Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

A Mixed-Methods Study to Better Measure Patient-Reported Pain and Fatigue in Soft Tissue Sarcoma.

INTRODUCTION: Pain and fatigue are commonly reported by patients with soft tissue sarcoma (STS) as distressing symptoms, yet no patient-reported outcome (PRO) measures have been validated or developed specifically for STS. This study aimed to develop novel PRO scales using existing item banks to measure pain and fatigue in STS. METHODS: A three-stage mixed-methods approach was used. Stage 1: a literature review examined the development and validation of the European Organization for Research and Treatment of Cancer (EORTC) library, Patient-Reported Outcomes Measurement Information System (PROMIS) pain/fatigue item banks, Functional Assessment of Cancer Therapy-General, and FACIT-Fatigue. Conceptual models were developed for pain and fatigue. Stage 2: semi-structured interviews were conducted with clinical experts (n = 3) and STS patients (n = 28) to ensure conceptual coverage and cognitively debrief the selected PRO items. Stage 3: exploratory Rasch measurement theory (RMT) analyses were performed to examine the measurement properties of the proposed scales. RESULTS: Stage 1: The conceptual model for fatigue was organized into two overarching domains: fatigability and fatigue, further split into two subdomains: symptoms and impact. The conceptual model for pain had one overarching domain split into two subdomains: descriptors and impact. Pain (n = 56) and fatigue (n = 40) items were selected from the EORTC item library. Stage 2: qualitative findings ensured conceptual coverage, provided insight into the relevance and comprehension of the items, and informed subsequent item reduction. Stage 3: The total item number was reduced to 43 (pain n = 18, fatigue n = 25). Exploratory RMT analyses supported the final scales' psychometric properties. CONCLUSIONS: This mixed-methods research generated important information on the experience of pain and fatigue in specific subtypes of STS. Five novel PRO scales have been developed through careful item selection in consultation with experts and supported by qualitative and quantitative evidence. These scales may be of value to future clinical trials for STS.

Modulating Macrophage Clearance of Nanoparticles: Comparison of Small-Molecule and Biologic Drugs as Pharmacokinetic Modifiers of Soft Nanomaterials.

Nanomedicines show benefits in overcoming the limitations of conventional drug delivery systems by reducing side effects, toxicity, and exhibiting enhanced pharmacokinetic (PK) profiles to improve the therapeutic window of small-molecule drugs. However, upon administration, many nanoparticles (NPs) prompt induction of host innate immune responses, which in combination with other clearance pathways such as renal and hepatic, eliminate up to 99% of the administered dose. Here, we explore a drug predosing strategy to transiently suppress the mononuclear phagocyte system (MPS), subsequently improving the PK profile and biological behaviors exhibited by a model NP system [hyperbranched polymers (HBPs)] in an immunocompetent mouse model. In vitro assays allowed the identification of five drug candidates that attenuated cellular association. Predosing of lead compounds chloroquine (CQ) and zoledronic acid (ZA) further showed increased HBP retention within the circulatory system of mice, as shown by both fluorescence imaging and positron emission tomography-computed tomography. Flow cytometric evaluation of spleen and liver tissue cells following intravenous administration further demonstrated that CQ and ZA significantly reduced HBP association with myeloid cells by 23 and 16%, respectively. The results of this study support the use of CQ to pharmacologically suppress the MPS to improve NP PKs.

Oncostatin M expression induced by bacterial triggers drives airway inflammatory and mucus secretion in severe asthma.

Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.

Clinical and cost-effectiveness of an online-delivered group-based pain management programme in improving pain-related disability for people with persistent pain-protocol for a non-inferiority randomised controlled trial (iSelf-help trial).

