Community trial evaluating the integration of Indigenous healing practices and a harm reduction approach with principles of seeking safety in an Indigenous residential treatment program in northern Ontario.

OBJECTIVE: Our primary objective was to evaluate how the Indigenous Healing and Seeking Safety (IHSS) model impacted residential addiction treatment program completion rates. Our secondary objective was to evaluate health service use 6 months before and 6 months after residential treatment for clients who attended the program before and after implementing IHSS. METHODS: We observed clients of the Benbowopka Residential Treatment before IHSS implementation (from April 2013 to March 31, 2016) and after IHSS implementation (from January 1, 2018 - March 31, 2020). The program data were linked to health administration data, including the Ontario Health Insurance Plan (OHIP) physician billing, the Registered Persons Database (RPDB), the National Ambulatory Care Reporting System (NACRS), and the Discharge Abstract Database (DAD). Chi-square tests were used to compare patient characteristics in the no-IHSS and IHSS groups. We used logistic regression to estimate the association between IHSS and treatment completion. We used generalized estimating equation (GEE) regression model to evaluate health service use (including primary care visits, ED visits overall and for substance use, hospitalizations and mental health visits), Results: There were 266 patients in the no-IHSS group and 136 in the IHSS group. After adjusting for individual characteristics, we observed that IHSS was associated with increased program completion rates (odds ratio = 1.95, 95% CI 1.02-3.70). There was no significant association between IHSS patients' health service use at time one or time two. Primary care visits time 1: aOR 0.55, 95%CI 0.72-1.13, time 2: aOR 1.13, 95%CI 0.79-1.23; ED visits overall time 1: aOR 0.91, 95%CI 0.67-1.23, time 2: aOR 1.06, 95%CI 0.75-1.50; ED visits for substance use time 1: aOR 0.81, 95%CI 0.47-1.39, time 2: aOR 0.79, 95%CI 0.37-1.54; Hospitalizations time 1: aOR 0.78, 95%CI 0.41-1.47, time 2: aOR 0.76, 95%CI 0.32-1.80; Mental health visits time 1: aOR 0.66, 95%CI 0.46-0.96, time 2: aOR 0.92 95%CI 0.7-1.40. CONCLUSIONS: Our results indicate that IHSS positively influenced program completion but had no significant effect on health service use. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov (identifier number NCT04604574). First registration 10/27/2020.

A study protocol for a quasi-experimental community trial evaluating the integration of indigenous healing practices and a harm reduction approach with principles of seeking safety in an indigenous residential treatment program in Northern Ontario.

BACKGROUND: Indigenous communities in Canada face significant challenges with intergenerational trauma, which manifests in substance use disorders. There is consensus that connecting treatment approaches to culture, land, community, and spiritual practices is a pathway to healing trauma and substance use disorders for Indigenous peoples. Indigenous residential addiction treatment programs have been established as the primary intervention to provide healing for Indigenous peoples with substance use disorders and intergenerational trauma. However, there is limited evidence demonstrating the effectiveness of these programs. In collaboration with the Benbowopka Treatment Centre, this paper describes a study protocol which aims to evaluate the effectiveness of blending Indigenous Healing Practices and Seeking Safety for the treatment of Indigenous patients with intergenerational trauma and substance use disorders. METHODS: We will conduct a pre/post Quasi Experimental Community trial, to compare historical treatment outcomes for patients following the implementation of Indigenous Healing and Seeking Safety. We will conduct quantitative and qualitative analyses to understand the differences before and after the intervention is implemented. The pre- Indigenous Healing and Seeking Safety intervention study window will span from 2013 to 2016; n = 343, and the post-Indigenous Healing and Seeking Safety intervention study window from 2018 to 2020; n > 300. All participants will be enrolled in the Benbowopka residential treatment for the first time during the study periods. All data will be anonymized at the time of data entry. Propensity matching will be undertaken for patient characteristics, including sex/gender, age, and substance use type. RESULTS AND CONCLUSIONS: The study findings could be used to inform intergenerational trauma and substance use disorders residential treatment programming for Indigenous communities across Canada. Our work will contribute to the field of community-based intergenerational trauma and substance use disorders programming by addressing objectives that consider: (a) the patient perspective, (b) the program perspective, and (c) the community perspective. The study findings may validate an innovative approach for evaluating the effectiveness of residential addiction treatment and particularly the effective and appropriate care for Indigenous patients with intergenerational trauma and substance use disorders.

