Entrepreneurial mental health in the wake of COVID-19 in China with an emphasis on attention deficit hyperactivity disorder (ADHD) and dyslexia analysis.

The COVID-19 pandemic has precipitated a global mental health crisis, with a particularly pronounced impact on the entrepreneurial sector. This paper presents a comparative analysis of mental health challenges among entrepreneurs in China during the pandemic, with a specific focus on attention deficit hyperactivity disorder (ADHD) and Dyslexia. The study assesses the prevalence of ADHD and dyslexia symptoms among established and emerging entrepreneurs in China, finding notable occurrences within this group. The research also examines the self-care practices of these entrepreneurs, shedding light on their approaches during the pandemic period. The findings highlight a complex interplay between mental health issues and entrepreneurial activities, suggesting that certain ADHD and dyslexia traits may offer unexpected benefits in the entrepreneurial realm. These insights are critical for developing supportive frameworks that leverage the strengths of neurodiverse entrepreneurs while mitigating associated challenges, especially in a post-pandemic economic landscape. The study concludes with policy and practice recommendations to bolster the wellbeing and resilience of entrepreneurs facing the multifaceted impacts of the pandemic.

Continuous ketamine infusion for the management of opioid-induced hyperalgesia following amputation.

We discuss the use of an inpatient multi-day continuous intravenous ketamine infusion for the treatment of opioid-induced hyperalgesia (OIH) and high fentanyl requirements in the case of a patient with a background of fibromyalgia/central sensitisation syndrome who underwent a complicated post-operative course following a right below-knee amputation for high-grade myxoid fibrosarcoma. The patient was successfully tapered off a total fentanyl patch dose of 162 mcg/hour every 72 hours (morphine equivalent dose of 389 mg/day) to short-acting hydromorphone 2 mg orally two times per day as needed (equivalent of 8 mg morphine sustained-release twice per day) during a 2-week admission with only mild withdrawal symptoms. We discuss the pharmacology of ketamine and its possible application in the treatment of OIH.

Therapeutic effects of 7- to 14-day subanesthetic ketamine infusions for chronic pain on standardized psychiatric measures.

Background: We have previously shown that subanesthetic ketamine infusions effectively reduce refractory pain. However, the effects of ketamine infusions on comorbid conditions of depression and anxiety have not been explored in this patient population. Methods: We investigated the effects of ketamine on mood and anxiety in patients with refractory chronic pain treated with 7-14 days of subanesthetic continuous intravenous ketamine infusions, using well-validated clinical scales. Results: There was a significant 52% reduction in pain severity and 33% reduction in pain interference scores following ketamine treatment. Ketamine treatment also reduced scores on the depression module of the Patient Health Questionnaire (PHQ-9) by 28% and scores on the Generalised Anxiety and Depression Assessment (GAD-7) by 36%. Conclusion: Multiday subanesthetic ketamine infusions effectively reduce pain, anxiety and depression in patients with complex chronic pain.

What questions did we seek to answer? Chronic pain is a common problem with limited effective treatments. We have previously shown that supervised, multiday ketamine treatments given in the hospital can effectively reduce pain levels, with benefit for months for patients with persistent chronic pain. However, pain is quite complex and often co-occurs with other conditions, particularly depression and anxiety. We aimed to investigate how our ketamine infusions would impact these two important classes of disorder. We assessed our patients with chronic pain undergoing ketamine treatments using thoroughly researched clinical measures of pain, mood and anxiety before and after the infusions. What were the results? Patients had significant reductions in the standardized measures of pain and anxiety, and improvements in mood. We statistically checked whether these reductions were related, and found that reduced pain levels did not correlate with improvements in mood and anxiety levels. What do the results suggest? Ketamine treatments given in a carefully monitored hospital setting are effective in reducing anxiety and improving mood in patients undergoing treatment for chronic pain. The absence of a correlation between the change in pain levels and the change in anxiety and depression levels suggests that ketamine might affect different parts of the brain to achieve these independent effects.

OnabotulinumtoxinA Reduces Health Resource Utilization in Chronic Migraine: PREDICT Study.

