A Canadian Simulation Model for Major Depressive Disorder: Study Protocol.

BACKGROUND: Major depressive disorder (MDD) is a common, often recurrent condition and a significant driver of healthcare costs. People with MDD often receive pharmacological therapy as the first-line treatment, but the majority of people require more than one medication trial to find one that relieves symptoms without causing intolerable side effects. There is an acute need for more effective interventions to improve patients' remission and quality of life and reduce the condition's economic burden on the healthcare system. Pharmacogenomic (PGx) testing could deliver these objectives, using genomic information to guide prescribing decisions. With an already complex and multifaceted care pathway for MDD, future evaluations of new treatment options require a flexible analytic infrastructure encompassing the entire care pathway. Individual-level simulation models are ideally suited for this purpose. We sought to develop an economic simulation model to assess the effectiveness and cost effectiveness of PGx testing for individuals with major depression. Additionally, the model serves as an analytic infrastructure, simulating the entire patient pathway for those with MDD. METHODS AND ANALYSIS: Key stakeholders, including patient partners, clinical experts, researchers, and modelers, designed and developed a discrete-time microsimulation model of the clinical pathways of adults with MDD in British Columbia (BC), including all publicly-funded treatment options and multiple treatment steps. The Simulation Model of Major Depression (SiMMDep) was coded with a modular approach to enhance flexibility. The model was populated using multiple original data analyses conducted with BC administrative data, a systematic review, and an expert panel. The model accommodates newly diagnosed and prevalent adult patients with MDD in BC, with and without PGx-guided treatment. SiMMDep comprises over 1500 parameters in eight modules: entry cohort, demographics, disease progression, treatment, adverse events, hospitalization, costs and quality-adjusted life-years (payoff), and mortality. The model predicts health outcomes and estimates costs from a health system perspective. In addition, the model can incorporate interactive decision nodes to address different implementation strategies for PGx testing (or other interventions) along the clinical pathway. We conducted various forms of model validation (face, internal, and cross-validity) to ensure the correct functioning and expected results of SiMMDep. CONCLUSION: SiMMDep is Canada's first medication-specific, discrete-time microsimulation model for the treatment of MDD. With patient partner collaboration guiding its development, it incorporates realistic care journeys. SiMMDep synthesizes existing information and incorporates provincially-specific data to predict the benefits and costs associated with PGx testing. These predictions estimate the effectiveness, cost-effectiveness, resource utilization, and health gains of PGx testing compared with the current standard of care. However, the flexible analytic infrastructure can be adapted to support other policy questions and facilitate the rapid synthesis of new data for a broader search for efficiency improvements in the clinical field of depression.

Cost-effectiveness of pharmacogenomic-guided treatment for major depression.

BACKGROUND: Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants. METHODS: We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC. RESULTS: Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation. INTERPRETATION: Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.

Students' resilience and mental health in the dental curriculum.

OBJECTIVES: Dental education is perceived as a source of students' psychological and occupational stress. Resilience has been proposed as a protective factor that may support students' in managing that stress. The objectives of this study were twofold: to map the mental health and well-being content in the curriculum of the Faculty of Dentistry (FoD) at the University of British Columbia (UBC) and to investigate factors influencing resilience levels amongst dental students at UBC. METHODS: The curricular database and website of UBC's FoD were used to gather information on mental health content. A survey with the Connor-Davidson 10-Item Resilience Scale was distributed to dental students at UBC (N = 289). Students' de-identified demographic data were also collected. RESULTS: Two main mental health and well-being curricular components were identified: one didactic session on stress management and one interactive workshop on resilience. The response rate for the survey was 68.2%. Students who did not receive any mental health content (2020/21 year 1 students) had higher resilience scores (p = .043) when compared to students who received both components (2019/20 year 1 students and 2018/19 year 2 students). The multiple regression analysis highlighted North American/European ethnic origins as a predictor for higher resilience levels (p = .008). CONCLUSIONS: The results of this study showed that ethnic origins and major life events, such as the pandemic, influenced resilience. Curricular activities promoting resilience seemed to not necessarily impact students' resilience. Further longitudinal studies are needed to assess the curricular and non-curricular activities influence over dental students' well-being.