A critical hybrid realist-outcomes systematic review of relationships between medical education programmes and communities: BEME Guide No. 35.

BACKGROUND: The relationships between medical schools and communities have long inspired and troubled medical education programmes. Successive models of community-oriented, community-based and community-engaged medical education have promised much and delivered to varying degrees. A two-armed realist systematic review was undertaken to explore and synthesize the evidence on medical school-community relationships. METHOD: One arm used standard outcomes criteria (Kirkpatrick levels), the other a realist approach seeking out the underlying contexts, mechanisms and outcomes. 38 reviewers completed 489 realist reviews and 271 outcomes reviews; 334 articles were reviewed in the realist arm and 181 in the outcomes arm. Analyses were based on: descriptive statistics on both articles and reviews; the outcomes involved; the quality of the evidence presented; realist contexts, mechanisms, and outcomes; and an analysis of underlying discursive themes. FINDINGS: The literature on medical school-community relationships is heterogeneous and largely idiographic, with no common standards for what a community is, who represents communities, what a relationship is based on, or whose needs are or should be being addressed or considered. CONCLUSIONS: Community relationships can benefit medical education, even if it is not always clear why or how. There is much opportunity to improve the quality and precision of scholarship in this area.

Implementation and evaluation of a two-eyed seeing approach using traditional healing and seeking safety in an indigenous residential treatment program in Northern Ontario.

Indigenous clients in need of residential care for substance use disorders (SUD) often present with the diagnosis of substance use disorder (SUD) combined with intergenerational trauma (IGT) or both. SUD is exceedingly prevalent amongst Indigenous peoples due to the health impacts of colonisation, residential school trauma, and IGT on this population's health. We evaluated the effectiveness of a Two-Eyed Seeing approach in a four-week harm reduction residential treatment programme for clients with a history of SUD and IGT. This treatment approach blended Indigenous Healing practices with Seeking Safety based on Dr. Teresa Marsh's research work known as Indigenous Healing and Seeking Safety (IHSS). The data presented in this study was drawn from a larger trial. This qualitative study was undertaken in collaboration with the Benbowopka Treatment Centre in Blind River, Northern Ontario, Canada. Patient characteristic data were collected from records for 157 patients who had enrolled in the study from April 2018 to February 2020. Data was collected from the Client Quality Assurance Survey tool. We used the qualitative thematic analysis method to analyse participants' descriptive feedback about the study. Four themes were identified: (1) Motivation to attend treatment; (2) Understanding Benbowopka's treatment programme and needs to be met; (3) Satisfaction with all interventions; and (4) Moving forward. We utilised a conceptualised descriptive framework for the four core themes depicted in the medicine wheel. This qualitative study affirmed that cultural elements and the SS Western model were highly valued by all participants. The impact of the harm reduction approach, coupled with traditional healing methods, further enhanced the outcome. This study was registered with clinicaltrials.gov (identifier number NCT0464574).

Pain and Opioid Addiction: A Systematic Review and Evaluation of Pain Measurement in Patients with Opioid Dependence on Methadone Maintenance Treatment.

