Impact of COVID-19 pandemic on hepatocellular carcinoma surveillance in British Columbia, Canada: An interrupted time series study.

We assessed the impact of the COVID-19 pandemic on hepatocellular carcinoma (HCC) surveillance among individuals with HCV diagnosed with cirrhosis in British Columbia (BC), Canada. We used data from the British Columbia Hepatitis Testers Cohort (BC-HTC), including all individuals in the province tested for or diagnosed with HCV from 1 January 1990 to 31 December 2015, to assess HCC surveillance. To analyse the impact of the pandemic on HCC surveillance, we used pre-policy (January 2018 to February 2020) and post-policy (March to December 2020) periods. We conducted interrupted time series (ITS) analysis using a segmented linear regression model and included first-order autocorrelation terms. From January 2018 to December 2020, 6546 HCC screenings were performed among 3429 individuals with HCV and cirrhosis. The ITS model showed an immediate decrease in HCC screenings in March and April 2020, with an overall level change of -71 screenings [95% confidence interval (CI): -105.9, -18.9]. We observed a significant decrease in HCC surveillance among study participants, regardless of HCV treatment status and age group, with the sharpest decrease among untreated HCV patients. A recovery of HCC surveillance followed this decline, reflected in an increasing trend of 7.8 screenings (95% CI: 0.6, 13.5) per month during the post-policy period. There was no level or trend change in the number of individuals diagnosed with HCC. We observed a sharp decline in HCC surveillance among people living with HCV and cirrhosis in BC following the COVID-19 pandemic control measures. HCC screening returned to pre-pandemic levels by mid-2020.

Addition of liposomal bupivacaine to standard bupivacaine versus standard bupivacaine alone in the supraclavicular brachial plexus block: a randomized controlled trial.

BACKGROUND: The analgesic effect of adding liposomal bupivacaine to standard bupivacaine in supraclavicular brachial plexus block is not known. We hypothesized that addition of liposomal bupivacaine would reduce acute postoperative pain compared to standard bupivacaine alone. METHODS: A randomized controlled trial was conducted. Patients and outcome assessors were blinded. Eighty patients undergoing distal radial fracture fixation under regional anesthesia with supraclavicular brachial plexus block were randomized into two groups. The liposomal bupivacaine (LB-BPB) group received 10ml of 0.5% plain bupivacaine immediately followed by 10ml of 1.33% liposomal bupivacaine (n=40). The standard bupivacaine (S-BPB) group received 20ml of 0.5% plain bupivacaine (n=40). The primary outcome was weighted area under curve (AUC) numerical rating scale (NRS) pain score at rest over the first 48 hours after surgery. Secondary outcomes included AUC scores for pain with movement, overall benefit with analgesia score (OBAS) and other functional scores. RESULTS: For the primary outcome, LB-BPB group was associated with statistically significantly lower AUC pain score at rest (0.6 vs 1.4, p-value < 0.001) in the first 48 hours. Of the secondary outcomes, no difference between treatment groups reached statistical significance with the exception of AUC score for pain with movement (2.3 vs 3.7, adjusted p-value < 0.001) and OBAS (1.1 vs 1.7, adjusted p-value = 0.020) in the first 48 hours, as well as NRS pain score at rest (0.5 vs 1.9, adjusted p-value < 0.001) and with movement (2.7 vs 4.9, adjusted p-value < 0.001) on postoperative day (POD) 1. Differences in NRS pain scores on POD2, POD3 and POD4 did not reach the level of statistical significance. There were no statistically significant differences in sensory function. CONCLUSION: Liposomal bupivacaine given via supraclavicular brachial plexus block reduced pain at rest in the early postoperative period.

Interventions to prevent and treat delirium: An umbrella review of randomized controlled trials.

