Chronic wound-related pain, wound healing and the therapeutic potential of cannabinoids and endocannabinoid system modulation.

Chronic wounds represent a significant burden on the individual, and the healthcare system. Individuals with chronic wounds report pain to be the most challenging aspect of living with a chronic wound, with current therapeutic options deemed insufficient. The cutaneous endocannabinoid system is an important regulator of skin homeostasis, with evidence of system dysregulation in several cutaneous disorders. Herein, we describe the cutaneous endocannabinoid system, chronic wound-related pain, and comorbidities, and review preclinical and clinical evidence investigating endocannabinoid system modulation for wound-related pain and wound healing. Based on the current literature, there is some evidence to suggest efficacy of endocannabinoid system modulation for promotion of wound healing, attenuation of cutaneous disorder-related inflammation, and for the management of chronic wound-related pain. However, there is 1) a paucity of preclinical studies using validated models, specific for the study of chronic wound-related pain and 2) a lack of randomised control trials and strong clinical evidence relating to endocannabinoid system modulation for wound-related pain. In conclusion, while there is some limited evidence of benefit of endocannabinoid system modulation in wound healing and wound-related pain management, further research is required to better realise the potential of targeting the endocannabinoid system for these therapeutic applications.

Systematic review of topical interventions for the management of pain in chronic wounds.

Chronic wounds adversely affect quality of life. Pain is associated with chronic wounds, and its impact can vary according to wound aetiology, condition, and patient factors. This systematic review examined the effectiveness of topical interventions in the management chronic wound-related pain guided by PRISMA recommendations of randomised controlled trials (RCTs) where pain reduction is the primary outcome. Inclusion criteria were adults (older than 18 years) with chronic venous, arterial, diabetic, or pressure ulcers where pain has been managed through topical administration of pharmacological/nonpharmacological agents. Searches were conducted in Ovid Embase, Ovid MEDLINE, EBSCOhost, CINAHL, CENTRAL, PubMed, Web of Science, and Scopus. Studies were screened for eligibility; risk of bias and data were extracted by 2 independent assessors. Searches retrieved 10,327 titles and abstracts (7760 after deduplication). Nine full texts (1323 participants) examining ibuprofen (n = 4), morphine (n = 2), BWD + PHMB [polihexanide-containing biocellulose wound dressing] (n = 1), and EMLA (n = 2) were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Meta-analysis was not possible, but initial exploration suggests improved outcomes (reduced pain) for ibuprofen when compared with controls. Two studies involving morphine showed conflicting findings. Included studies often had small samples, and considering confounding factors (eg, comorbidities), the results should be interpreted with caution. Review of included studies suggests that topical interventions may provide pain relief in individuals with chronic wounds. Further adequately powered RCTs are recommended to assess the efficacy of topical interventions for the management of chronic wound-related pain.

Adaptation and Formative Evaluation of Online Decision Support to Implement Evidence-Based Strategies to Increase HPV Vaccination Rates in Pediatric Clinics.

Human papilloma virus (HPV) vaccination rates remain below national goals in the United States despite the availability of evidence-based strategies to increase rates. The Adolescent Vaccination Program (AVP) is a multi-component intervention demonstrated to increase HPV vaccination rates in pediatric clinics through the implementation of six evidence-based strategies. The purpose of this study, conducted in Houston, Texas, from 2019-2021, was to adapt the AVP into an online decision support implementation tool for standalone use and to evaluate its feasibility for use in community clinics. Phase 1 (Adaptation) comprised clinic interviews (n = 23), literature review, Adolescent Vaccination Program Implementation Tool (AVP-IT) design documentation, and AVP-IT development. Phase 2 (Evaluation) comprised usability testing with healthcare providers (HCPs) (n = 5) and feasibility testing in community-based clinics (n = 2). AVP-IT decision support provides an Action Plan with tailored guidance on implementing six evidence-based strategies (immunization champions, assessment and feedback, continuing education, provider prompts, parent reminders, and parent education). HCPs rated the AVP-IT as acceptable, credible, easy, helpful, impactful, and appealing (≥80% agreement). They rated AVP-IT supported implementation as easier and more effective compared to usual practice (p ≤ 0.05). The clinic-based AVP-IT uses facilitated strategy implementation by 3-month follow-up. The AVP-IT promises accessible, utilitarian, and scalable decision support on strategies to increase HPV vaccination rates in pediatric clinic settings. Further feasibility and efficacy testing is indicated.

