Initiations of safer supply hydromorphone increased during the COVID-19 pandemic in Ontario: An interrupted time series analysis.

AIMS: Calls to prescribe safer supply hydromorphone (SSHM) as an alternative to the toxic drug supply increased during the COVID-19 pandemic but it is unknown whether prescribing behaviour was altered. We aimed to evaluate how the number of new SSHM dispensations changed during the pandemic in Ontario. METHODS: We conducted a retrospective interrupted time-series analysis using provincial administrative databases. We counted new SSHM dispensations in successive 28-day periods from March 22, 2016 to August 30, 2021. We used segmented Poisson regression methods to test for both a change in level and trend of new dispensations before and after March 17, 2020, the date Ontario's pandemic-related emergency was declared. We adjusted the models to account for seasonality and assessed for over-dispersion and residual autocorrelation. We used counterfactual analysis methods to estimate the number of new dispensations attributable to the pandemic. RESULTS: We identified 1489 new SSHM dispensations during the study period (434 [mean of 8 per 28-day period] before and 1055 [mean of 56 per 28-day period] during the pandemic). Median age of individuals initiating SSHM was 40 (interquartile interval 33-48) with 61.7% (N = 919) male sex. Before the pandemic, there was a small trend of increased prescribing (incidence rate ratio [IRR] per period 1.002; 95% confidence interval [95CI] 1.001-1.002; p<0.001), with a change in level (immediate increase) at the pandemic date (relative increase in IRR 1.674; 95CI 1.206-2.322; p = 0.002). The trend during the pandemic was not statistically significant (relative increase in IRR 1.000; 95CI 1.000-1.001; p = 0.251). We estimated 511 (95CI 327-695) new dispensations would not have occurred without the pandemic. CONCLUSION: The pandemic led to an abrupt increase in SSHM prescribing in Ontario, although the rate of increase was similar before and during the pandemic. The absolute number of individuals who accessed SSHM remained low throughout the pandemic.

Interrater reliability of criterion A of the alternative model for personality disorder (Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-Section III): A meta-analysis.

The alternative model for personality disorder (AMPD) is currently included in Section III of the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). This review sought to summarize the literature concerning the interrater reliability (IRR) of the AMPD. Despite high heterogeneity, meta-analysis provided tentative support for the IRR of Criterion A of the AMPD, with pooled intraclass correlation coefficients (ICCs) for the Level of Personality Functioning Scale (LPFS) and its domains falling above DSM acceptability levels. Subgroup analysis of the LPFS suggested IRR scores could be improved by using a specific AMPD Structured Clinical Interview (SCI). Further research should in particular consider the IRR of Criterion B elements of the AMPD and overall PD diagnosis, where insufficient data were available to draw conclusions in the present study. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Harm reduction in the hospital: An overdose prevention site (OPS) at a Canadian hospital.

BACKGROUND: Substance use management in hospitals can be challenging. In response, a Canadian hospital opened an overdose prevention site (OPS) where community members and hospital inpatients can inject pre-obtained illicit drugs under supervision. This study aims to: (1) describe program utilization patterns; (2) characterize OPS visits; and (3) evaluate overdose events and related outcomes. METHODS: A retrospective chart review was completed at one hospital in Vancouver, Canada. All community members and hospital inpatients who visited the OPS between May 2018 and July 2019 were included. Client measures included: hospital inpatient status, use of intravenous access line for drug injection, and substances used. Program measures included: number of visits (daily/monthly), overdose (fatal/non-fatal) events and overdose-related outcomes. RESULTS: Overall, 11,673 OPS visits were recorded. Monthly visits increased from 306 to 1198 between May 2018 and July 2019 respectively. On average, 26 visits occurred daily. Among all visits, 20% reported being a hospital inpatient, and 5% reported using a hospital intravenous access line for drug injection. Opioids (56%) and stimulants (24%) were the most common substances used. Overall 39 overdose events occurred - 82% required naloxone reversal, 28% required transfer to the hospital's emergency department and none were fatal. Overdose events were more common among hospital inpatients compared to community clients (6.6 vs 2.2 per 1000 visits respectively; p value = 0.046). CONCLUSIONS: This unique OPS is an example of a hospital-based harm reduction initiative. Use of the site increased over time among both groups with no fatal overdose events occurring.

"They have their security, we have our community": Mutual support among people experiencing homelessness in encampments in Toronto during the COVID-19 pandemic.