BACKGROUND: While chronic pain has been said to impact patient's response to methadone maintenance treatment for opioid dependence, the reported findings are inconsistent. These discrepancies may be a direct result of variations in the measurement of chronic pain or definitions of response to methadone treatment. The goal of this study is to evaluate the association between pain and substance use behaviour to determine the real impact of comorbid pain in the methadone population. We also aim to examine sources of variation across the literature with a specific focus on the measurement of pain. METHODS/DESIGN: We performed a systematic review using an electronic search strategy across CINAHL, MEDLINE, Web of Science, PsychINFO, EMBASE, and the Cochrane Library including Cochrane Reviews and the Cochrane Central Register of Controlled Trials databases. Title, abstract, as well as full text screening and extraction were performed in duplicate. Studies evaluating the association between chronic pain and methadone maintenance treatment response were eligible for inclusion in this review. Using a sample of 297 methadone patients from the Genetics of Opioid Addiction (GENOA) research collaborative, we assessed the reliability of patient self-reported pain and the validated Brief Pain Inventory (BPI) assessment tool. RESULTS: After screening 826 articles we identified five studies eligible for full text extraction, of which three showed a significant relationship between the presence of pain and the increase in substance abuse among patients on methadone for the treatment of opioid dependence. Studies varied largely in the definitions and measurement of both pain and response to treatment. Results from our validation of pain measurement in the GENOA sample (n=297) showed the use of a simple self-reported pain question is highly correlated to the use of the BPI. Simply asking patients whether they have pain showed a 44.2% sensitivity, 88.8% specificity, 84.4% PPV and 53.6% NPV to the BPI. The area under the ROC curve was 0.67 and the Pearson χ(2) was 37.3; (p<0.0001). DISCUSSION: The field of addiction medicine is at a lack of consensus as to the real effect of chronic pain on treatment response among opioid dependent patients. Whether it be the lack of a single "gold standard" measurement of response, or a lack of consistent measurement of pain, it is difficult to summarize and compare the results of these relatively small investigations. In comparison to the BPI, use of the simple self-reported pain has lower sensitivity for identifying patients with pain, suggesting the inconsistencies in these studies may result from differences in pain measurement. Future validation studies of pain measurement are required to address the predictive value of self-reported pain.

Effect of fasting on hepatocytes cold stored in University of Wisconsin solution for 24 hours.

Although there have been improvements in liver preservation, liver dysfunction still remains a serious consequence of liver transplantation. This may be related to cold ischemic injury since the incidence of dysfunction increases with longer preservation times. However, even some livers preserved for short periods of time (less than 15 hr) develop liver dysfunction. One possible cause may be the lack of adequate nutritional support, and the donor may be exposed to prolonged periods of hyponutrition. In this study, we have compared the effects of fasting on functions of hepatocytes isolated from the rat. Hepatocytes were cold stored in University of Wisconsin solution for 24 hr and analyzed at the end of preservation as well as at the end of rewarming in Krebs-Henseleit buffer for 120 min. The glycogen content of fed cells was 1.57 mumol/mg protein and this was reduced by 95% in cells from fasted rats. After cold storage and rewarming, hepatocytes from fasted rats lost 84.2 +/- 2.5% of the total cellular lactate dehydrogenase versus only 32.7 +/- 3.8% (P < 0.001) in cells from fed rats. Also, ATP and reduced glutathione content of fasted cells were significantly reduced, free fatty acids were higher (P = 0.0154), and protein synthesis was reduced to 41% of controls (versus only 88% in fed cells), although there were no differences in phospholipid content. When hepatocytes from fasted rats were rewarmed in Krebs-Henseleit buffer containing fructose (10 mM), lactate dehydrogenase release was reduced from 80% to 34.4 +/- 0.2% and ATP content was significantly higher with fructose than without. Hepatocytes from fasted rats, therefore, are more sensitive to cold ischemic injury than cells from fed rats. The increased sensitivity appears related to the lack of glycogen as a source of substrates for metabolism during rewarming. This is supported by the fact that addition of fructose, which is metabolized readily by hepatocytes through glycolysis, suppressed rewarming injury to cells from fasted rats. The nutritional status of the donor, therefore, may play a pivotal role in the results of liver preservation and transplantation. Effective donor nutritional management may reduce the incidence of liver dysfunction after transplantation.

Oxygen-derived free radical damage in organ preservation: activity of superoxide dismutase and xanthine oxidase.

It has been suggested that the generation of oxygen-derived free radicals during the reperfusion of injured tissue causes organ dysfunction. The mechanism apparently involves the xanthine oxidase (XOD) enzyme system, which becomes activated during reperfusion and generates oxygen-derived free radicals faster than their dismutation by naturally occurring superoxide dismutase (SOD). In this study, we measured the XOD and SOD activities of liver and kidney tissue in species used for organ preservation studies (rats, dogs, and human beings). We also measured the effect that up to 5 days of hypothermic preservation has on the activity of SOD and XOD in canine kidneys and expressed activities as the ratio of SOD to XOD; large ratios suggest lower susceptibility to oxygen-derived free radical damage. The SOD:XOD ratios for rat tissue were consistently lower (kidney = 2.7 X 10(4), liver = 8.9 X 10(3)) than for canine tissue (kidney = 7.0 X 10(5), liver = 4.1 X 10(4)) and human tissue (kidney = 1.1 X 10(6), liver = 6.4 X 10(5)). Canine kidneys perfused for 3 days showed no change in SOD:XOD ratio. After 5 days of perfusion, the SOD:XOD ratio decreased by 50% but was still quite large (5 X 10(5]. This high SOD:XOD ratio in canine and human tissues suggests that they may be less sensitive to oxygen-derived free radical damage than rat tissues.