INTRODUCTION: Persistent non-cancer pain affects one in five adults and is more common in Maori-the Indigenous population of New Zealand (NZ), adults over 65 years, and people living in areas of high deprivation. Despite the evidence supporting multidisciplinary pain management programmes (PMPs), access to PMPs is poor due to long waiting lists. Although online-delivered PMPs enhance access, none have been codesigned with patients or compared with group-based, in-person PMPs. This non-inferiority trial aims to evaluate the clinical and cost-effectiveness of a cocreated, culturally appropriate, online-delivered PMP (iSelf-help) compared with in-person PMP in reducing pain-related disability. METHODS AND ANALYSIS: Mixed-methods, using a modified participatory action research (PAR) framework, involving three phases. Phase I involved cocreation and cultural appropriateness of iSelf-help by PAR team members. Phase II: The proposed iSelf-help trial is a pragmatic, multicentred, assessor-blinded, two-arm, parallel group, non-inferiority randomised controlled trial. Adults (n=180, age ≥18 years) with persistent non-cancer pain eligible for a PMP will be recruited and block randomised (with equal probabilities) to intervention (iSelf-help) and control groups (in-person PMP). The iSelf-help participants will participate in two 60-minute video-conferencing sessions weekly for 12 weeks with access to cocreated resources via smartphone application and a password-protected website. The control participants will receive group-based, in-person delivered PMP. Primary outcome is pain-related disability assessed via modified Roland Morris Disability Questionnaire at 6 months post intervention. Secondary outcomes include anxiety, depression, stress, pain severity, quality of life, acceptance, self-efficacy, catastrophising and fear avoidance. Data will be collected at baseline, after the 12-week intervention, and at 3 and 6 months post intervention. We will conduct economic analyses and mixed-method process evaluations (Phase IIA). ETHICS AND DISSEMINATION: The Health and Disability Ethics Committee approved the study protocol (HDEC18/CEN/162). Phase III involves dissemination of findings guided by the PAR team as outcomes become apparent. TRIAL REGISTRATION NUMBER: ACTRN 12619000771156.

Overeating and food addiction in Major Depressive Disorder: Links to peripheral dopamine.

The concept of food addiction refers to addiction-like behaviours that develop in association with the intake of highly palatable foods. Previous research indicates that a high proportion of individuals with Major Depressive Disorder (MDD) meet the criteria for food addiction, and are also at an increased risk of weight gain and chronic disease. In the central nervous system, dopamine is a neurotransmitter associated with reward salience and food intake, whereas peripheral dopamine is involved in sympathetic stress regulation, digestion and gastrointestinal motility. However, little research has examined relationships between peripheral dopamine, depressive symptoms and problematic eating behaviours in MDD. Biometrics, psychopathology and plasma dopamine levels were compared between participants with MDD (n = 80) and controls (n = 60). Participants were sub-categorised into those meeting or not meeting Yale Food Addiction Scale (YFAS) criteria. Psychometric measures of mood and appetite were used to assess MDD symptoms, problematic eating behaviours and food-addiction related symptoms. Twenty-three (23; 29%) MDD participants met the Yale criteria for food addiction. Depressed individuals meeting YFAS criteria had significantly greater psychopathology scores for both mood and eating compared to depressed individuals not meeting YFAS criteria and controls. A significant interaction between food addiction status and sex was also observed for plasma dopamine levels. Plasma dopamine levels correlated positively with disordered eating behaviours in females, and negatively in males. The results provide evidence that depressogenic excess eating and weight gain are associated with peripheral dopamine levels. Longitudinal research is warranted investigating endocrine dysregulation and excess eating in MDD, which may inform interventions and reduce chronic disease risk in affected individuals.

Predictors for surgical intervention and surgical outcomes in neonates with cystic fibrosis.