Unaffordable housing is a growing crisis in Canada, exacerbated by the COVID-19 pandemic, yet perspectives of people living outdoors in encampments have primarily gone unheard. We conducted qualitative interviews with encampment residents to explore how mutual support occurred within the social context of encampments. We found that mutually supportive interactions helped residents meet basic survival needs, as well as health and social needs, and reduced common health and safety risks related to homelessness. The homelessness sector should acknowledge that encampment residents form their own positive communities, and ensure policies and services do not isolate people from these beneficial social connections.

Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud.

Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however, the mechanisms that govern the initiation of Shh expression are incomplete. Here we report that ETV2 initiates Shh expression by changing the chromatin status of the developmental limb enhancer, ZRS. Etv2 expression precedes Shh in limb buds, and Etv2 inactivation prevents the opening of limb chromatin, including the ZRS, resulting in an absence of Shh expression. Etv2 overexpression in limb buds causes nucleosomal displacement at the ZRS, ectopic Shh expression, and polydactyly. Areas of nucleosome displacement coincide with ETS binding site clusters. ETV2 also functions as a transcriptional activator of ZRS and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS, suggesting that ETV2 dosage regulates ZRS activation. These studies identify ETV2 as a pioneer transcription factor (TF) regulating the onset of Shh expression, having both a chromatin regulatory role and a transcriptional activation role.

Characterizing safer supply prescribing of immediate release hydromorphone for individuals with opioid use disorder across Ontario, Canada.

BACKGROUND: In response to the ongoing overdose crisis, some clinicians in Canada have started prescribing immediate release hydromorphone (IRH) as an alternative to the toxic unregulated drug supply. This practice is often referred to as safer supply. We aimed to identify and characterize patients receiving safer supply IRH and their prescribers in Ontario. METHODS: Using provincial administrative health data, we identified individuals with opioid use disorder prescribed safer supply IRH from January 2016 to March 2020 and reported the number of initiations over time. We summarized demographic, health, and medication use characteristics among patients who received safer supply IRH, and examined select clinical outcomes including retention and death. Finally, we characterized prescribers of safer supply IRH and compared frequent and infrequent prescribers. RESULTS: We identified 534 initiations of safer supply IRH (447 distinct individuals) from 155 prescribers. Initiations increased over time with a peak in the third quarter of 2019 (103 initiations). Patients' median age was 42 (interquartile range [IQR] 34-50), and most were male (60.2%), urban residents, (96.2%), and in the lowest neighborhood income quintile (55.7%), with 13.9% having overdosed in the previous one year. The prevalence of HIV was 13.9%. The median duration on IRH was 272 days (IQR 30-1,244) and OAT was co-prescribed in 62.9% of courses. Death while receiving IRH or within 7 days of discontinuation was rare (≤5 courses;≤0.94 per person-year for each). CONCLUSIONS: Clinicians are increasingly prescribing safer supply IRH in Ontario. Patients prescribed safer supply IRH had demographic and clinical characteristics associated with high risk of death from opioid-related overdose. Short-term deaths among people receiving safer supply IRH were rare.

Trends in Hospitalizations for Serious Infections Among People With Opioid Use Disorder in Ontario, Canada.

OBJECTIVES: Opioid use among people who inject drugs can lead to serious complications, including infections. We sought to study trends in rates of these complications among people with an opioid use disorder (OUD) and the sequelae of those hospitalizations. METHODS: We analyzed all inpatient hospitalizations for serious infections (infective endocarditis [IE], spinal infections, nonvertebral bone infections, and skin or soft tissue infections) among people with OUD in Ontario between 2013 and 2019. We reported the population adjusted rate of hospitalizations for serious infections annually, stratified by type of infection and prevalence of prior opioid agonist therapy and hydromorphone prescribing. We reported characteristics of hospitalizations and 30-day mortality in the most recent 2 years. RESULTS: Among people with OUD there was a 167% increase in rates of IE (7.7-20.6 per million residents; P < 0.01), a 394% increase in rates of spinal infections (3.4-16.8 per million residents; P < 0.01), a 191% increase in rates of nonvertebral bone infections (8.9 to 25.9 per million residents; P < 0.01), and a 147% increase in infections of the skin or soft tissue (32.1-79.4 per million residents; P < 0.01) over 7 years in Ontario. Death in-hospital and within 30 days of discharge was highest among those with IE (11.5% and 15.9%, respectively), and lower among those with other infections (<5%). CONCLUSIONS: Rates of serious infections among people with OUD are rising, placing a significant burden on patients. These findings suggest that early intervention and treatment of infections in this population are needed to prevent downstream harm.

Challenges with buprenorphine inductions in the context of the fentanyl overdose crisis: A case series.