Topical interventions for the management of pain in chronic wounds: A protocol for a systematic review.

Background: Venous, arterial, diabetic and pressure ulcers, collectively known as chronic wounds, negatively impact individuals across psychological, social and financial domains. Chronic wounds can be painful and the nature, frequency and impact of pain can differ depending on wound aetiology, wound state and on numerous patient factors. While systemic pharmaceutical agents have some effect in managing pain, there is a need to examine topical agents applied to the wound bed for pain relief. The objective of this study is to examine and synthesise existing literature on the effectiveness of topical agents in managing pain in venous, diabetic, pressure, arterial and mixed venous/arterial ulcers. Methods: We will use Cochrane Systematic Review methodology to identify and synthesise eligible randomised controlled trials (RCTs) evaluating the effectiveness of topical agents in reducing pain in chronic wounds. Embase, Medline, PubMed, CENTRAL, CINAHL, Scopus and Web of Science will be searched from inception to end of June 2022 without language limits. We will independently extract data on the pharmaceutical agent, participant demographics, aetiology, condition of the wound, and type, nature and frequency of pain using a pre-designed data extraction form. Subgroup and sensitivity analysis will be performed to address heterogeneity across studies if appropriate. Further stratification and analyses will be based on included study variables and outcomes. Discussion: Wound pain is primarily managed via systemic pharmaceutical agents. However, patients express reluctance regarding systemic analgesic drugs, fearing addiction. Additionally, persons with chronic wounds have co-morbidities including hypertension, diabetes, or cardiovascular disease and are already taking multiple medications. Topical analgesia can potentially mitigate some of the perceived disadvantages of systemic agents but the available range of these agents and their effectiveness in managing pain in chronic wounds is not so well understood. This review will focus on such agents across a range of the most common chronic wounds.

Group B Streptococcal Cellulitis-Adenitis Syndrome in Infants: Insights From 24 Years of Experience.

This series of 28 infants with group B streptococcal (GBS) cellulitis-adenitis from a single institution over 24 years offers insights important to the early recognition, spectrum of findings, and optimal management of this rare manifestation of invasive GBS disease.

Pharmacological Blockade of PPARα Exacerbates Inflammatory Pain-Related Impairment of Spatial Memory in Rats.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that exist in three isoforms: PPARα, PPARß/δ and PPARγ. Studies suggest that the PPAR signalling system may modulate pain, anxiety and cognition. The aim of the present study was to investigate whether endogenous signalling via PPARs differentially modulates innate anxiety responses and mnemonic function in the presence and absence of inflammatory pain. We examined the effects of intraperitoneal administration of GW6471 (PPARα antagonist), GSK0660 (PPARß/δ antagonist), GW9662 (PPARγ antagonist), and N-palmitoylethanolamide (PEA) on rat behaviour in the elevated plus maze (EPM), open field (OF), light-dark box (LDB), and novel object recognition (NOR) tests in the presence or absence of chronic inflammatory pain. Complete Freund's Adjuvant (CFA)-injected rats exhibited impaired recognition and spatial mnemonic performance in the NOR test and pharmacological blockade of PPARα further impaired spatial memory in CFA-treated rats. N-oleoylethanolamide (OEA) levels were higher in the dorsal hippocampus in CFA-injected animals compared to their counterparts. The results suggest a modulatory effect of CFA-induced chronic inflammatory pain on cognitive processing, but not on innate anxiety-related responses. Increased OEA-PPARα signalling may act as a compensatory mechanism to preserve spatial memory function following CFA injection.

Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain.

ABSTRACT: We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.

Monoclonal antibodies targeting ST2L Domain 1 or Domain 3 differentially modulate IL-33-induced cytokine release by human mast cell and basophilic cell lines.

The cell-surface receptor ST2L triggers cytokine release by immune cells upon exposure to its ligand IL-33. To study the effect of ST2L-dependent signaling in different cell types, we generated antagonist antibodies that bind different receptor domains. We sought to characterize their activities in vitro using both transfected cells as well as basophil and mast cell lines that endogenously express the ST2L receptor. We found that antibodies binding Domain 1 versus Domain 3 of ST2L differentially impacted IL-33-induced cytokine release by mast cells but not the basophilic cell line. Analysis of gene expression in each cell type in the presence and absence of the Domain 1 and Domain 3 mAbs revealed distinct signaling pathways triggered in response to IL-33 as well as to each anti-ST2L antibody. We concluded that perturbing the ST2L/IL-33/IL-1RAcP complex using antibodies directed to different domains of ST2L have a cell-type-specific impact on cytokine release, and may indicate the association of additional receptors to the ST2L/IL-33/IL-1RAcP complex in mast cells.