Delirium is a common condition across different settings and populations. The interventions for preventing and managing this condition are still poorly known. The aim of this umbrella review is to synthesize and grade all preventative and therapeutic interventions for delirium. We searched five databases from database inception up to March 15th, 2023 and we included meta-analyses of randomized controlled trials (RCTs) to decrease the risk of/the severity of delirium. From 1959 records after deduplication, we included 59 systematic reviews with meta-analyses, providing 110 meta-analytic estimates across populations, interventions, outcomes, settings, and age groups (485 unique RCTs, 172,045 participants). In surgery setting, for preventing delirium, high GRADE evidence supported dexmedetomidine (RR=0.53; 95%CI: 0.46-0.67, k=13, N=3988) and comprehensive geriatric assessment (OR=0.46; 95%CI=0.32-0.67, k=3, N=496) in older adults, dexmedetomidine in adults (RR=0.33, 95%CI=0.24-0.45, k=7, N=1974), A2-adrenergic agonists after induction of anesthesia (OR= 0.28, 95%CI= 0.19-0.40, k=10, N=669) in children. High certainty evidence did not support melatonergic agents in older adults for delirium prevention. Moderate certainty supported the effect of dexmedetomidine in adults and children (k=4), various non-pharmacological interventions in adults and older people (k=4), second-generation antipsychotics in adults and mixed age groups (k=3), EEG-guided anesthesia in adults (k=2), mixed pharmacological interventions (k=1), five other specific pharmacological interventions in children (k=1 each). In conclusion, our work indicates that effective treatments to prevent delirium differ across populations, settings, and age groups. Results inform future guidelines to prevent or treat delirium, accounting for safety and costs of interventions. More research is needed in non-surgical settings.

Intrinsic and extrinsic actions of human neural progenitors with SUFU inhibition promote tissue repair and functional recovery from severe spinal cord injury.

Neural progenitor cells (NPCs) derived from human pluripotent stem cells(hPSCs) provide major cell sources for repairing damaged neural circuitry and enabling axonal regeneration after spinal cord injury (SCI). However, the injury niche and inadequate intrinsic factors in the adult spinal cord restrict the therapeutic potential of transplanted NPCs. The Sonic Hedgehog protein (Shh) has crucial roles in neurodevelopment by promoting the formation of motorneurons and oligodendrocytes as well as its recently described neuroprotective features in response to the injury, indicating its essential role in neural homeostasis and tissue repair. In this study, we demonstrate that elevated SHH signaling in hNPCs by inhibiting its negative regulator, SUFU, enhanced cell survival and promoted robust neuronal differentiation with extensive axonal outgrowth, counteracting the harmful effects of the injured niche. Importantly, SUFU inhibition in NPCs exert non-cell autonomous effects on promoting survival and neurogenesis of endogenous cells and modulating the microenvironment by reducing suppressive barriers around lesion sites. The combined beneficial effects of SUFU inhibition in hNPCs resulted in the effective reconstruction of neuronal connectivity with the host and corticospinal regeneration, significantly improving neurobehavioral recovery in recipient animals. These results demonstrate that SUFU inhibition confers hNPCs with potent therapeutic potential to overcome extrinsic and intrinsic barriers in transplantation treatments for SCI.

Influence of pulmonary rehabilitation on symptoms of anxiety and depression in interstitial lung disease: A systematic review of randomized controlled trials.

BACKGROUND: Interstitial lung diseases (ILDs) cause fibrosis of lung parenchyma, leading to impaired quality of life, dyspnea, and functional decline. Individuals with ILD experience a high prevalence of anxiety and depression. Recent research has demonstrated pulmonary rehabilitation (PR) alleviates symptoms of anxiety and depression in those with COPD. RESEARCH QUESTION: What is the influence of PR on symptoms of anxiety and depression in individuals with ILD? STUDY DESIGN: We conducted a PRISMA-2020-compliant systematic review of randomized controlled trials (RCTs) investigating PR's effect on anxiety and depression in patients with ILD. We searched MEDLINE, EMBASE, Cochrane, and PsycINFO from inception until April 3, 2023. A narrative synthesis was conducted where a quantitative approach was not feasible. RESULTS: Five RCTs (n = 281) were included. Idiopathic pulmonary fibrosis (IPF) was the most common type of ILD (k = 3). One study reported clinically-significant improvements in symptoms of anxiety among patients with IPF, and two studies for symptoms of depression among patients with sarcoidosis. Dropout rates were similar between intervention and control groups. All studies were at a high risk of bias. INTERPRETATION: Pulmonary rehabilitation is not detrimental to anxiety or depression for patients with ILD, and may improve symptoms of anxiety in IPF and depression in sarcoidosis. However, no conclusion can be drawn from available evidence, which is limited by heterogeneous populations/interventions, sample sizes and unexpectedly low prevalences of clinically-significant anxiety or depression. Further adequately powered RCTs that focus on anxiety and depressive symptoms as primary outcomes are needed.

Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study.

OBJECTIVES: To quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population. DESIGN: Population based cohort study. SETTING: British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only). PARTICIPANTS: 21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019. MAIN OUTCOME MEASURES: Crude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates. RESULTS: 1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates. CONCLUSION: Mortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals.

Sub-anaesthetic dose of propofol attenuates mechanical allodynia in chronic post-ischaemic pain via regulation of PTEN/PI3K/IL-6 signalling.

Background: Propofol is an intravenous anaesthetic drug that has been shown to reduce inflammatory pain. Complex regional pain syndrome (CRPS) type I is a pain condition characterized by autonomic, motor and sensory disturbance. The chronic post-ischaemic pain (CPIP) model is a well-established model to recapture CRPS-I syndromes pre-clinically by non-invasive ischaemic-reperfusion (IR) injury. In this study, we investigated the analgesic effects of propofol and underlying mechanisms in mitigating CRPS pain using the CPIP model. Methods: Sub-anaesthetic dose of propofol (25 mg/kg) was intravenously delivered to the CPIP model and sham control. Nociceptive behavioural changes were assayed by the von Frey test. Molecular assays were used to investigate expression changes of PTEN, PI3K, AKT and IL-6 underlying propofol-mediated analgesic effects. Pharmacological inhibition was applied for PTEN/PI3K/AKT pathway manipulation. Results: Both pre- and post-operative administration of propofol attenuated mechanical allodynia induced by CPIP. Propofol could modulate PTEN/PI3K/AKT signalling pathway by increasing active PTEN and reducing phosphorylated PI3K, phosphorylated AKT and IL-6 expression in the spinal dorsal horn, which promoted pain relief in the CPIP model. Inhibition of PTEN with bpV abolished the analgesic effects produced by propofol in CPIP mice. Conclusion: Sub-anaesthetic dose of propofol administration resulted in the activation of PTEN, inhibition of both PI3K/AKT signalling and IL-6 production in the spinal cord, which dramatically reduced CPIP-induced pain. Our findings lay the foundation in using propofol for the treatment of CRPS with great therapeutic implications.

Use of pain-related gene features to predict depression by support vector machine model in patients with fibromyalgia.

The prevalence rate of depression is higher in patients with fibromyalgia syndrome, but this is often unrecognized in patients with chronic pain. Given that depression is a common major barrier in the management of patients with fibromyalgia syndrome, an objective tool that reliably predicts depression in patients with fibromyalgia syndrome could significantly enhance the diagnostic accuracy. Since pain and depression can cause each other and worsen each other, we wonder if pain-related genes can be used to differentiate between those with major depression from those without. This study developed a support vector machine model combined with principal component analysis to differentiate major depression in fibromyalgia syndrome patients using a microarray dataset, including 25 fibromyalgia syndrome patients with major depression, and 36 patients without major depression. Gene co-expression analysis was used to select gene features to construct support vector machine model. The principal component analysis can help reduce the number of data dimensions without much loss of information, and identify patterns in data easily. The 61 samples available in the database were not enough for learning based methods and cannot represent every possible variation of each patient. To address this issue, we adopted Gaussian noise to generate a large amount of simulated data for training and testing of the model. The ability of support vector machine model to differentiate major depression using microarray data was measured as accuracy. Different structural co-expression patterns were identified for 114 genes involved in pain signaling pathway by two-sample KS test (p < 0.001 for the maximum deviation D = 0.11 > D critical = 0.05), indicating the aberrant co-expression patterns in fibromyalgia syndrome patients. Twenty hub gene features were further selected based on co-expression analysis to construct the model. The principal component analysis reduced the dimension of the training samples from 20 to 16, since 16 components were needed to retain more than 90% of the original variance. The support vector machine model was able to differentiate between those with major depression from those without in fibromyalgia syndrome patients with an average accuracy of 93.22% based on the expression levels of the selected hub gene features. These findings would contribute key information that can be used to develop a clinical decision-making tool for the data-driven, personalized optimization of diagnosing depression in patients with fibromyalgia syndrome.