Substance of choice, impact of heroin or opium on treatment retention in a multicentre randomised controlled trial in Iran.

INTRODUCTION: In the Middle East and Asia, illicit opioid use exists across a spectrum between heroin and opium. The impact of primary opioid of choice on opioid agonist treatment retention has not been well evaluated previously, especially for opium tincture, an increasingly popular form of opioid agonist treatment in Iran. This study investigates the relationship between primary opioid of choice, namely heroin or opium, and retention in opium tincture and methadone treatment. METHODS: Participants with opioid use disorder (n = 204) were randomised to receive opium tincture or methadone. All participants were categorised as mainly using opium or heroin. Bivariate analyses between treatment retention and primary opioid of choice (P < 0.05) and logistic regression were conducted. RESULTS: Among the 191 participants included in this analysis, heroin was the primary substance of choice for 135 participants (70.7%) and opium for 56 (29.3%). Bivariate analysis showed that the opium group was more likely to be satisfied with family situation, employed and retained in treatment than the heroin group while less likely to experience incarceration and use multiple substances. When adjusting for covariates, primary opioid of choice was not significantly associated with retention in either methadone or opium tincture treatment arm. DISCUSSION AND CONCLUSIONS: Positive factors, such as employment, housing and family support, seem to collectively explain the higher retention in treatment among those who primarily use opium compared to those who use heroin. To optimise retention in opioid agonist treatment, biopsychosocial care models should be further evaluated to improve psychosocial functioning.

Mental health and wellness in Canadian dental schools: Findings from a national study.

OBJECTIVES: To survey the mental health and wellbeing content in the curricula, services, and activities of the 10 Canadian dental schools, and to explore the specifics of this area in the Faculty of Dentistry (FoD) at The University of British Columbia (UBC). METHODS: An electronic survey consisted of four major categories: curricular activities and services, structural approaches, infrastructural approaches, and evaluation methods, was distributed to all Canadian dental schools. A situational analysis was conducted at UBC's FoD via document appraisal and key informants' exploratory interviews. RESULTS: Eight dental schools responded to the survey showing that didactic sessions being the pedagogical method to deliver resilience content. None of the responding schools reported formally evaluating their mental health content. Through situational analysis, a relational map that identified four major areas contributing to students' mental health at UBC's FoD was generated which includes four major aspects: (1) curricular content on mental health, (2) informal wellbeing and mental health networks, (3) protective, and (4) risk factors influencing students' mental health. CONCLUSIONS: As this study described the mental health and wellbeing activities, services, and curricular content across multiple Canadian dental schools, the diverse approaches each school adopted and how personal and professional aspects of students' lives being attempted to be addressed are a critical starting point to engage educators in dentistry. The situational analysis outcome, where a detailed description of the mental health situation at UBC's FoD, can be used to guide in-depth studies of the area of wellbeing at other dental schools.

A Strategy to Simultaneously Cure Type 1 Diabetes and Diabetic Nephropathy by Transplant of Composite Islet-Kidney Grafts.

In recent years islet cell transplant has proven itself to be a viable clinical option for a select group of diabetic patients. Graft loss after transplant however continues to hinder the long-term success of the procedure. Transplanting the islets as a pre-vascularized composite islet-kidney graft has emerged as a relevant solution. Much groundbreaking research has been done utilizing this model in conjunction with strategies aimed towards islet cell survival and prolongation of function in the host. Transplanting the islet cells as a prevascularized graft under the capsule of the donor kidney as a composite islet-kidney graft has been shown to provide long term durable blood glucose control in large animal studies by limiting graft apoptosis as well as providing a physical barrier against the host immune response. While promising, this technique is limited by long term immunosuppression requirements of the host with its well-known adverse sequelae. Research into tolerance inducing strategies of the host to the allogeneic and xenogeneic islet-kidney graft has shown much promise in the avoidance of long-term immunosuppression. In addition, utilizing xenogeneic tissue grafts could provide a near-limitless supply of organs. The islet-kidney model could provide a durable and long-term cure for diabetes. Here we summarize the most recent data, as well as groundbreaking strategies to avoid long term immunosuppression and promote graft acceptance.

Electrocardiograms Revealing Epsilon Waves Following Use of Hormone Supplements in Young Cardiac Arrest Patient.