Silica Measurement with High Flow Rate Respirable Size Selective Samplers: A Field Study.

High and low flow rate respirable size selective samplers including the CIP10-R (10 l min(-1)), FSP10 (11.2 l min(-1)), GK2.69 (4.4 l min(-1)), 10-mm nylon (1.7 l min(-1)), and Higgins-Dewell type (2.2 l min(-1)) were compared via side-by-side sampling in workplaces for respirable crystalline silica measurement. Sampling was conducted at eight different occupational sites in the USA and five different stonemasonry sites in Ireland. A total of 536 (268 pairs) personal samples and 55 area samples were collected. Gravimetric analysis was used to determine respirable dust mass and X-ray diffraction analysis was used to determine quartz mass. Ratios of respirable dust mass concentration, quartz mass concentration, respirable dust mass, and quartz mass from high and low flow rate samplers were compared. In general, samplers did not show significant differences greater than 30% in respirable dust mass concentration and quartz mass concentration when outliers (ratio <0.3 or >3.0) were removed from the analysis. The frequency of samples above the limit of detection and limit of quantification of quartz was significantly higher for the CIP10-R and FSP10 samplers compared to low flow rate samplers, while the GK2.69 cyclone did not show significant difference from low flow rate samplers. High flow rate samplers collected significantly more respirable dust and quartz than low flow rate samplers as expected indicating that utilizing high flow rate samplers might improve precision in quartz measurement. Although the samplers did not show significant differences in respirable dust and quartz concentrations, other practical attributes might make them more or less suitable for personal sampling.

Biofilm-associated bacterial amyloids dampen inflammation in the gut: oral treatment with curli fibres reduces the severity of hapten-induced colitis in mice.

BACKGROUND/OBJECTIVES: A disruption of epithelial barrier function can lead to intestinal inflammation. Toll-like receptor (TLR) 2 activation by microbial products promotes intestinal epithelial integrity and overall gut health. Several bacterial species, including enteric bacteria, actively produce amyloid proteins as a part of their biofilms. Recognition of amyloid fibres found in enteric biofilms, termed curli, by the Toll-like receptor (TLR)2/1 complex reinforces barrier function. Here, we investigated the effect of purified curli fibres on inflammation in a mouse model of acute colitis. METHODS: Bone marrow-derived macrophages as well as lamina propria cells were treated with curli fibres of both pathogenic Salmonella enterica serovar Typhimurium and commensal Escherichia coli Nissle 1917 biofilms. Mice were given 0.1 or 0.4 mg of purified curli orally 1 day post administration of 1% 2,4,6-trinitrobenzene sulphonic acid (TNBS) enema. Histopathological analysis was performed on distal colonic tissue taken 6 days post TNBS enema. RNA extracted from colonic tissue was subjected to RT-PCR. RESULTS: Here we show that curli fibres of both pathogenic and commensal bacteria are recognised by TLR2 leading to the production of IL-10, immunomodulatory cytokine of intestinal homeostasis. Treatment of mice with a single dose of curli heightens transcript levels of Il10 in the colon and ameliorates the disease pathology in TNBS-induced colitis. Curli treatment is comparable to the treatment with anti-tumour necrosis factor alpha (anti-TNFα) antibodies, a treatment known to reduce the severity of acute colitis in humans and mice. CONCLUSION: These results suggest that the bacterial amyloids had a role in helping to maintain immune homeostasis in the intestinal mucosa via the TLR2/IL-10 axis. Furthermore, bacterial amyloids may be a potential candidate therapeutic to treat intestinal inflammatory disorders owing to their remarkable immunomodulatory activity.

An evaluation of on-tool shrouds for controlling respirable crystalline silica in restoration stone work.