The analgesic effect of total intravenous anaesthesia with propofol versus inhalational anaesthesia for acute postoperative pain after hepatectomy: a randomized controlled trial.

BACKGROUND: Postoperative pain control can be challenging in patients undergoing hepatectomy. A previous retrospective study on hepatobiliary/ pancreatic surgeries showed better postoperative pain control in patients who received propofol TIVA. The aim of this study was to determine the analgesic effect of propofol TIVA for hepatectomy. This clinical study has been registered at ClinicalTrials.gov (NCT03597997). METHODS: A prospective randomized controlled trial was performed to compare the analgesic effect of propofol TIVA versus inhalational anaesthesia. Patients aged between 18 and 80 years old with an American Society of Anesthesiologist (ASA) physical status of I-III scheduled for elective hepatectomy were recruited. Ninety patients were randomly allocated to receive either propofol TIVA (TIVA group) or inhalational anaesthesia with sevoflurane (SEVO group). Perioperative anaesthetic/analgesic management was the same for both groups. Numerical rating scale (NRS) pain scores, postoperative morphine consumption, quality of recovery, patient satisfaction and adverse effects were evaluated during the acute postoperative period and at 3 and 6 months after surgery. RESULTS: No significant differences were found for acute postoperative pain scores (both at rest and during coughing) and postoperative morphine consumption between TIVA and SEVO groups. Patients given TIVA had lower pain scores with coughing at 3 months after surgery (p = 0.014, and FDR < 0.1). TIVA group was associated with better quality of recovery on postoperative day (POD) 3 (p = 0.038, and FDR < 0.1), less nausea (p = 0.011, and FDR < 0.1 on POD 2; p = 0.013, and FDR < 0.1 on POD 3) and constipation (p = 0.013, and FDR < 0.1 on POD 3). CONCLUSION: Propofol TIVA did not improve acute postoperative pain control compared to inhalational anaesthesia in patients who underwent hepatectomy. Our results do not support the use of propofol TIVA for reducing acute postoperative pain after hepatectomy.

Efficacy of Peripheral Nerve Field Stimulation for the Management of Chronic Low Back Pain and Persistent Spinal Pain Syndrome: A Narrative Review.

OBJECTIVES: Various approaches have been developed with a view to treating the back pain component in patients with chronic low back pain (CLBP) and persistent spinal pain syndrome (PSPS). Emerging evidence shows that peripheral nerve field stimulation (PNFS) may be an efficacious therapeutic modality against axial low back pain. Hence, the aim of the review was to evaluate the analgesic efficacy and safety of PNFS, when used alone or as an adjunct to spinal cord stimulation (SCS), for managing CLBP and PSPS. MATERIALS AND METHODS: A comprehensive search for clinical studies on PNFS and PNFS + SCS used for the management of CLBP and/or PSPS was performed using PubMed, EMBASE, MEDLINE via Proquest, and Web of Science. RESULTS: A total of 15 studies were included, of which four were randomized controlled trials (RCTs), nine were observational studies, and two were case series. For patients receiving PNFS, a significant decrease in back pain intensity and analgesic consumption, together with a significant improvement in physical functioning, was observed upon implant of the permanent system. Meanwhile, the addition of PNFS to SCS in refractory cases was associated with a significant reduction in back and leg pain, respectively. CONCLUSIONS: This review suggests that PNFS, when used alone or in combination with SCS, appears to be effective in managing back pain. However, high-quality evidence that supports the long-term analgesic efficacy and safety is still lacking. Hence, RCTs with a larger patient population and of a longer follow-up duration are warranted.

Chronic hepatitis C infection is associated with higher incidence of extrahepatic cancers in a Canadian population based cohort.