INTRODUCTION: An underlying cardiomyopathy should be suspected in young patients presenting with ventricular arrhythmias and sudden cardiac arrest. Electrocardiograms revealing epsilon waves are associated with many serious conditions such as arrhythmogenic right ventricular cardiomyopathy, posterior myocardial infarction, right ventricular infarction, infiltration disease, sarcoidosis, Brugada Syndrome, Tetralogy of Fallot, and hypothermia. This case report features epsilon waves in a young cardiac arrest patient suspected of having an unrecognized cardiomyopathy that resulted in a fatal arrhythmia in the setting of exogenous bovine thyroid hormone and steroid use.  Case presentation: A previously healthy 33-year-old male with a history of anabolic steroid use and bovine thyroid hormone use presented to the emergency department following witnessed cardiac arrest with bystander cardiopulmonary resuscitation (CPR). Upon emergency medical service (EMS) arrival, the patient was in ventricular fibrillation and received defibrillation with the return of spontaneous circulation. In the emergency department, he was unresponsive and required norepinephrine to maintain blood pressure. An epsilon wave and a prolonged QTc interval were noted on his electrocardiogram (ECG). CT angiogram of the chest and CT head were negative for acute abnormalities. Pertinent laboratory work-up included a lactate level of 12.0 mmol/L, thyroid-stimulating hormone of 0.02 ulU/L, and a free thyroxine level of 0.04 ng/dL. Cardiac ultrasound showed globally decreasedleft ventricular function with an ejection fraction of 25-30% and mild dilation of the right ventricle. A cardiac MRI was ordered but the patient had recurrent ventricular fibrillation and was too unstable to complete. He suffered anoxic brain injury with no improvements in neurologic function and was transitioned to comfort care. The patient died two months later in hospice care. The cause of cardiac arrest was attributed to the patient's steroid and bovine thyroid supplementation, but autopsy results revealed histologic evidence of possible arrhythmogenic right ventricular cardiomyopathy.  Discussion: Epsilon waves are widely known to be associated with structural abnormalities of the heart, most notably, arrhythmogenic right ventricular cardiomyopathies. Epsilon waves may be present in a variety of other medical conditions including posterior myocardial infarction, right ventricular infarction, infiltration disease, sarcoidosis, Brugada Syndrome, Tetralogy of Fallot, and hypothermia. This case report describes an epsilon wave found in a patient with suspected arrhythmogenic right ventricular cardiomyopathy that suffered a fatal arrhythmia triggered by bovine thyroid hormone and steroid use.

Role of hydrogen peroxide injection for penetrating abdominal injury in creating CT Tractogram.

Penetrating abdominal trauma is responsible for approximately 35% of patients admitted to urban trauma centers, and up to 12% of those admitted in suburban or rural centers in the United States. Current protocol relies heavily on CT imaging as the diagnostic tool in evaluating for peritoneal violation in hemodynamically stable patients, however it is associated with false negative rates. In addition, visualization of the fascia of the rectus abdominis, the transversalis fascia, and the peritoneum cannot be reliably identified with CT. Studies have probed into the use of injecting IV contrast dyes prior to imaging to establish a CT tractography. We present a case of a 31-year-old male presenting to the emergency department for evaluation of stab wounds following an altercation. On exam, a 1 cm penetrating wound to the LUQ of his abdomen was noted. A CT scan of the abdomen and pelvis was performed with 91 mL of Omnipaque-350 intravenous contrast. Prior to imaging, 30 mL of hydrogen peroxide was injected directly into the opening site of the stab wound to amplify the wound tract. The result was a well-visualized intact peritoneum. We propose hydrogen peroxide as an alternative method to liquid contrast in reestablishing the stab wound tract. This method creates a negative contrast level to augment the ability of CT imaging to determine peritoneal penetration. Key Words: Penetrating Abdominal Injury, CT Tractography, Abdominal Trauma, Hydrogen Peroxide, Trauma Management.

Individual specialist physical activity assessment and intervention in advanced cancer patients on a palliative care ward; the 3STEPS-study.