INTRODUCTION AND AIMS: North America is currently experiencing an epidemic of opioid overdose deaths, driven by the proliferation of fentanyl in the street drug market. Although buprenorphine/naloxone (BUP/NX) is an evidence-based, first-line opioid agonist for the management of opioid use disorder, a key challenge in its prescribing lies in the fact that it can precipitate opioid withdrawal during its initial induction process. At this time, there is minimal literature on the BUP/NX induction process in individuals who use illicit fentanyl regularly. DESIGN, METHODS AND RESULTS: A case series from a Vancouver, Canada addiction medicine clinic of three fentanyl-exposed patients who experienced unexpected, precipitated withdrawal when initiating BUP/NX. DISCUSSION AND CONCLUSION: These cases describe incidents of precipitated opioid withdrawal occurring after unusually long periods of fentanyl abstention. Although fentanyl is experienced as a short-acting opioid, the drug persists much longer in the body's peripheral tissues. Here, we highlight the new challenges fentanyl may pose to current BUP/NX induction strategies, and explore the possibility of a long-acting pharmacokinetic effect of fentanyl in the setting of repeated illicit use.

Buprenorphine/naloxone associated with a reduced odds of fentanyl exposure among a cohort of people who use drugs in Vancouver, Canada.

BACKGROUND: Little is known about the relationship between opioid agonist therapy (OAT) and fentanyl use, specifically. This study aimed to estimate the association between current use of different forms of OAT, including methadone, buprenorphine/naloxone (BUP/NX), slow release oral morphine (SROM), or injectable opioid agonist treatment (iOAT), and the likelihood of a fentanyl-positive urine drug test (UDT) as compared to no OAT. METHODS: Data were obtained from three community-recruited prospective cohort studies of people who use drugs in Vancouver, Canada from December 2016 through November 2018. Using multivariable Generalized Estimating Equations (GEE), we examined the association between current use of each form of OAT, as compared to no OAT, and fentanyl-positive UDT among participants who use opioids. RESULTS: The 915 participants contributed 2112 UDTs over a median of two follow-up visits. The majority of UDTs (74.9 %) were positive for fentanyl. After adjustment for a priori defined confounding factors, compared to no OAT, current use of BUP/NX was associated with lower odds of fentanyl-positive UDT (odds ratio [OR] = 0.36, 95 % confidence interval [CI]: 0.22-0.58) while current use of methadone (OR = 0.84, 95 % CI: 0.65-1.07), iOAT (OR = 1.30, 95 % CI: 0.75-2.28), and SROM (OR = 1.34, 95 % CI: 0.74-2.43) were not. CONCLUSIONS: In this cohort of people who use opioids in Vancouver, only use of BUP/NX was associated with lower odds of fentanyl-positive UDT. Our findings highlight high rates of ongoing fentanyl use despite the use of OAT and support the expansion of BUP/NX for the treatment of people who use fentanyl.

High-dose intravenous hydromorphone for patients who use opioids in the hospital setting: time to reduce the barriers.

Individuals who use opioids have higher rates of hospitalization compared to the general population. Insufficiently treated withdrawal and pain are major factors contributing to high rates of self-initiated hospital discharges (also referred to as leaving against medical advice) in this population. While injectable opioid agonist therapy is limited or unavailable in the majority of Canadian communities, intravenous hydromorphone (IV HM) is widely available in the hospital setting and high-dose IV HM may be a useful treatment adjunct to improve comfort and engagement in inpatient care for some individuals who use opioids. However, major barriers to its use exist including lack of comfort amongst healthcare providers and hospital policies restricting administration. In this commentary, we highlight the potential usefulness of high-dose IV HM as a treatment adjunct for individuals who use opioids in the hospital setting and advocate for expanded hospital policies to facilitate its use.

Localization of kisspeptin, NKB, and NK3R in the hypothalamus of gilts treated with the progestin altrenogest.

Mechanisms in the brain controlling secretion of gonadotropin hormones in pigs, particularly luteinizing hormone (LH), are poorly understood. Kisspeptin is a potent LH stimulant that is essential for fertility in many species, including pigs. Neurokinin B (NKB) acting through neurokinin 3 receptor (NK3R) is involved in kisspeptin-stimulated LH release, but organization of NKB and NK3R within the porcine hypothalamus is unknown. Hypothalamic tissue from ovariectomized (OVX) gilts was used to determine the distribution of immunoreactive kisspeptin, NKB, and NK3R cells in the arcuate nucleus (ARC). Almost all kisspeptin neurons coexpressed NKB in the porcine ARC. Immunostaining for NK3R was distributed throughout the preoptic area (POA) and in several hypothalamic areas including the periventricular and retrochiasmatic areas but was not detected within the ARC. There was no colocalization of NK3R with gonadotropin-releasing hormone (GnRH), but NK3R-positive fibers in the POA were in close apposition to GnRH neurons. Treating OVX gilts with the progestin altrenogest decreased LH pulse frequency and reduced mean circulating concentrations of LH compared with OVX control gilts (P < 0.01), but the number of kisspeptin and NKB cells in the ARC did not differ between treatments. The neuroanatomical arrangement of kisspeptin, NKB, and NK3R within the porcine hypothalamus confirms they are positioned to stimulate GnRH and LH secretion in gilts, though differences with other species exist. Altrenogest suppression of LH secretion in the OVX gilt does not appear to involve decreased peptide expression of kisspeptin or NKB.