Trichothecene mycotoxins from Fusarium culmorum cultures.

Chemical analysis of the culture filtrates of Fusarium culmorum CMI 14764 has demonstrated the presence of seven trichothecene mycotoxins. Major metabolites are 3-acetyldeoxynivalenol and 7 alpha, 8 alpha-dihydroxycalonectrin, with 3,15-diacetyldeoxynivalenol, deoxynivalenol, calonectrin, isotrichodermin and 12,13-epoxytrichothec-9-ene (EPT) as minor products. The occurrence of the rarely encountered unsubstituted trichothecene EPT is significant in that this compound may function as a common intermediate in the biosynthetic pathways to all natural trichothecenes. The structures of the known trichothecenes isolated from F. culmorum suggest a route in which EPT is sequentially oxygenated to the more complex deoxynivalenol derivatives.

Cholinoceptor-mediated mechanical and electrical responses of rat oesophageal striated musculature. A comparison of two in vitro methods.

1. Both muscarinic and nicotinic cholinoceptor agonists produce a contractile response of the rat oesophageal tunica muscularis externa (TME) in vitro. 2. The muscarinic receptor-mediated responses were confined to the distal 0.5 cm of the TME, which contains an admixture of smooth muscle. 3. Nicotinic receptor-mediated responses were obtained throughout the length of the TME striated musculature and consisted of a fast and slow component, representing TTX-sensitive contractions, associated with muscle action potentials, and electrically silent contractures, respectively. 4. Contractions were observed only in superfused preparations. 5. Contractures were resistant to changes in extracellular cation concentrations designed to eliminate generation of nerve and muscle action potentials or release of neurotransmitters.

Hypothermic preservation of hepatocytes. II. Importance of Ca2 and amino acids.

The importance of the components of a tissue culture media, Leibovitz-15 (L-15), for maintaining viability of hypothermically preserved hepatocytes was analyzed. Hepatocytes isolated from rat livers were incubated at 5 degrees C in an oxygenated environment with continuous shaking (to simulate organ perfusion preservation). L-15 + 5 g% polyethylene glycol (PEG) or variants of this solution were used as the preservation media. After 48 hr of storage, hepatocyte viability was assessed by measuring the release of LDH into the incubation medium and cell volumes were determined. Following 90 min of normothermic incubation (to simulate organ reperfusion), mitochondrial function was measured. Hepatocytes stored in the complete L-15 solution were about 90% viable at the end of 48 hr of storage, while cells stored in a solution containing only the principle electrolytes (PE) lost viability (70% viable). Only the addition of a combination of divalent cations (Ca/Mg) and amino acids was sufficient to maintain viability equivalent to that obtained in the complete L-15 mixture. Hepatocytes suspended in L-15 maintained normal cell volumes (3.85 microliters/mg protein), while cells in the PE solution were swollen with cell volumes of 4.66 microliters/mg protein. Only the addition of Ca/Mg to the PE solution was effective at suppressing cell swelling similar to the complete L-15 media. Both basal and uncoupler-stimulated respiration were depressed in cells stored in the PE solution (15 and 28 nmol O2/min/mg protein) as compared to cells in L-15 (21 and 41 nmol O2/min/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of isolated hepatocytes and tissue slices for study of liver hypothermic preservation/reperfusion injury.