BACKGROUND: PREDICT was a Canadian, multicenter, prospective, observational study in adults naïve to onabotulinumtoxinA treatment for chronic migraine (CM). We descriptively assess health resource utilization, work productivity, and acute medication use. METHODS: OnabotulinumtoxinA (155-195 U) was administered every 12 weeks over 2 years (≤7 treatment cycles). Participants completed a 4-item health resource utilization questionnaire and 6-item Work Productivity and Activity Impairment Questionnaire: Specific Health Problem V2.0. Acute medication use was recorded in daily headache diaries. Treatment-emergent adverse events were recorded throughout the study. RESULTS: A total of 197 participants were enrolled, and 184 received ≥1 treatment with onabotulinumtoxinA and were included in the analysis. Between baseline and the final visit, there were decreases in the percentage of participants who reported headache-related healthcare professional visit(s) (96.2% to 76.8%) and those who received headache-related diagnostic testing (37.5% to 9.9%). Reductions from baseline were also observed in the mean number of headache-related visits to an emergency room/urgent care clinic (2.5 to 1.4) and median headache-related hospital admissions (4.0 to 1.0). OnabotulinumtoxinA improved work productivity and reduced the mean (standard deviation) number of hours missed from work over a 7-day period (6.1 [9.7] to 3.0 [6.8]). Mean (standard deviation) acute medication use decreased from baseline (15.2 [7.6] to 9.1 [6.5] days). No new safety signals were identified. CONCLUSIONS: Real-world evidence from PREDICT demonstrates that onabotulinumtoxinA treatment for CM in the Canadian population reduces health resource utilization and acute medication use and improves workplace productivity, supporting the long-term benefits of using onabotulinumtoxinA for CM.

The effects of a multiday (10-14 days) subanesthetic dose IV ketamine infusion in the treatment of refractory chronic pain.

Aim: Ketamine is an anesthetic agent that at lower doses can be a potent analgesic. There has been an interest in the use of low dose ketamine in treatment of chronic pain syndromes. Patients & methods: We report the results of a retrospective observational study for patients diagnosed with a chronic noncancer pain syndrome receiving a 2-week continuous subanesthetic IV ketamine infusion. Results & conclusion: We conclude that a 10-14 days of subanesthetic ketamine infusion in chronic patients results in clinically significant lowering of patients' numerical pain score. Further studies looking at subanesthetic ketamine infusion in a prospective trial of multi-day IV ketamine infusion in chronic refractory chronic neuropathic pain are needed to further assess the efficacy of ketamine.

Ketamine is a pharmacological agent that was developed in the 1960s. There has been an increase in interest in the use of ketamine at low doses in the treatment of chronic pain syndromes. In this study, we report the results of a study that investigated patients diagnosed with a chronic noncancer pain syndrome that received a 2-week continuous ketamine infusion. We hypothesized that patients receiving IV ketamine infusion will experience acute and chronic lowering of pain intensity on the numerical rating pain level scale and reduce patient's opioid requirements. We concluded that a 10­14 day of subanesthetic ketamine infusion in chronic patients results in clinically significant lowering of patients' numerical pain score during the ketamine infusion.

OnabotulinumtoxinA Improves Quality of Life in Chronic Migraine: The PREDICT Study.

BACKGROUND: The PREDICT study assessed real-world, long-term health-related quality of life in adults with chronic migraine (CM) receiving onabotulinumtoxinA. METHODS: Canadian, multicenter, prospective, observational study in adults naïve to onabotulinumtoxinA for CM. OnabotulinumtoxinA (155-195 U) was administered every 12 weeks over 2 years (≤7 treatment cycles). Primary endpoint: mean change in Migraine-Specific Quality of Life Questionnaire (MSQ) at treatment 4 (Tx4) versus baseline. Secondary endpoints: mean change in MSQ at final visit versus baseline, and headache days. RESULTS: 184 participants (average age 45 years; 84.8% female; 94.6% Caucasian) received ≥1 onabotulinumtoxinA treatment; 150 participants completed 4 treatments (1 year) and 123 completed all 7 treatment cycles (2 years). Mean (SD) onabotulinumtoxinA dose per treatment cycle was 171 (18) U and treatment interval was 13.2 (1.8) weeks. Baseline mean (SD) 20.9 (6.7) headache days/month decreased (Tx1: -3.5 [6.3]; Tx4: -6.5 [6.6]; p < 0.0001 versus baseline). Mean (SD) increased from baseline in MSQ at Tx4 (restrictive: 21.5 [24.3], preventive: 19.5 [24.7], emotional: 22.9 [32.9]) and the final visit (restrictive: 21.3 [23.0], preventive: 19.2 [23.7], emotional: 27.4 [30.7]), exceeding minimal important differences (all p < 0.0001). Seventy-seven (41.8%) participants reported 168 treatment-emergent adverse events (TEAEs); 38 TEAEs (12.0%) were considered treatment-related. Four (2.2%) participants reported six serious TEAEs; none were considered treatment-related. No new safety signals were identified. CONCLUSIONS: Real-world evidence from PREDICT demonstrates that onabotulinumtoxinA for CM in Canada improved MSQ scores and reduced headache frequency and severity, adding to the body of evidence on the long-term safety and effectiveness of onabotulinumtoxinA for CM.

Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control.

AIMS: Opioid misuse and overuse have contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids. RESULTS: In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid-related complications, despite psychological or physical interventions. There was consensus observed to initiate with a cannabidiol (CBD)-predominant oral extract in the daytime and consider adding tetrahydrocannabinol (THC). When adding THC, start with 0.5-3 mg, and increase by 1-2 mg once or twice weekly up to 30-40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as-needed medication to control pain and/or the cannabis dose has been optimised. The opioid tapering schedule may be 5%-10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥30% reduction in pain intensity, a ≥25% reduction in opioid dose, a reduction in opioid dose to <90 mg MED and/or reduction in opioid-related adverse events. CONCLUSIONS: This five-stage modified Delphi process led to the development of consensus-based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.

Continuous Glucose Monitoring Versus Self-Monitoring of Blood Glucose to Assess Glycemia in Gestational Diabetes.

Background: Gestational diabetes mellitus (GDM) management using self-monitoring blood glucose (SMBG) does not normalize pregnancy outcomes. Objective: We aimed to conduct an observational study to explore if continuous glucose monitoring (CGM) could identify elevated glucose levels not apparent in women with GDM managed using SMBG. Study Design: A 7-day masked-CGM (iPro; Medtronic) was performed within 2 weeks of GDM diagnosis, immediately post-GDM education, but before insulin commencement as determined by SMBG. CGM data regarding hyperglycemia (sensor glucose >126 mg/dL [06:00-00:00 h] and >99 mg/dL [00:00-06:00 h] for >10% of time), time with health care professionals, treatment, and pregnancy outcome were collected. Comparisons (Mann-Whitney test) were performed between subjects subsequently commenced on insulin versus those continued with diet and lifestyle measures alone. Results: Ninety women of mean (standard deviation) gestational age weeks 27(1) were studied. Those prescribed insulin (n = 34) compared with those managed with diet and lifestyle alone (n = 56) had a greater time in hyperglycemia (P = 0.0001). Of those not prescribed insulin, 35/56 (61%) breached CGM cutoffs between 00:00 and 06:00 h; 11/56 (20%) breached 6.00-00.00 h CGM cutoffs for >10% of the time; and 21/45 (47%) with optimal CGM glucose levels during the daytime spent >10% time in hyperglycemia between 00.00 and 06:00 h. In contrast, SMBG measurements exceeded the clinical targets of <120 mg/dL postdinner in 5.4% and <100 mg/dL fasting in 0% of the subjects. Conclusions: CGM provides a more comprehensive assessment of nocturnal hyperglycemia than SMBG and could improve targeting of interventions in GDM. Larger studies to better define CGM targets are required, which once established will inform studies aimed at targeting nocturnal glucose levels.

Understanding the microbial basis of body odor in pre-pubescent children and teenagers.

BACKGROUND: Even though human sweat is odorless, bacterial growth and decomposition of specific odor precursors in it is believed to give rise to body odor in humans. While mechanisms of odor generation have been widely studied in adults, little is known for teenagers and pre-pubescent children who have distinct sweat composition from immature apocrine and sebaceous glands, but are arguably more susceptible to the social and psychological impact of malodor. RESULTS: We integrated information from whole microbiome analysis of multiple skin sites (underarm, neck, and head) and multiple time points (1 h and 8 h after bath), analyzing 180 samples in total to perform the largest metagenome-wide association study to date on malodor. Significant positive correlations were observed between odor intensity and the relative abundance of Staphylococcus hominis, Staphylococcus epidermidis, and Cutibacterium avidum, as well as negative correlation with Acinetobacter schindleri and Cutibacterium species. Metabolic pathway analysis highlighted the association of isovaleric and acetic acid production (sour odor) from enriched S. epidermidis (teen underarm) and S. hominis (child neck) enzymes and sulfur production from Staphylococcus species (teen underarm) with odor intensity, in good agreement with observed odor characteristics in pre-pubescent children and teenagers. Experiments with cultures on human and artificial sweat confirmed the ability of S. hominis and S. epidermidis to independently produce malodor with distinct odor characteristics. CONCLUSIONS: These results showcase the power of skin metagenomics to study host-microbial co-metabolic interactions, identifying distinct pathways for odor generation from sweat in pre-pubescent children and teenagers and highlighting key enzymatic targets for intervention.