The effect of a Housing First intervention on primary care retention among homeless individuals with mental illness.

BACKGROUND: Primary care retention, defined as ongoing periodic contact with a consistent primary care provider, is beneficial for people with serious chronic illnesses. This study examined the effect of a Housing First intervention on primary care retention among homeless individuals with mental illness. METHODS: Two hundred individuals enrolled in the Toronto site of the At Home Project and randomized to Housing First or Treatment As Usual were studied. Medical records were reviewed to determine if participants were retained in primary care, defined as having at least one visit with the same primary care provider in each of two consecutive six-month periods during the 12 month period preceding and following randomization. RESULTS: Medical records were obtained for 47 individuals randomized to Housing First and 40 individuals randomized to Treatment As Usual. During the one year period following randomization, the proportion of Housing First and Treatment As Usual participants retained in primary care was not significantly different (38.3% vs. 47.5%, p = 0.39). The change in primary care retention rates from the year preceding randomization to the year following randomization was +10.6% in the Housing First group and -5.0% in the Treatment As Usual group. CONCLUSION: Among homeless individuals with mental illness, Housing First did not significantly affect primary care retention over the follow-up period. These findings suggest Housing First interventions may need to place greater emphasis on connecting clients with primary care providers.

A Case Report: Rapid Micro-Induction of Buprenorphine/Naloxone to Administer Buprenorphine Extended-Release in an Adolescent With Severe Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: Buprenorphine extended-release (BUP-XR) is a monthly injectable form of opioid agonist therapy. Before its administration, a minimum 7-day induction period with a transmucosal buprenorphine-containing product is recommended. METHODS: Case report (n = 1). RESULTS: A 16-year-old female with active, severe opioid use disorder (OUD) and stimulant use disorder, hepatitis C virus, co-occurring mental health disorders, and complex social stressors had five recent overdoses requiring naloxone. She had previously been treated with methadone and several trials of sublingual buprenorphine/naloxone, but would quickly discontinue the treatment. Using a rapid micro-induction protocol, buprenorphine/naloxone was administered for 3 days. On day 4, 300 mg BUP-XR was administered subcutaneously. Minimal withdrawal symptoms occurred, despite recent fentanyl use. DISCUSSION AND CONCLUSIONS: A rapid sublingual buprenorphine/naloxone micro-induction was successfully used to initiate BUP-XR, thereby eliminating the abstinence period prior to buprenorphine/naloxone administration, shortening the induction period, and minimizing withdrawal. SCIENTIFIC SIGNIFICANCE: This is the first reported case of using rapid micro-induction as a bridge to initiate BUP-XR. By reducing the length of induction to 4 days and minimizing withdrawal, this induction method can make BUP-XR more accessible to patients who would otherwise refuse the medication due to concerns of enduring withdrawal. (Am J Addict 2020;29:531-535).

Initiation of injectable opioid agonist treatment in hospital: A case report.

Uncontrolled opioid withdrawal and pain often drive inpatients with opioid use disorder to leave hospital against medical advice, resulting in suboptimal medical and addiction treatment. When oral opioid agonist treatments such as methadone and buprenorphine/naloxone fail for management of craving and withdrawal, injectable opioid agonist treatment may serve to retain patients in care and link them to addiction services. We describe the case of a 47-year-old man with a severe, active opioid use disorder and daily use of illicitly manufactured fentanyl, who was re-admitted to hospital for post-operative management after leaving against medical advice due to uncontrolled opioid withdrawal. Intravenous hydromorphone was used to retain him in care, allowing for completion of his antibiotics and enrolment in ongoing community injectable opioid agonist treatment.

CRISPR/Cas9-mediated genome editing reveals 30 testis-enriched genes dispensable for male fertility in mice†.