Introduction: Chronic infection with hepatitis C virus (HCV) is an established risk factor for liver cancer. Although several epidemiologic studies have evaluated the risk of extrahepatic malignancies among people living with HCV, due to various study limitations, results have been heterogeneous. Methods: We used data from the British Columbia Hepatitis Testers Cohort (BC-HTC), which includes all individuals tested for HCV in the Province since 1990. We assessed hepatic and extrahepatic cancer incidence using data from BC Cancer Registry. Standardized incidence ratios (SIR) comparing to the general population of BC were calculated for each cancer site from 1990 to 2016. Results: In total, 56,823 and 1,207,357 individuals tested positive and negative for HCV, respectively. Median age at cancer diagnosis among people with and without HCV infection was 59 (interquartile range (IQR): 53-65) and 63 years (IQR: 54-74), respectively. As compared to people living without HCV, a greater proportion of people living with HCV-infection were men (66.7% vs. 44.7%, P-value <0.0001), had comorbidities (25.0% vs. 16.3%, P-value <0.0001) and were socially deprived (35.9% vs. 25.0%, P-value <0.0001). The SIRs for liver (SIR 33.09; 95% CI 29.80-36.39), anal (SIR: 2.57; 95% CI 1.52-3.63), oesophagus (SIR: 2.00; 95% CI 1.17-2.82), larynx (SIR: 3.24; 95% CI 1.21-5.27), lung (SIR: 2.20; 95% CI 1.82-2.58), and oral (SIR: 1.78; 95% CI 1.33-2.23) cancers were significantly higher among individuals living with HCV. The SIRs for bile duct and pancreatic cancers were significantly elevated among both individuals living with (SIR; 95% CI: 2.20; 1.27-3.14; 2.18; 1.57-2.79, respectively) and without HCV (SIR; 95% CI: 2.12; 1.88-2.36; 1.20; 1.11-1.28, respectively). Discussion/Conclusion: In this study, HCV infection was associated with increased incidence of several extrahepatic cancers. The elevated incidence of multiple cancers among negative HCV testers highlights the potential contributions of screening bias and increased cancer risks associated with factors driving acquisition of infection among this population compared to the general population. Early HCV diagnosis and treatment as well as public health prevention strategies are needed to reduce the risk of extrahepatic cancers among people living with HCV and potentially populations who are at higher risk of HCV infection.

Prescription opioid treatment for non-cancer pain and initiation of injection drug use: large retrospective cohort study.

OBJECTIVE: To assess the association between long term prescription opioid treatment medically dispensed for non-cancer pain and the initiation of injection drug use (IDU) among individuals without a history of substance use. DESIGN: Retrospective cohort study. SETTING: Large administrative data source (containing information for about 1.7 million individuals tested for hepatitis C virus or HIV in British Columbia, Canada) with linkage to administrative health databases, including dispensations from community pharmacies. PARTICIPANTS: Individuals age 11-65 years and without a history of substance use (except alcohol) at baseline. MAIN OUTCOME MEASURES: Episodes of prescription opioid use for non-cancer pain were identified based on drugs dispensed between 2000 and 2015. Episodes were classified by the increasing length and intensity of opioid use (acute (lasting <90 episode days), episodic (lasting ≥90 episode days; with <90 days' drug supply and/or <50% episode intensity), and chronic (lasting ≥90 episode days; with ≥90 days' drug supply and ≥50% episode intensity)). People with a chronic episode were matched 1:1:1:1 on socioeconomic variables to those with episodic or acute episodes and to those who were opioid naive. IDU initiation was identified by a validated administrative algorithm with high specificity. Cox models weighted by inverse probability of treatment weights assessed the association between opioid use category (chronic, episodic, acute, opioid naive) and IDU initiation. RESULTS: 59 804 participants (14 951 people from each opioid use category) were included in the matched cohort, and followed for a median of 5.8 years. 1149 participants initiated IDU. Cumulative probability of IDU initiation at five years was highest for participants with chronic opioid use (4.0%), followed by those with episodic use (1.3%) and acute use (0.7%), and those who were opioid naive (0.4%). In the inverse probability of treatment weighted Cox model, risk of IDU initiation was 8.4 times higher for those with chronic opioid use versus those who were opioid naive (95% confidence interval 6.4 to 10.9). In a sensitivity analysis limited to individuals with a history of chronic pain, cumulative risk for those with chronic use (3.4% within five years) was lower than the primary results, but the relative risk was not (hazard ratio 9.7 (95% confidence interval 6.5 to 14.5)). IDU initiation was more frequent at higher opioid doses and younger ages. CONCLUSIONS: The rate of IDU initiation among individuals who received chronic prescription opioid treatment for non-cancer pain was infrequent overall (3-4% within five years) but about eight times higher than among opioid naive individuals. These findings could have implications for strategies to prevent IDU initiation, but should not be used as a reason to support involuntary tapering or discontinuation of long term prescription opioid treatment.