Hyperelastic Mechanical Properties of Ex Vivo Normal and Intrauterine Growth Restricted Placenta.

Intrauterine Growth Restriction (IUGR) is a serious and prevalent pregnancy complication that is due to placental insufficiency and IUGR babies suffer significantly higher risks of mortality and morbidity. Current detection rate for IUGR is generally poor and thus an alternative diagnostic tool is needed to improve the IUGR detection. Elastography, a non-invasive method that measures the tissue stiffness, has been proposed as one such technique. However, to date, we have limited information on the mechanical properties of IUGR placenta. In this study, we investigated the mechanical properties of normal and IUGR placentae and prescribed a suitable hyperelastic model to describe their mechanical behaviors. A total of 46 normal and 43 IUGR placenta samples were investigated. Results showed that placenta samples were isotropic, but had a high spatial variability of stiffness. The samples also had significant viscoelasticity. IUGR placenta was observed to be slightly stiffer than normal placenta but the difference was significant only at compression rate of 0.25 Hz and with 20% compression depth. Three simple hyperelastic models-Yeoh, Ogden and Fung models, were found to be able to fit the experimentally measured mechanical behaviors, and Fung model performed slightly better. These results may be useful for optimizing placenta elastography for the detection of IUGR.

The IMPROVE-GAP Trial aiming to improve evidence-based management of community-acquired pneumonia: study protocol for a stepped-wedge randomised controlled trial.

BACKGROUND: Community-acquired pneumonia is a leading worldwide cause of hospital admissions and healthcare resource consumption. The largest proportion of hospitalisations now occurs in older patients, with high rates of multimorbidity and complex care needs. In Australia, this population is usually managed by hospital inpatient general internal medicine units. Adherence to consensus best-practice guidelines is poor. Ensuring evidence-based care and reducing length of stay may improve patient outcomes and reduce organisational costs. This study aims to evaluate an alternative model of care designed to improve adherence to four Level 1 or 2 evidence-supported interventions (routine corticosteroids, early switch to oral antibiotics, early mobilisation and routine malnutrition screening). METHODS/DESIGN: The IMPROVing Evidence-based treatment Gaps and outcomes in community-Acquired Pneumonia (IMPROVE-GAP) trial is a pragmatic, investigator-initiated, stepped-wedge randomised trial. Patients hospitalised under a general internal medicine unit who meet a standard case definition for community-acquired pneumonia will be included. Eight general internal medicine units at two Australian hospitals in a single health service will be randomised using concealed allocation to: (i) usual medical, nursing and allied health care delivered according to existing organisational practice or (ii) care supported by a dedicated "community-acquired pneumonia service": a multidisciplinary team deploying algorithm-based implementation of a bundle of the four evidence-based interventions. The primary outcome measure will be length of hospital stay. Secondary outcome measures include inpatient mortality, 30 and 90 day readmission rates and mortality and health-service utilisation costs. Protocol adherence will be measured and reported, and serious adverse events (rates of hyperglycaemia requiring new insulin; falls during mobilisation) will be collected and reported. DISCUSSION: IMPROVE-GAP represents an important and unique precedent for testing a new service-delivery model for improving compliance with a number of evidence-based interventions. Its stepped-wedge randomised controlled trial design provides a means to address some significant ethical, organisational and other methodological challenges to evaluating the effectiveness of health-service interventions in complex hospital populations. The new service-delivery model will effectively be fully implemented by trial completion, facilitating rapid, seamless translation into practice should care outcomes be superior. This trial is currently recruiting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02835040. Prospectively registered on 22 May 2016.

Vitamin D receptor gene polymorphisms and prognosis of breast cancer among African-American and Hispanic women.