More than 1000 genes are predicted to be predominantly expressed in mouse testis, yet many of them remain unstudied in terms of their roles in spermatogenesis and sperm function and their essentiality in male reproduction. Since individually indispensable factors can provide important implications for the diagnosis of genetically related idiopathic male infertility and may serve as candidate targets for the development of nonhormonal male contraceptives, our laboratories continuously analyze the functions of testis-enriched genes in vivo by generating knockout mouse lines using the CRISPR/Cas9 system. The dispensability of genes in male reproduction is easily determined by examining the fecundity of knockout males. During our large-scale screening of essential factors, we knocked out 30 genes that have a strong bias of expression in the testis and are mostly conserved in mammalian species including human. Fertility tests reveal that the mutant males exhibited normal fecundity, suggesting these genes are individually dispensable for male reproduction. Since such functionally redundant genes are of diminished biological and clinical significance, we believe that it is crucial to disseminate this list of genes, along with their phenotypic information, to the scientific community to avoid unnecessary expenditure of time and research funds and duplication of efforts by other laboratories.

Evaluation of the Brief Alcohol Withdrawal Scale Protocol at an Academic Medical Center.

OBJECTIVES: The standard of care for treatment of alcohol withdrawal is symptom-triggered dosing of benzodiazepines using a withdrawal scale. Abbreviated scales are desired for clinician efficiency. The objective of this study was to evaluate the use of the 5-item Brief Alcohol Withdrawal Scale (BAWS) protocol. METHODS: This single-center, retrospective, observational, cohort study assessed patients ordered the BAWS protocol between August 1, 2016 and July 31, 2017. Data were collected on benzodiazepine exposure, duration of treatment, withdrawal severity, agitation, over-sedation, and delirium while being treated for alcohol withdrawal. Comparisons were made to analyze predetermined patient subgroups. RESULTS: Seven hundred ninety-nine patients were initiated on the BAWS protocol. Patients received a median (IQR) of 0 (0-4) lorazepam equivalents (LEs) and were on the BAWS protocol for a median (IQR) of 44.9 (22.4-77.2) hours. Of the patients that received benzodiazepines while on the BAWS protocol, a median (IQR) of 4 (2-11) LEs were given. Seventeen (2.1%) patients had severe withdrawal. Days of agitation, over-sedation, and delirium were minimal, with the median (IQR) of 0 (0-0). Few patients received adjunctive medications for symptom management. Intensive care unit (ICU) patients had more severe withdrawal than non-ICU patients, but received the same cumulative benzodiazepine dose. CONCLUSIONS: Most patients on the BAWS protocol received little-to-no benzodiazepines; severe withdrawal, agitation, delirium, or over-sedation were uncommon. This is the first evaluation of the BAWS protocol on a diverse population of hospitalized patients.

A Tool to Guide Clinical Nurse Specialist Orientation, Professional Development, and Evaluation.

PURPOSE/OBJECTIVES: Currently, orientation for clinical nurse specialists (CNSs) in the Baltimore region is based on past practices: facility-specific or position-specific. A Chesapeake Bay affiliate work group identified a need to develop a theory-driven, competency-based program and tool to guide orientation and ongoing professional development reflecting the scope of CNS practice. DESCRIPTION OF THE PROJECT/PROGRAM: The tool incorporates Benner's concepts of novice-to-expert competence levels, guides progressive development of the CNS, and has relevant assessment metrics that highlight contributions to the patient, nurse, and system. OUTCOME: The group developed a comprehensive orientation tool grounded in the spheres of influence and advanced practice competencies and specific, measurable behavioral statements related to competencies from the 2018 National Association of Clinical Nurse Specialists' draft. This program is adaptable to guide the practice of a CNS in any facility, validate competence, and relate to those with varied experience in the role. CONCLUSION: In a method similar to the process for developing nationally recognized educational standards used to develop the competencies, the program was revised based on an iterative, stepwise process. It was distributed to the membership for evaluation and feedback, which was incorporated into the final version.

Expanding supervised injection facilities across Canada: lessons from the Vancouver experience.

The opioid crisis has led to an unprecedented rise in the number of overdose deaths across Canada. In response, there has been an expansion of supervised injection facilities (SIFs), with several new SIFs approved or under review across the country. Much of the evidence for the benefits of SIFs in reducing overdose mortality, infectious-related complications, and public disorder comes from Insite in Vancouver, North America's first SIF. While implementing SIFs in other Canadian cities is a major step forward in combating the opioid epidemic, the diversity within our country's socio-demographic and political landscape leaves the application of SIFs in these new settings a matter of uncertainty. This commentary highlights key lessons learned from Vancouver and the potential modifications required to enhance implementation in other cities to ensure the success of new SIFs across Canada.