Women in the 2019 hepatitis C cascade of care: findings from the British Columbia Hepatitis Testers cohort study.

BACKGROUND: Women living with hepatitis C virus (HCV) are rarely addressed in research and may be overrepresented within key populations requiring additional support to access HCV care and treatment. We constructed the HCV care cascade among people diagnosed with HCV in British Columbia, Canada, as of 2019 to compare progress in care and treatment and to assess sex/gender gaps in HCV treatment access. METHODS: The BC Hepatitis Testers Cohort includes 1.7 million people who tested for HCV, HIV, reported cases of hepatitis B, and active tuberculosis in BC from 2000 to 2019. Test results were linked to medical visits, hospitalizations, cancers, prescription drugs, and mortality data. Six HCV care cascade stages were identified: (1) antibody diagnosed; (2) RNA tested; (3) RNA positive; (4) genotyped; (5) initiated treatment; and (6) achieved sustained virologic response (SVR). HCV care cascade results were assessed for women, and an 'inverse' cascade was created to assess gaps, including not being RNA tested, genotyped, or treatment initiated, stratified by sex. RESULTS: In 2019, 52,638 people with known sex were anti-HCV positive in BC; 37% (19,522) were women. Confirmatory RNA tests were received by 86% (16,797/19,522) of anti-HCV positive women and 83% (27,353/33,116) of men. Among people who had been genotyped, 68% (6756/10,008) of women and 67% (12,640/18,828) of men initiated treatment, with 94% (5023/5364) of women and 92% (9147/9897) of men achieving SVR. Among the 3252 women and 6188 men not yet treated, higher proportions of women compared to men were born after 1975 (30% vs. 21%), had a mental health diagnosis (42% vs. 34%) and had used injection drugs (50% vs. 45%). Among 1619 women and 2780 men who had used injection drugs and were not yet treated, higher proportions of women than men used stimulants (64% vs. 57%), and opiates (67% vs. 60%). CONCLUSIONS: Women and men appear to be equally engaged into the HCV care cascade; however, women with concurrent social and health conditions are being left behind. Treatment access may be improved with approaches that meet the needs of younger women, those with mental health diagnoses, and women who use drugs.

Cohort profile: development and characteristics of a retrospective cohort of individuals dispensed prescription opioids for non-cancer pain in British Columbia, Canada.

PURPOSE: Prescription opioids (POs) are widely prescribed for chronic non-cancer pain but are associated with several risks and limited long-term benefit. Large, linked data sources are needed to monitor their harmful effects. We developed and characterised a retrospective cohort of people dispensed POs. PARTICIPANTS: We used a large linked administrative database to create the Opioid Prescribing Evaluation and Research Activities cohort of individuals dispensed POs for non-cancer pain in British Columbia (BC), Canada (1996-2015). We created definitions to categorise episodes of PO use based on a review of the literature (acute, episodic, chronic), developed an algorithm for inferring clinical indication and assessed patterns of PO use across a range of characteristics. FINDINGS TO DATE: The current cohort includes 1.1 million individuals and 3.4 million PO episodes (estimated to capture 40%-50% of PO use in BC). The majority of episodes were acute (81%), with most prescribed for dental or surgical pain. Chronic use made up 3% of episodes but 88% of morphine equivalents (MEQ). Across the acute to episodic to chronic episode gradient, there was an increasing prevalence of higher potency POs (hydromorphone, oxycodone, fentanyl, morphine), long-acting formulations and chronic pain related indications (eg, back, neck, joint pain). Average daily dose (MEQ) was similar for acute/episodic but higher for chronic episodes. Approximately 7% of the cohort had a chronic episode and chronic pain was the characteristic most strongly associated with chronic PO use. Individuals initiating a chronic episode were also more likely to have higher social/material deprivation and previous experience with a mental health condition or a problem related to alcohol or opioid use. Overall, these findings suggest our episode definitions have face validity and also provide insight into characteristics of people initiating chronic PO therapy. FUTURE PLANS: The cohort will be refreshed every 2 years. Future analyses will explore the association between POs and adverse outcomes.