BACKGROUND: Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). Although African-Americans have the lowest levels of serum vitamin D, there is a dearth of information on VDR gene polymorphisms and breast cancer among African-Americans and Hispanics. This study examines whether VDR gene polymorphisms are associated with breast cancer in these cohorts. METHODS: Blood was collected from 232 breast cancer patients (Cases) and 349 non-cancer subjects (Controls). Genotyping for four polymorphic variants of VDR (FokI, BsmI, TaqI and ApaI) was performed using the PCR-RFLP method. RESULTS: An increased association of the VDR-Fok1 f allele with breast cancer was observed in African-Americans (OR = 1.9, p = 0.07). Furthermore, the FbTA, FbtA and fbtA haplotypes were associated with breast cancer among African-Americans (p<0.05). Latinas were more likely to have the VDR-ApaI alleles (Aa or aa) (p = 0.008). The VDR-ApaI aa genotype was significantly associated with poorly-differentiated breast tumors (p = 0.04) in combined Cases. Kaplan-Meier survival analysis showed decreased 5-year disease-free-survival (DFS) in breast cancer patients who had the VDR-Fok1 FF genotype (p<0.05). The Cox regression with multivariate analysis revealed the independent predictor value of the VDR-FokI polymorphism for DFS. The other three variants of VDR (BsmI, TaqI and ApaI) were not associated with disease outcome. CONCLUSIONS: VDR haplotypes are associated with breast cancer in African-Americans, but not in Hispanic/Latinas. The VDR-FokI FF genotype is linked with poor prognosis in African-American women with breast cancer.

CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL function synergistically in the circadian clock of Arabidopsis.

The circadian clock is an endogenous mechanism that coordinates biological processes with daily and seasonal changes in the environment. Heterodimerization of central clock components is an important way of controlling clock function in several different circadian systems. CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) are Myb-related proteins that function in or close to the central oscillator in Arabidopsis (Arabidopsis thaliana). Single mutants of cca1 and lhy have a phenotype of short-period rhythms. cca1 lhy double mutants show an even shorter period phenotype than the cca1 single mutant, suggesting that CCA1 and LHY are only partially functionally redundant. To determine whether CCA1 and LHY act in parallel or synergistically in the circadian clock, we examined their expression in both light-grown and etiolated seedlings. We have shown that LHY and CCA1 bind to the same region of the promoter of a Light-harvesting chlorophyll a/b protein (Lhcb, also known as CAB). CCA1 and LHY can form homodimers, and they also colocalize in the nucleus and heterodimerize in vitro and in vivo. In Arabidopsis, CCA1 and LHY physically interact in a manner independent of photoperiod. Moreover, results from gel filtration chromatography indicate that CCA1 and LHY are present in the same large complex in plants. Taken together, these results imply that CCA1 and LHY function synergistically in regulating circadian rhythms of Arabidopsis.

Role of health care professionals in multidisciplinary pain treatment facilities in Canada.

PURPOSE: To examine the role of health care professionals in multidisciplinary pain treatment facilities (MPTF) for the treatment of chronic pain across Canada. METHODS: MPTF were defined as clinics that advertised specialized multidisciplinary services for the diagnosis and management of chronic pain, and had staff from a minimum of three different health care disciplines (including at least one medical specialty) available and integrated within the facility. Administrative leaders at eligible MPTF were asked to complete a detailed questionnaire on their infrastructure as well as clinical, research, teaching and administrative activities. RESULTS: A total of 102 MPTF returned the questionnaires. General practitioners, anesthesiologists and physiatrists were the most common types of physicians integrated in the MPTF (56%, 51% and 32%, respectively). Physiotherapists, psychologists and nurses were the most common nonphysician professionals working within these MPTF (75%, 68% and 57%, respectively), but 33% to 56% of them were part-time staff. Only 77% of the MPTF held regular interdisciplinary meetings to discuss patient management, and 32% were staffed with either a psychologist or psychiatrist. The three most frequent services provided by physiotherapists were patient assessment, individual physiotherapy or exercise, and transcutaneous electrical nerve stimulation. The three most common services provided by psychologists were individual counselling, cognitive behavioural therapy and psychodynamic therapy. The major roles of nurses were patient assessment, assisting in interventional procedures and patient education. CONCLUSION: Different health care professionals play a variety of important roles in MPTF in Canada. However, few of them are involved on a full-time basis and the extent to which pain is assessed and treated in a truly multidisciplinary manner is questionable.

Challenges in accessing multidisciplinary pain treatment facilities in Canada.