BACKGROUND/PURPOSE: To identify prenatal and perinatal predictors of surgery and describe surgical findings/outcomes of neonates with Meconium Ileus (MI) secondary to Cystic Fibrosis (CF). METHODS: Potential risk factors (prenatal bowel echogenicity, CF genotype, birthweight, prematurity and sex) for MI and surgery were examined in a retrospective cohort of neonates with CF presenting to a tertiary center between 1997 and 2015. Following univariable analysis, predictors of MI and surgery were determined using multivariable logistic regression. For surgical patients, detailed operative findings and outcomes were examined. RESULTS: MI was diagnosed in 26/120 (21.7%) neonates with CF and 19/26 (73.0%) required surgery. Prematurity was significantly associated with increased risk of MI and operative intervention (p-value 0.022 and p-value 0.016 respectively); lower birthweight was associated with operative intervention (p-value 0.039); genotype and echogenic bowel were associated with neither. Surgical data were available for 17/19 patients; median age at surgery was 2 days (IQR1-3), 4/17 had an atresia and 6/17 received an ostomy. Median NICU and hospital stays were 34.5 and 70 days while median time on TPN and time to ostomy reversal were 28.5 and 97 days, respectively. CONCLUSIONS: In patients with CF, prematurity and lower birthweight were identified as risk factors for meconium ileus and need for surgery. Specific genotypes and echogenic bowel were not predictors of either. LEVEL OF EVIDENCE: Level III.

Decision-Making Criteria for Observational Management of Congenital Pulmonary Airway Malformations (CPAMs).

PURPOSE: The purpose of this study was to determine practice patterns of Canadian surgeons managing congenital pulmonary airway malformations (CPAMs) and factors influencing practice. METHODS: Pediatric surgeons in Canada were surveyed regarding their experience, evaluation, and management CPAMs, and what factors they feel qualify patients for observation vs resection. Data were summarized, and Fisher's-Exact and Kruskal-Wallis Tests applied where appropriate. RESULTS: Sixty eight percent (n=46) of surgeons responded. However, three surveys were incomplete and excluded. The median age of initial assessment by a pediatric surgeon was one month. 98% (42/43) use CXR for initial imaging, and 83% (36/43) recommend CT scan for further evaluation. Observation is offered always, almost always, or sometimes by 2%, 35% and 37%, respectively. Only 16% almost never, and 9% never offer it. Years in practice was not associated with this decision (p=0.41). Of surgeons who offer observation, 78% (28/37) use morphology to guide their decision, and 63% (21/37) use lesion size (<1cm to <5cms). 68%(23/37) consider the number of lesions, and 61%(14/23) of those only offer observation to solitary lesions. CONCLUSION: Most pediatric surgeons in Canada offer observational management to patients with asymptomatic CPAMs. While practice variations exist, detailed imaging with a CT scan early in life to determine the morphology, size, and number of lesions guides practice. LEVEL OF EVIDENCE: V.

Chylothorax after congenital diaphragmatic hernia repair: a population-based study.

PURPOSE: Chylothorax is a recognized complication of congenital diaphragmatic hernia (CDH) repair. Our aims were to describe the frequency and outcomes of chylothorax and to seek predictors of chylothorax occurrence within a population-based CDH cohort. METHODS: Records for patients with CDH born between 2006 and 2010 were abstracted from a national database and were compared according to presence/absence of postrepair chylothorax. Univariate, and where appropriate, multivariate analyses were performed for group comparisons and chylothorax outcome prediction. RESULTS: Of 243 newborns with CDH surviving to repair, 11 (4.5%) developed a chylothorax. All were managed nonoperatively. Factors predictive of chylothorax outcome on multivariate analysis included need for preoperative transfusion (odds ratio, 13.2; 95% confidence interval, 2.1-83.7; P = .006) and preoperative high-frequency oscillatory ventilation (odds ratio, 7.1; 95% confidence interval, 1.6-31.2; P = .01). Preoperative vasopressor use was significant on univariate analysis only. The groups were comparable for survival, length of stay, and duration of ventilation, but chylothorax patients had prolonged total parenteral nutrition (53 vs 21 days, P = .006) and more central line days (46 vs 24 days, P = .03). CONCLUSIONS: Our data suggest that severity of preoperative cardiopulmonary derangement and not anatomical or technical factors predicts chylothorax occurrence after CDH repair.