The aim of this prospective study was to evaluate the feasibility and outcome of an activity assessment and intervention on a specialized palliative care ward. All patients admitted between May 2017 and April 2018 were screened for basic assessment (Step 1). Whenever possible the Tinetti-mobility test (TT) was performed by a physiotherapist. A comparison between physician and nurse-led assessment and patient report was performed (Step 2), followed by a low-intensity individually adapted activity intervention (Step 3). Physical function and global quality of life was measured at intervention start and at discharge. Home care training adherence was controlled by phone call. In total, 437 patients were admitted in one year. In 248 patients, a basic assessment was done of which 131 performed a TT. In this group, median age was 63 years. Types of cancer were gastrointestinal (n=39), lung (n=27), urogenital (n=20), non-cancer (n=26) and other (n=26). Median length of stay was 13 days. Correlations between assessment methods were low to moderate, the highest between the TT and the nurse led assessment. Six patients started the intervention. Four patients completed the intervention, of which two continued with the home based training. In all four patients, an improvement in outcomes was measured. In conclusion in around a quarter of patients on a palliative care ward a TT could be performed. The TT correlated to most with nurse led mobility assessment. In the few accrued patients, the activity intervention showed an effect.

Preliminary Studies of the Impact of CXCL12 on the Foreign Body Reaction to Pancreatic Islets Microencapsulated in Alginate in Nonhuman Primates.

BACKGROUND: We previously demonstrated that the incorporation of the chemokine CXCL12 into alginate microbeads supported long-term survival of microencapsulated auto-, allo-, and xenogeneic islets in murine models of diabetes without systemic immune suppression. The purpose of this study was to test whether CXCL12 could abrogate foreign body responses (FBRs) against alginate microbeads which were empty or contained autologous islets in healthy nonhuman primates (NHPs; n = 4). METHODS: Two NHPs received intraperitoneal implants of 400 000 alginate microbeads with or without CXCL12, and postimplantation immunological and histopathological changes were evaluated up to 6 months postimplantation. A similar evaluation of autologous islets in CXCL12-containing alginate microbeads was performed in NHPs (n = 2). RESULTS: CXCL12-containing alginate microbeads were associated with a markedly reduced FBR to microbeads. Host responses to microbead implants were minimal, as assessed by clinical observations, blood counts, and chemistry. Evaluation of encapsulated islets was limited by the development of necrotizing pancreatitis after hemipancreatectomy in 1 NHP. A limited number of functioning islets were detectable at 6 months posttransplantation in the second NHP. In general, empty microbeads or islet-containing beads were found to be evenly distributed through the intraperitoneal cavity and did not accumulate in the Pouch of Douglas. CONCLUSIONS: Inclusion of CXCL12 in alginate microbeads minimized localized FBR. The NHP autologous islet implant model had limited utility for excluding inflammatory/immune responses to implanted islets because of the complexity of pancreatic surgery (hemipancreatectomy) before transplantation and the need to microencapsulate and transplant encapsulated autologous islets immediately after pancreatectomy and islet isolation.

Xenogeneic Heterotopic Auxiliary Liver transplantation (XHALT) promotes native liver regeneration in a Post-Hepatectomy Liver failure model.

The liver's regenerative capacity is unique, but too small a segment can overwhelm its ability to simultaneously regenerate and support the host, resulting in liver dysfunction and death. Here we tested a temporary Xenogeneic Heterotopic Auxiliary Liver Transplant (XHALT) from Gal-KO miniature swine in a baboon model of Post-Hepatectomy Liver Failure (PHLF) by 90%- hepatectomy. Immunosuppression consisted of CVF, ATG, FK 506 and steroids. 90%-hepatectomized animals died within 4-5 days with the clinical picture of PHLF, (high LFTs and bilirubin, ascites, encephalopathy and coagulopathy). The 10% remnants had macroscopic and histological evidence of severe steatosis and absence of hepatocyte replication. In contrast, the addition of XHALT prolonged survival up to 11 days, with the cause of death being sepsis, rather than liver failure. The remnant liver appeared grossly normal, and on histology, there was no evidence of fatty infiltration, but there was pronounced Ki-67 staining. In conclusion, temporary auxiliary xenografts have the potential to support a small for size liver graft while it grows to adequate size or provide an opportunity for organ recovery in acute liver failure.

The Impact of the Opioid Antagonist Naloxone on Experimentally Induced Craving in Nicotine-Dependent Individuals.