PURPOSE: The objective of this survey was to examine the services offered by multidisciplinary pain treatment facilities (MPTFs) across Canada and to compare access to care at these MPTFs. METHODS: A MPTF was defined as a clinic that advertised specialized multidisciplinary services for the diagnosis and management of patients with chronic pain, having a minimum of three different health care disciplines (including at least one medical speciality) available and integrated within the facility. The search method included approaching all hospital and rehabilitation centre administrators in Canada, the Insurance Bureau of Canada, the Workplace Safety and Insurance Board or similar body in each province. Designated investigators were responsible for confirming and supplementing MPTFs from the preliminary list for each province. Administrative leads at each eligible MPTF were asked to complete a detailed questionnaire regarding their MPTF infrastructure, clinical, research, teaching and administrative activities. RESULTS: Completed survey forms were received from 102 MPTFs (response rate 85%) with 80% concentrated in major cities, and none in Prince Edward Island and the Territories. The MPTFs offer a wide variety of treatments including non-pharmacological modalities such as interventional, physical and psychological therapy. The median wait time for a first appointment in public MPTFs is six months, which is approximately 12 times longer than non-public MPTFs. Eighteen pain fellowship programs exist in Canadian MPTFs and 64% engage in some form of research activities CONCLUSION: Canadian MPTFs are unable to meet clinical demands of patients suffering from chronic pain, both in terms of regional accessibility and reasonable wait time for patients' first appointment.

Dedicated multidisciplinary pain management centres for children in Canada: the current status.

PURPOSE: The objective of this study was to examine the services currently offered by multidisciplinary pain treatment facilities (MPTFs) dedicated for pediatric chronic pain management across Canada. METHODS: A MPTF was defined as a clinic that advertised specialized multidisciplinary services for the diagnosis and management of chronic pain and had a minimum of three different health care disciplines (including at least one medical speciality) available and integrated within the facility. The search method was previously described in an accompanying article. Designated investigators were responsible for confirming and supplementing MPTFs from the preliminary list in their respective provinces. Administrative leads at each eligible MPTF were asked to complete a detailed questionnaire on their infrastructure, clinical, research, teaching and administrative activities. Only MPTFs dedicated to pediatric populations were included. RESULTS: Only five centres surveyed had dedicated pediatric MPTFs, all located in major cities in five different provinces. While the median wait time was four weeks, it could be as long as nine months in one MPTF. Headache and neuropathic pain were the most commonly treated pain syndromes. All MPTFs included physicians, nurses and psychologists, and used a rehabilitation model that incorporated a wide variety of pharmacological, psychological and physical therapies. All centres provided training for medical and other healthcare professionals, and three of the five centres conducted research. Government funding was the major source of funding for patient services and overhead costs. CONCLUSIONS: There are very few pediatric MPTFs in Canada. These facilities exist in five of ten provinces, each within large urban centres. Limited accessibility leads to variable and prolonged wait times for pediatric patients suffering from chronic pain.

Identification and synthesis of norhydromorphone, and determination of antinociceptive activities in the rat formalin test.

The main objective of this paper is to report the identification and synthesis of norhydromorphone, a novel metabolite of hydromorphone, and its antinociceptive activities when tested in the formalin test as compared to other known analgesics. In addition, we are reporting for the first time the lack of antinociceptive activities of hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide in the rat formalin test. Norhydromorphone was isolated and identified as a metabolite of hydromorphone in a cancer patient's urine. An authentic standard of norhydromorphone was synthesized. The identity of norhydromorphone in the urine sample was confirmed by comparing the LC retention time and MS ion fragmentation with the synthetic standard using a liquid chromatographic-mass spectrometric-mass spectrometric (LC-MS-MS) assay. Norhydromorphone was found to be a minor metabolite of hydromorphone in the urine. Additionally, the antinociceptive activities of norhydromorphone, hydromorphone, morphine, dihydromorphine, dihydroisomorphine, hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide were determined in the rat formalin test following intraperitoneal (i.p.) administration. Only limited antinociception was observed and no significant increase in antinociception was detected at the three doses tested. The increased polarity of norhydromorphone as compared to hydromorphone due to the primary piperidine nitrogen may make it less favorable to cross the blood-brain-barrier (BBB), which may be partly responsible. In addition, lower intrinsic antinociceptive activity, which remains to be determined, could also contribute to the low antinociception. Our results also show that hydromorphone was five times as potent as morphine in the formalin test, while dihydromorphine and dihydroisomorphine were equipotent to and 36% as potent as morphine, respectively. Hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide did not exhibit any antinociceptive effect at the doses tested. The results further underscore the importance of a free C3-OH to the analgesic effect of morphine alkaloids.