Simple models are needed that effectively test the variables that may be important in liver preservation. Two such models are isolated hepatocytes and tissue slices. In this study the effects of hypothermic preservation on the viability of hepatocytes (HC) and tissue slices (TS) from rat livers were measured by LDH leakage after cold storage and rewarming. We compared how glycine, calcium, and fasting, shown previously to affect preservation injury in hepatocytes, affected both HC and TS viability. Hepatocytes were cold-stored in University of Wisconsin organ preservation solution for up to 48 h and rewarmed in Krebs-Henseleit Bicarbonate (KHB) for 120 min. Tissue slices were studied in two ways. Either livers were cold-stored intact and then tissue slices (TS-A) prepared and rewarmed in KHB, or tissue slices were prepared from the fresh liver, cold-stored, and then rewarmed (TS-B). The latter method may be similar to cold storage of HC. Freshly prepared samples (HC, TS-A, or TS-B) showed < 15% LDH leakage during the rewarming phase. Cold storage for 24 h resulted in < 30% LDH leakage in all preparations. After 48 h cold storage there was a significant increase in LDH leakage (HC, 65.1 +/- 5.1%; TS-A, 52.9 +/- 0.8%, TS-B, 53.6 +/- 2.6%). Glycine (3 mM) or calcium (1.5 mM) included in the KHB significantly reduced LDH leakage from 48 h cold-stored HC to 20.7 +/- 1.8 and 26.3 +/- 2.4%, respectively. These agents caused a smaller decrease in LDH release from tissue slices (around 40%). Hepatocytes appear more susceptible to preservation/reperfusion damage than the more structurally intact tissue slices as suggested by the greater release of LDH. Another difference was that the agents which improved preservation quality of HC were not as effective in TS. Hepatocytes may be more vulnerable to preservation/reperfusion damage because of the harsh methods used in their preparation. The damage induced during preparation appears amenable to suppression by glycine or calcium. Tissue slices, which are intact pieces of liver tissue, may be more suitable for studies related to development of better methods for liver preservation. The intact cells in TS have not been exposed to harsh conditions and maintain a more natural cell-cell relationship.

The role of oxygen free radicals in organ preservation.

There is controversy over the role of oxygen free radical-induced damage in preserved organs following reperfusion. Furthermore, there has been no definitive study that shows a dramatic improvement in organ functions, delayed graft functions, or improved longevity in organ transplants with oxygen free radical scavenger therapy. However, the presence of glutathione in a new organ preservation solution (University of Wisconsin, UW, solution) yields improved preservation of the liver and heart. The beneficial effect of glutathione may involve in scavenging of cytotoxic products of oxygen metabolism. The results discussed here show that glutathione improves liver preservation. Also, it is shown that glycine, and amino acid component of glutathione, can also give cytoprotection to the rabbit and dog liver tested by either isolated perfusion or orthotopic transplantation. Thus, there may be an involvement of oxygen free radicals in damage to organs hypothermically preserved and transplanted. The injury may occur within the cells or may be due to oxygen within the cells or may be due to oxygen free radicals generated in the extracellular environment.

The effect of pH on the viability of hypothermically stored rat hepatocytes.

Hepatocytes isolated from the rat liver were stored for up to 72 hr at 4 degrees C in a tissue culture medium (Liebovitz-15) at different pH values to determine how pH affects hepatocyte viability. This is a model to simulate cold storage of livers for transplantation and determine the optimal pH for maintenance of liver cell function. The cells were stored in the absence of oxygen. At the end of cold storage the percentage of the total cellular LDH released into the extracellular medium was used as a measure of hepatocyte viability. Also, lactate dehydrogenase (LDH) release was determined in hepatocytes incubated at normothermia (37 degrees C) for 90 min following 72 hr of cold storage. The results demonstrate that hepatocytes tolerate a wide range of pH values in the storage medium and that only about 10% of the total LDH was released from hepatocytes stored up to 72 hr at pH's from 5.0 to 8.0. Normothermic incubation, however, demonstrated that the pH of the storage medium affected viability. After 48 hr of storage only hepatocytes stored at pH values from 7.0 to 8.0 remained viable (LDH release similar to that of freshly incubated hepatocytes = 28 +/- 7.2%). After 72 hr of storage and 90 min of normothermic incubation, hepatocytes incubated at all pH values studied were nonviable (greater than 60% release of LDH). These results suggest that the optimal pH for storage of hepatocytes at 4 degrees C is near neutrality (7.0 to 7.4).

Urea and protein synthesis in cold-preserved isolated rat hepatocytes.