OBJECTIVE: Preclinical and clinical findings suggest a substantial association of the endogenous opioid system in nicotine dependence. The present study investigates the possible dose-dependent influence of naloxone, an unspecific opioid-receptor-antagonist, combined with cue exposure on the physiological state, locomotor activity, craving and the hypothalamic-pituitary-adrenal axis in nicotine-dependent humans. METHODS: Twenty nicotine-dependent, outpatient participants were deprived of nicotine for over 4 h, before receiving challenges with naloxone (1.6 mg or 3.2 mg q70 kg IV) or the placebo. Additionally, following drug administration, either smoking-related cues or neutral images were presented. Nicotine withdrawal was monitored by evaluating the following objective signs - skin conductance, heart rate, temperature, respiration, locomotor activity, cortisol, prolactin and ACTH levels as well as craving. RESULTS: With respect to subjective effects, participants administered a higher dosage of naloxone and those who were shown smoking-related cues were significantly less pleased (p = 0.019), felt more depressed (p = 0.033) and thought smoking would make them feel better (p = 0.028) than participants given naloxone and shown neutral cues. Participants given no naloxone but with smoking-related cues felt a higher urge to smoke than participants given naloxone and shown neutral cues (p = 0.042). Naloxone - in both dosages - also decreased the desire and intention to smoke in comparison to placebo. Compared to the placebo group, significantly higher cortisol, prolactin and ACTH values were observed after administration of lower and higher dosage of naloxone followed by smoking-related cues. CONCLUSION: Naloxone influenced nicotine withdrawal and strengthened significantly by cue exposure, both on objective measurement and on craving scales. These findings suggest an involvement of the endogenous opioid system in the development and maintenance of nicotine dependence.

ß Cell Replacement Therapy: The Next 10 Years.

ß cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. ß cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the ß cell like clusters. Exciting developments and rapid progress in all areas of ß cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of ß cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.

PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes.

Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy ß cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D.

Testing of microencapsulated porcine hepatocytes in a new model of fulminant liver failure in baboons.

BACKGROUND: There is no standard therapy for acute liver failure. Hepatocyte transplantation has been proposed for temporary liver function support, while the injured liver regenerates or while waiting for transplantation. We have previously shown such efficacy for microencapsulated porcine hepatocytes in mice with fulminant liver failure. We aimed to establish a large animal model for fulminant liver failure to assess the efficacy of microencapsulated porcine hepatocytes in temporary liver function support. METHODS: The model was developed in baboons; for testing microencapsulated hepatocytes, the best condition was 75% hepatectomy and 60 min warm ischemia time. Fulminant liver failure was characterized by steep increases in liver biochemical parameters, severe steatosis, and massive hepatocyte necrosis during the first 10 days. Hepatocytes from miniature swine were microencapsulated in alginate-poly-l-lysine microspheres, and transplanted intraperitoneally immediately after hepatectomy and warm ischemia (80-120 mL packed hepatocytes in 200-350 mL microspheres, about 30%-50% of the baboon's native liver volume). RESULTS: In the control group, three of five animals were sacrificed after 6-10 days because of fulminant liver failure, and two of five animals recovered normal liver function and survived until elective euthanasia (28 days). In the treatment group of four animals, one animal developed liver failure but survived to 21 days, and three animals recovered completely with normal liver function. CONCLUSIONS: The results indicate that microencapsulated porcine hepatocytes provide temporary liver function support in baboons with fulminant liver failure. These data support development of this cell therapy product toward clinical trials in patients with acute liver failure.

Islet cell transplant: Update on current clinical trials.

In the last 15 years clinical islet transplantation has made the leap from experimental procedure to standard of care for a highly selective group of patients. Due to a risk-benefit calculation involving the required systemic immunosuppression the procedure is only considered in patients with type 1 diabetes, complicated by severe hypoglycemia or end stage renal disease. In this review we summarize current outcomes of the procedure and take a look at ongoing and future improvements and refinements of beta cell therapy.

Immunogenicity of ß-cells for autologous transplantation in type 1 diabetes.