Novel approach to reduce SARS-CoV-2 transmission during trans-oral robotic surgery.

This study describes a novel approach in the reduction of SARS-CoV-2 transmission during trans-oral robotic surgery (TORS). Eight patients underwent TORS between 01 February 2020 and 07 September 2020. A sterile plastic sheet draped over sterile supports with water-tight seal around each cannula was used to create a sterile working space within which the robotic arms could freely move during operation. This set-up acts as an additional physical barrier against droplet and aerosol transmission. Operative diagnosis; droplet count and distribution on plastic sheet and face shields of console and assistant surgeons, and scrub nurse were documented. TORS tumour excision was performed for patients with suspected tonsillar tumour (n = 3) and tongue base tumour (n = 2). TORS tonsillectomy and tongue base mucosectomy was performed for cervical nodal metastatic carcinoma of unknown origin (n = 3). Droplet contamination was noted on all plastic drapes (n = 8). Droplet contamination was most severe over the central surface at 97.2% (91.7-100.0%), with the highest droplet count along the centre-most column where it overlies the site of operation in the oral cavity 33.3% (n = 31). Droplet count decreased towards the periphery. Contamination rate was 2.8% (0.0-8.3%) over the right lateral surface. There was no droplet contamination over the vertex and left lateral surface of plastic drapes. No droplet contamination was noted on face shields of all parties. The use of sterile plastic drapes with water-tight seal around each robotic cannula can help reduce viral transmission to healthcare providers during TORS.

Elevated risk of colorectal, liver, and pancreatic cancers among HCV, HBV and/or HIV (co)infected individuals in a population based cohort in Canada.

INTRODUCTION: Studies of the impact of hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV mono and co-infections on the risk of cancer, particularly extra-hepatic cancer, have been limited and inconsistent in their findings. METHODS: In the British Columbia Hepatitis Testers Cohort, we assessed the risk of colorectal, liver, and pancreatic cancers in association with HCV, HBV and HIV infection status. Using Fine and Gray adjusted proportional subdistribution hazards models, we assessed the impact of infection status on each cancer, accounting for competing mortality risk. Cancer occurrence was ascertained from the BC Cancer Registry. RESULTS: Among 658,697 individuals tested for the occurrence of all three infections, 1407 colorectal, 1294 liver, and 489 pancreatic cancers were identified. Compared to uninfected individuals, the risk of colorectal cancer was significantly elevated among those with HCV (Hazard ration [HR] 2.99; 95% confidence interval [CI] 2.55-3.51), HBV (HR 2.47; 95% CI 1.85-3.28), and HIV mono-infection (HR 2.30; 95% CI 1.47-3.59), and HCV/HIV co-infection. The risk of liver cancer was significantly elevated among HCV and HBV mono-infected and all co-infected individuals. The risk of pancreatic cancer was significantly elevated among individuals with HCV (HR 2.79; 95% CI 2.01-3.70) and HIV mono-infection (HR 2.82; 95% CI 1.39-5.71), and HCV/HBV co-infection. DISCUSSION/CONCLUSION: Compared to uninfected individuals, the risk of colorectal, pancreatic and liver cancers was elevated among those with HCV, HBV and/or HIV infection. These findings highlight the need for targeted cancer prevention and diligent clinical monitoring for hepatic and extrahepatic cancers in infected populations.

Central Endothelin-1 Confers Analgesia by Triggering Spinal Neuronal Histone Deacetylase 5 (HDAC5) Nuclear Exclusion in Peripheral Neuropathic Pain in Mice.

The rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant). Notably, ET-1 administration increased spinal glutamate acid decarboxylases (GAD65/67) expression via initiating HDAC5 nuclear exportation and increased the acetylation of histone 3 at lysine 9 (Acetyl-H3K9) in the promotor regions of spinal Gad1 and Gad2 genes. This was reversed by blocking endothelin A receptor function or by inhibiting the spinal neuronal nuclear exportation of HDAC5. Therefore, inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain. PERSPECTIVE: Neuropathic pain is intractable in a clinical setting, and epigenetic regulation is considered to contribute to this processing. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain.

