reversible oxidation and 161 cysteine thiols that are not susceptible to oxidation. Each cysteine was represented by a set of 12 parameters, one of which was a label (1/0) to indicate whether its thiol moiety is susceptible to oxidation. A computer program (the C4.5 decision tree classifier re-implemented as the J48 classifier) segregated cysteines into oxidation-susceptible and oxidation-non-susceptible classes. The classifier selected three parameters critical for prediction of thiol oxidation susceptibility: (1) distance to the nearest cysteine sulfur atom, (2) solvent accessibility, and (3) pKa. The classifier was optimized to correctly predict 136 of the 161 cysteine thiols susceptible to oxidation. Leave-one-out cross-validation analysis showed that the percent of correctly classified cysteines was 80.1% and that 16.1% of the oxidation-susceptible cysteine thiols were incorrectly classified. The algorithm developed from these parameters, named the Cysteine Oxidation Prediction Algorithm (COPA), is presented here. COPA prediction of oxidation-susceptible sites can be utilized to locate protein cysteines susceptible to redox-mediated regulation and identify possible enzyme catalytic sites with reactive cysteine thiols.

Megan C Riddle,1,* Jiahui Lin,3,* Jonathan B Steinman,2 Joshua D Salvi,2 Margaret M Reynolds,3 Anne S Kastor,3,† Christina Harris,4 Carla Boutin-Foster3 1Department of Psychiatry and Behavioral Sciences, University of Washington, 2Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD–PhD Program, 3Department of Internal Medicine, Weill Cornell Medical College, New York, NY, 4Department of Medicine, Division of General Internal Medicine, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, LA, USA *These authors contributed equally to this work †Anne S Kastor passed away on July 5, 2013. Abstract: As the health care delivery landscape changes, medical schools must develop creative strategies for preparing future physicians to provide quality care in this new environment. Despite the growing prominence of the patient-centered medical home (PCMH) as an effective model for health care delivery, few medical schools have integrated formal education on the PCMH into their curricula. Incorporating the PCMH model into medical school curricula is important to ensure that students have a comprehensive understanding of the different models of health care delivery and can operate effectively as physicians. The authors provide a detailed description of the process by which the Weill Cornell Community Clinic (WCCC), a student-run free clinic, has integrated PCMH principles into a service-learning initiative. The authors assessed patient demographics, diagnoses, and satisfaction along with student satisfaction. During the year after a PCMH model was adopted, 112 students and 19 licensed physicians volunteered their time. A review of the 174 patients seen from July 2011 to June 2012 found that the most common medical reasons for visits included management of hypertension, hyperlipidemia, diabetes, gastrointestinal conditions, arthritis, anxiety, and depression. During the year after the adoption of the PCMH model, 87% were very or extremely satisfied with their care, and 96% of the patients would recommend the WCCC to others. Students who participate in the WCCC gain hands-on experience in coordinating care, providing continuity of care, addressing issues of accessibility, and developing quality and safety metrics. The WCCC experience provides an integrative model that links service-learning with education on health care delivery in a primary care setting. The authors propose that adoption of this approach by other student-run clinics provides a substantial opportunity to improve medical education nationwide and better prepare future physicians to practice within this new model of health care delivery. Keywords: medical education, patient-centered medical home, medical students, service-learning, student-run free clinic.

Hurler syndrome (mucopolysaccharidosis type I/H; MPS I/H) is a lethal heritable enzymopathy that leads to an accumulation of glycosaminoglycans (GAGs) and dysfunction of multiple organs of the body, including the heart. As gender-related differences are common in heart disease and a murine model for mucopolysaccharidosis type I (MPSI) has been used for the preclinical evaluation of strategies to correct heart valve disease in Hurler syndrome, the study aim was to determine the impact of gender on heart disease in the murine MPSI model.Murine hearts were examined by high-resolution ultrasound biomicroscopy, the tissue and urinary contents of GAGs were measured, and the quantitative reverse transcribed ribonucleic acid polymerase chain reaction for metalloproteinase (MMP) -9 and -12 determined.In MPSI mice, aortic insufficiency (AI) in conjunction with depressed myocardial function was observed significantly more often in males than females. Neither the total body GAG burden nor myocardial GAG content was responsible for this difference. In contrast, in the aorta the expression of extracellular matrix tissue MMP-12, but not MMP-9, was significantly elevated in males with AI when compared to females with AI.Gender-related dimorphism occurs in cardiac valvular disease in MPSI mice. Male MPSI mice showed an increased incidence of AI associated with an increase in the MMP-12 content of the aortic arch. The evaluation of findings in relation to gender is important in the experimental treatment of murine models of disease, so that gender-related variations in genetic penetrance are not mistaken for disease correction.

Cellular therapy with non-hematopoietic adult stem cells (ASC) has emerged as a novel strategy for treatment of myocardial infarction (MI). Cells from non-identical donors, however, are typically rejected by the immune system of recipient. To overcome this barrier to transplantation we induced MI by left coronary artery ligation followed by direct intramyocardial injection of ASC or saline in cohorts of syngeneic C57BL/6 (B6) immune competent versus B6 Rag/IL2Rγc (Rag/γc) T-, B- and natural killer-cell immune deficient mice. We made an unexpected observation that heart function was significantly improved in ASC-treated B6 mice, but not in ASC-treated Rag/γc mice; and that the beneficial effect of ASC was inversely correlated with ASC persistence (i.e., ACS were rejected by B6 mice but engrafted in Rag/γc mice). As the donor cells were rejected within several weeks by B6 animals we hypothesized that the host immune system and ASC provided trophic signals for cardiac repair early after injury. In search for anatomical correlation, we first assessed changes in capillary density. Four weeks after MI, significantly more capillaries (normalized to number of nuclei) were observed in the border zone of B6 animals treated with ASC versus saline (p = 0.01), and significantly fewer capillaries were found in the infarct zone when B6 animals (treated with ASC) were depleted of T-cells and NK-cells (p = 0.03). To gain mechanistic insight into the early events in the ASC-mediated repair, next we have assessed one week after MI ± ASC messenger RNA expression of genes known to be engaged in angiogenesis. In B6 mice the most prominent change in response to MI injury was 17-fold increased expression of tissue inhibitor of metalloproteinases 1. The ASC mediated response to MI injury was defined by increased expression of fibroblast growth factor 2, integrin αV, phophorylated form of vascular endothelial growth factor receptor 2 and endothelial-specific receptor tyrosine kinase (all p < 0.01). These data are the first to define the paracrine tissue repair factors necessary to produce therapeutic benefit in response to donor ASC after MI. Importantly, our data also suggest that MI is not solely a heart lesion, but rather a systemic inflammatory condition controlled by host immune system. This research has received full or partial funding support from the American Heart Association, AHA National Center.