The success of clinical islet transplantation calls for a broader application of this curative treatment for type 1 diabetes mellitus. The toxicity of immunosuppression, limited organ donor supply and high procedural costs are deterrents to expand this therapy to patients with uncomplicated diabetes. The use of pancreatic ß-cell like cells derived from the patient's own induced pluripotent cells (iPSC) holds potential to overcome these barriers. In this review, we discuss the practicality of this regenerative medicine approach and existing evidence regarding the true immunogenicity of iPSC derived cells.

Monitoring of Allogeneic Islet Grafts in Nonhuman Primates Using MRI.

BACKGROUND: Information regarding the longevity of transplanted pancreatic islet grafts could provide valuable information for treatment options. In our previous studies, we showed that isolated autologous pancreatic islets could be labeled with iron oxide nanoparticles and monitored after transplantation using MRI. Here, we report on in vivo monitoring of a secondary damage that occurs at the later stages because of allogeneic immune rejection. METHODS: In the proof-of-principle studies, iron oxide-labeled autologous pancreatic islets were transplanted under the renal capsules of nonhuman primates. To demonstrate acute graft loss, the animals were injected with streptozotocin. Graft monitoring was performed by in vivo MRI. Next, iron oxide-labeled allogeneic islets were transplanted into the liver and monitored by MRI after withdrawal of immunosuppression. RESULTS: In autologous model, we observed a pronounced drop in graft volume after streptozotocin challenge as assessed by MRI. In allogeneic model of islet transplantation, there was an initial islet loss after the procedure followed by relative stabilization of the graft volume. After immunosuppression was discontinued, there was a noticeable drop in graft volume that gradually continued during the course of the study. Importantly, the loss of graft volume observed on MR preceded the raise in blood glucose. CONCLUSIONS: This study demonstrated that in vivo MRI was able to reveal graft volume loss before any changes in blood glucose that can be measured by standard methods. We believe that these results could provide means for clinicians to follow islet fate noninvasively and longitudinally using clinically relevant scanners.

Stimulants and Cannabis Use Among a Marginalized Population in British Columbia, Canada: Role of Trauma and Incarceration.

High rates of substance use, especially cannabis and stimulant use, have been associated with homelessness, exposure to trauma, and involvement with the criminal justice system. This study explored differences in substance use (cannabis vs. stimulants) and associations with trauma and incarceration among a homeless population. Data were derived from the BC Health of the Homeless Study (BCHOHS), carried out in three cities in British Columbia, Canada. Measures included sociodemographic information, the Maudsley Addiction Profile (MAP), the Childhood Trauma Questionnaire (CTQ), and the Mini International Neuropsychiatric Interview (MINI) Plus. Stimulant users were more likely to be female (43%), using multiple substances (3.2), and engaging in survival sex (14%). Cannabis users had higher rates of lifetime psychotic disorders (32%). Among the incarcerated, cannabis users had been subjected to greater emotional neglect (p < .05) and one in two cannabis users had a history of lifetime depressive disorders (p < .05). Childhood physical abuse and Caucasian ethnicity were also associated with greater crack cocaine use. One explanation for the results is that a history of childhood abuse may lead to a developmental cascade of depressive symptoms and other psychopathology, increasing the chances of cannabis dependence and the development of psychosis.

Assessment of ß-cell mass and α- and ß-cell survival and function by arginine stimulation in human autologous islet recipients.

We used intravenous arginine with measurements of insulin, C-peptide, and glucagon to examine ß-cell and α-cell survival and function in a group of 10 chronic pancreatitis recipients 1-8 years after total pancreatectomy and autoislet transplantation. Insulin and C-peptide responses correlated robustly with the number of islets transplanted (correlation coefficients range 0.81-0.91; P < 0.01-0.001). Since a wide range of islets were transplanted, we normalized the insulin and C-peptide responses to the number of islets transplanted in each recipient for comparison with responses in normal subjects. No significant differences were observed in terms of magnitude and timing of hormone release in the two groups. Three recipients had a portion of the autoislets placed within their peritoneal cavities, which appeared to be functioning normally up to 7 years posttransplant. Glucagon responses to arginine were normally timed and normally suppressed by intravenous glucose infusion. These findings indicate that arginine stimulation testing may be a means of assessing the numbers of native islets available in autologous islet transplant candidates and is a means of following posttransplant α- and ß-cell function and survival.