Television-related injuries in children--the British Columbia experience.

PURPOSE: In Canada, mortality from falling televisions (TVs) is the 15th leading cause of childhood death owing to injury. Frequency, characteristics, and outcomes of TV childhood injuries were examined to determine any at risk populations. METHODS: All TV-related traumas at a tertiary children's hospital from 1997 to 2011 were identified using the Canadian Hospitals Injury Reporting and Prevention Program database and the hospital's trauma database. Charts of admitted patients were reviewed. RESULTS: Analysis of 179 injuries (10-24 per year) revealed a high frequency of injury in the home and a preponderance of head and neck injuries. Toddlers were the most commonly injured age group. Eleven admitted patients were identified; 6 were admitted to intensive care unit with significant head injuries, 2 of whom required surgery. More than half of admitted patients were First Nations or recent immigrants. The length of stay for a ward vs intensive care unit admission was 1.3 days (range, <1-2 days) compared with 7.6 days (range, <1-20 days), respectively. One child had residual deficits requiring rehabilitation, but there were no mortalities. CONCLUSION: Injury severity appeared higher in patients from First Nations and recent immigrant families. Television injury would likely have been prevented by a securing device or support.

Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver.

A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of ß-amyloid peptides (Aß) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aß and a decrease in brain Aß monomer after 7 d, indicating increased transport of Aß from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aß-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aß levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aß. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aß, indicating that increase in liver LRP and sLRP occurring independent of Aß concentration could result in clearance of Aß. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aß clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.

A single center 26-year experience with treatment of esophageal achalasia: is there an optimal method?

PURPOSE: Treatment modalities for achalasia are evolving and remain controversial. Herein, we report the relative efficacy and outcomes after dilatation or myotomy in children with achalasia. METHODS: A retrospective analysis of all children treated for achalasia at a tertiary center from 1981 to 2007 was performed (n = 40). Demographics, presenting symptoms, perioperative parameters, and outcomes were analyzed using t tests and chi(2) statistics. RESULTS: Thirty patients were initially treated by esophageal dilatation (ED), whereas 10 were treated by laparoscopic or open Heller myotomy (HM). Both groups were similar with respect to age (10.6 vs 12.4 years; P = .19). There were 18 males and 12 females in the ED group, compared to 5 males and 5 females in the HM group (P = .72). Mean duration of symptoms before diagnosis, including dysphagia, vomiting, food sticking, chest pain, and weight loss, was 15.9 months for ED and 10.7 months for HM (P = .41). Mean time from diagnosis to initial intervention was 76 days in ED vs 86 days in HM (P = .78). Subsequent interventions by myotomy or both dilatation and myotomy were required in 9 (30%) of 30 patients in the ED group and 2 (20%) of 10 patients in the HM group (P = .70). A clear transition from open to laparoscopic approach occurred between 1995 and 2001. Mean operating times were comparable (186.3 vs 156.0 minutes; P = .48). Of 14 laparoscopic myotomies, 11 (79%) had fundoplication, and 2 (18%) of the 11 were converted to open procedure. Intraoperative mucosal perforation rates were similar between open and laparoscopic groups (17% vs 18%). At follow-up, 32% of ED patients vs 43% HM had complete symptom relief (mean follow-up duration, 75.2 months; SD, 196.5). CONCLUSION: Both dilatation and myotomy are effective immediate treatment of achalasia. A clear transition to and preference for laparoscopic approach has occurred in the treatment of achalasia in children.

Long-term bowel function and quality of life in children with Hirschsprung's disease.