Total Intravenous Anesthesia (TIVA) With Propofol for Acute Postoperative Pain: A Scoping Review of Randomized Controlled Trials.

Total intravenous anesthesia (TIVA) with propofol may improve acute postoperative pain control compared to inhalational anesthesia. The objective of this review was to comprehensively update and evaluate the existing literature on the analgesic efficacy of propofol TIVA. A systemized literature search for randomized controlled trials in adult patients was conducted in the PubMed and Cochrane CENTRAL (EMBASE source) databases up to August 2019. Clinical trials included compared propofol TIVA against inhalational isoflurane, sevoflurane, or desflurane. Only clinical trials that studied acute postoperative pain scores or analgesic consumption as a primary outcome were included. Sixteen randomized controlled trials were included. Surgical procedures evaluated included: radical gastrectomy, open vein stripping, breast cancer surgery, laparoscopic cholecystectomy, inguinal herniotomy, abdominoplasty, bariatric surgery, lumbar spine surgery, emergency neurosurgical operations, open and laparoscopic gynecological surgeries, and dental surgery. Propofol TIVA was associated with reduced postoperative pain scores and/or decreased opioid consumption in 9 out of 16 clinical trials. There was no difference in 5 clinical trials, and propofol TIVA was associated with worse analgesic outcomes in 2 trials. Propofol TIVA may improve acute postoperative analgesia after surgery, but different factors such as surgical procedures and anesthetic/analgesic techniques may influence its effectiveness.

Dysregulation of EAAT2 and VGLUT2 Spinal Glutamate Transports via Histone Deacetylase 2 (HDAC2) Contributes to Paclitaxel-induced Painful Neuropathy.

Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8 mg/kg) induced long-lasting mechanical allodynia (>28 days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and coexpressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and colocalization were confirmed following paclitaxel treatment using co-immunoprecipitation. Inhibition or knockdown of HDAC2 expression by valproic acid, BRD6688, or HDAC2 siRNA not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation, and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.

Impacts of Human Papillomavirus Immunization Programs on Rates of Anogenital Warts in British Columbia, Canada, 2000 to 2017.

BACKGROUND: In 2008, British Columbia (BC) implemented a school-based quadrivalent human papillomavirus (HPV-4) immunization program for girls born in 1994 or later. In 2015, an expanded clinic-based program included men who report sex with men (MSM) born in 1989 or later. To evaluate the impacts of HPV-4 programs on anogenital warts (AGWs), diagnosis rates were measured among women who report sex with men (WSM), men who report sex with women (MSW), and MSM. METHODS: Diagnoses of AGW were ascertained from 16 sexually transmitted infection clinics. Rates were calculated as new AGW diagnoses over person-years (py) at risk and stratified by age group, calendar period, and birth cohort. Adjusted relative rates (aRR) were estimated using multivariable Poisson regression. RESULTS: There were 204,832 clinic visits by 85,158 individuals: 28,366 (33%) WSM, 35,688 (42%) MSW, and 14,534 (17%) MSM. After adjusting for age and period, AGW rates in the 1994-1996 birth cohort decreased by 56% overall (1.21 vs. 2.72 cases/100 py; aRR, 0.44; 95% confidence interval [CI], 0.34-0.59), 65% among WSM (0.97 vs. 2.77 cases/100 py; aRR, 0.35; 95% CI, 0.22-0.57), 58% among MSW (1.60 vs. 3.78 cases/100 py; aRR, 0.42; 95% CI, 0.28-0.65), and 41% among MSM (1.14 vs. 1.19 cases/100 py; aRR, 0.59; 95% CI, 0.38-0.91) versus the 1991-1993 birth cohort. CONCLUSIONS: The HPV-4 programs had significant impacts on lowering AGW rates in BC. The greatest decrease was among WSM eligible for the school-based program, followed by birth cohorts of men who likely have sex with HPV-4 eligible women. The smallest decrease among MSM may reflect the later introduction of the clinic-based program.