We used an isolated-hepatocyte model to study how hypothermic storage (simulating liver preservation) affects metabolism after prolonged preservation. Rat hepatocytes were stored in the University of Wisconsin solution for up to 72 hr. After each day of storage, protein synthesis, urea synthesis, ATP content and lactate dehydrogenase release were determined in rewarmed (37 degrees C) and oxygenated hepatocytes. Protein synthesis ([3H]-leucine incorporation into protein) was depressed by 16% +/- 4%, 54% +/- 6% and 69% +/- 4% after 24 hr, 48 hr and 72 hr, respectively. Urea synthesis, ATP synthesis and lactate dehydrogenase release were similar to those in control hepatocytes (no preservation). Fasting of the rats before isolation of hepatocytes caused more rapid loss of protein-synthesis capabilities (59% in 24 hr) with no significant loss of lactate dehydrogenase, urea synthesis or ATP synthesis. Hepatocyte viability (lactate dehydrogenase release) as judged by membrane permeability, ATP synthesis and potassium content can be maintained after up to 6 days of cold storage. However, protein synthesis is depressed after only 48 hr of cold storage. Thus hypothermic storage of the liver causes a change in the metabolic capabilities of the hepatocytes, and the timing of the loss of protein synthesis is similar to the limits of successful cold storage of the whole liver (48 hr). Thus a limit to long-term storage of the liver may be related to loss of protein synthesis. In liver transplantation, one indication of poor preservation is a decrease in serum albumin and clotting factors with increased tissue edema and bleeding diathesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of solutions for preservation of the rabbit liver as tested by isolated perfusion.

The University of Wisconsin (UW) solution consists of a relatively complex mixture of agents. In this study we compared simpler preservation solutions, namely, histidine-tryptophan-ketoglutarate (HTK) and phosphate-buffered sucrose (PBS) with different compositions of UW solution in the isolated perfused rabbit liver model. Livers were stored cold for 24 and 48 h. After 24 h of preservation, the amount of bile produced in UW-preserved livers was significantly greater (P < 0.05) than that in HTK-preserved livers. Also, there was less LDH released into the perfusate in UW-preserved livers. There was more edema and lower K +/Na+rations in HTK-preserved livers than in UW-preserved livers (all data P < 0.05). After 48 h of preservation, the differences between livers preserved in UW or HTK solution were less noticeable than at 24 h and bile production was similar. LDH and AST release were greater in HTK-preserved livers than in UW livers, but these differences were not statistically significant. Preservation in PBS for 48 h was worse than in either UW or HTK solution. Substitution of polyethylene glycol (PEG) for hydroxyethyl starch (HES) in 48-h UW-preserved livers was not effective. We conclude that solutions simpler in composition than UW solution may be effective in kidney transplantation but do not appear suitable for successful liver preservation.

Effect of glycine on isolated, perfused rabbit livers following 48-hour preservation in University of Wisconsin solution without glutathione.

Glycine has been shown to decrease membrane injury in isolated cells due to hypoxia or cold ischemia. The mechanisms of action of glycine are not known, but glycine may be useful in organ preservation solutions or in treating recipients of liver transplantation. In this study the isolated, perfused rabbit liver was used to measure how glycine affected liver performance after 48-h preservation in University of Wisconsin (UW) solution without added glutathione. UW solution is less effective for 48-h liver preservation when glutathione is omitted. Rabbit livers stored for 48 h without glutathione show a large increase in enzyme release (LDH and AST) from the liver and a reduction in bile production. The addition of 15 mM glycine to UW solution, in place of glutathione, did not improve bile production or reduce enzyme release. However, infusion of 10 mM glycine into the reperfused liver lowered LDH release significantly (from 2383 +/- 562 units/100 g to 1426 +/- 286 units/100 g) during the initial reperfusion of the 48-h preserved liver. Hepatamine, a parenteral nutrition solution containing glycine, as well as other amino acids, was also effective in lowering LDH release from the preserved liver. Although glycine reduced LDH release, it did not decrease the amount of AST released from the liver, nor did it improve bile production. Thus, we conclude that glycine, either in UW solution or given to the liver upon reperfusion, has no significantly beneficial effect as tested in this model. Further testing of glycine, however, should be conducted in an orthotopic transplant model in the rat or dog.