BACKGROUND/PURPOSE: Little is known about the quality of life (QOL) of children with Hirschsprung's disease (HD) as they grow older. The purpose of this study was to measure the QOL and bowel function of these children as they mature. METHODS: All children who were surgically treated for HD at British Columbia Children's Hospital, Vancouver, British Columbia, Canada between 1986 and 2003 were invited to participate. Each family was sent 3 previously validated questionnaires exploring current QOL and bowel function. RESULTS: Fifty-one families participated (49%), with children between the ages of 3 and 21 years. Fecal continence improved significantly with age (P = .04) and was the strongest predictor of QOL scores of all variables in our study. There was no statistically significant difference in QOL scores between children with HD and healthy children, although a clinically relevant impairment in QOL may be present, especially in psychosocial scores. CONCLUSIONS: Fecal continence is an important predictor of overall QOL in children surgically treated for HD. Although continence tends to improve with age, a number of older children still have ongoing continence problems, and they seem to be a group at risk for impaired QOL. Our study indicates that interventions for children with incontinence may offer gains in QOL as well as bowel function.

In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system.

Thirty-one structurally diverse marketed central nervous system (CNS)-active drugs, one active metabolite, and seven non-CNS-active compounds were tested in three P-glycoprotein (P-gp) in vitro assays: transwell assays using MDCK, human MDR1-MDCK, and mouse Mdr1a-MDCK cells, ATPase, and calcein AM inhibition. Additionally, the permeability for these compounds was measured in two in vitro models: parallel artificial membrane permeation assay and apical-to-basolateral apparent permeability in MDCK. The exposure of the same set of compounds in brain and plasma was measured in P-gp knockout (KO) and wild-type (WT) mice after subcutaneous administration. One drug and its metabolite, risperidone and 9-hydroxyrisperidone, of the 32 CNS compounds, and 6 of the 7 non-CNS drugs were determined to have positive efflux using ratio of ratios in MDR1-MDCK versus MDCK transwell assays. Data from transwell studies correlated well with the brain-to-plasma area under the curve ratios between P-gp KO and WT mice for the 32 CNS compounds. In addition, 3300 Pfizer compounds were tested in MDR1-MDCK and Mdr1a-MDCK transwell assays, with a good correlation (R(2) = 0.92) between the efflux ratios in human MDR1-MDCK and mouse Mdr1a-MDCK cells. Permeability data showed that the majority of the 32 CNS compounds have moderate to high passive permeability. This work has demonstrated that in vitro transporter assays help in understanding the role of P-gp-mediated efflux activity in determining the disposition of CNS drugs in vivo, and the transwell assay is a valuable in vitro assay to evaluate human P-gp interaction with compounds for assessing brain penetration of new chemical entities to treat CNS disorders.

Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1.

The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (atorvastatin, lovastatin, and simvastatin in acid and lactone forms, and pravastatin in acid form only) with multidrug resistance gene 1 (MDR1, ABCB1) P-glycoprotein, multidrug resistance-associated protein 2 (MRP2, ABCC2), and organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO21A6). P-glycoprotein substrate assays were performed using Madin-Darby canine kidney (MDCK) cells expressing MDR1, and the efflux ratios [the ratio of the ratio of basolateral-to-apical apparent permeability and apical-to-basolateral permeability between MDR1 and MDCK] were 1.87, 2.32/4.46, 2.17/3.17, and 0.93/2.00 for pravastatin, atorvastatin (lactone/acid), lovastatin (lactone/acid), and simvastatin (lactone/acid), respectively, indicating that these compounds are weak or moderate substrates of P-glycoprotein. In the inhibition assays (MDR1, MRP2, Mrp2, and OATP1B1), the IC50 values for efflux transporters (MDR1, MRP2, and Mrp2) were >100 microM for all statins in acid form except lovastatin acid (>33 microM), and the IC50 values were up to 10-fold lower for the corresponding lactone forms. In contrast, the IC50 values for the uptake transporter OATP1B1 were 3- to 7-fold lower for statins in the acid form compared with the corresponding lactone form. These data demonstrate that lactone and acid forms of statins exhibit differential substrate and inhibitor activities toward efflux and uptake transporters. The interconversion between the lactone and acid forms of most statins exists in the body and will potentially influence drug-transporter interactions, and may ultimately contribute to the differences in pharmacokinetic profiles observed between statins.