OBJECTIVES: The task of grinding sandstone with a 5-inch angle grinder is a major source of exposure to respirable crystalline silica (RCS), known to cause diseases such as silicosis and lung cancer among workers who work with these materials. A shroud may be a suitable engineering control for this task. The objectives of this study were to evaluate the effectiveness of four commercially available shrouds at reducing respirable dust and RCS levels during the task of grinding sandstone using tools and accessories typical of restoration stone work. METHODS: The task of grinding sandstone with a 5-inch angle grinder, equipped with different grinding wheels, was carried out over three trials at a restoration stone masonry site. Photometric and RCS data were collected when a 5-inch grinder, equipped with different grinding wheels, was used to grind sandstone with and without a shroud. A total of 24 short duration samples were collected for each no shroud and with shroud combination. Worker feedback on the practicalities of each shroud evaluated was also collected. RESULTS: Respirable dust concentrations and RCS were both significantly lower (P < 0.001) when the grinders were equipped with a shroud compared with grinders without a shroud. Total geometric mean (GM) photometric respirable dust levels measured when grinding with a shroud were 0.5 mg m(-3), a reduction of 92% compared to grinding without a shroud (7.1 mg m(-3)). The overall GM RCS concentrations were reduced by the use of a shroud by 99%. GM photometric exposure levels were highest when using the Hilti 5-inch diamond grinding cup and Diamond turbo cup and lowest when using the Corundum grinding point. CONCLUSIONS: Concentrations of respirable dust and RCS can be significantly reduced by using commercially available shrouds while grinding sandstone with a 5-inch angle grinder in restoration stonework. The short-term photometric respirable dust and RCS measurements collected with and without a shroud indicate that dust and RCS concentrations are reduced by between 90 and 99%. Supplemental exposure controls such as respiratory protective equipment would be required to reduce worker 8-h time-weighted average RCS exposure to below the Scientific Committee on Occupational Exposure Limits recommended occupational exposure limit value of 0.05 mg m(-3) and the American Conference of Governmental Industrial Hygienists threshold limit value of 0.025 mg m(-3).

Determinants of respirable crystalline silica exposure among stoneworkers involved in stone restoration work.

OBJECTIVES: Crystalline silica occurs as a significant component of many traditional materials used in restoration stonework, and stoneworkers who work with these materials are potentially exposed to stone dust containing respirable crystalline silica (RCS). Exposure to RCS can result in the development of a range of adverse health effects, including silicosis and lung cancer. An understanding of the determinants of RCS exposure is important for selecting appropriate exposure controls and in preventing occupational diseases. The objectives of this study were to quantify the RCS exposure of stoneworkers involved in the restoration and maintenance of heritage properties and to identify the main determinants of RCS exposure among this occupational group. METHODS: An exposure assessment was carried out over a 3-year period amongst a group of stonemasons and stone cutters involved in the restoration and maintenance of heritage buildings in Ireland. Personal air samples (n = 103) with corresponding contextual information were collected. Exposure data were analysed using mixed-effects modelling to investigate determinants of RCS exposure and their contribution to the individual's mean exposure. Between-depot, between-worker, and within-worker variance components were also investigated. RESULTS: The geometric mean (GM) RCS exposure concentrations for all tasks measured ranged from <0.02 to 0.70mg m(-3). GM RCS exposure concentrations for work involving limestone and lime mortar were <0.02-0.01mg m(-3), tasks involving granite were 0.01-0.06mg m(-3), and tasks involving sandstone were <0.02-0.70mg m(-3). Sixty-seven percent of the 8-h time-weighted average (TWA) exposure measurements for tasks involving sandstone exceeded the Scientific Committee on Occupational Exposure Limits recommended occupational exposure limit value of 0.05mg m(-3). Highest RCS exposure values were recorded for the tasks of grinding (GM = 0.70mg m(-3)) and cutting (GM = 0.70mg m(-3)) sandstone. In the mixed-effects analyses, task was found to be significantly associated with RCS exposure, with the tasks of grinding and cutting resulting in average exposures of between 32 and 70 times the exposures recorded for the task of stone decorating. The between-depot, between-worker, and within-worker variance components were reduced by 46, 89, and 49%, respectively, after including task in the mixed effects model. CONCLUSIONS: Restoration stoneworkers are regularly overexposed (compared with 0.1 and 0.05mg m(-3) 8-h TWA) to RCS dust when working with sandstone. The results indicate that the tasks of cutting and grinding sandstone are predictors of increased exposure to RCS dust. In order to decrease exposure to RCS, efforts should be focused on developing and implementing interventions which focus on these high-risk tasks.

Performance of High-Flow-Rate Samplers for Respirable Crystalline Silica Measurement Under Field Conditions: Preliminary Study.

Restoration stone work regularly involves work with high-silica-content materials (e.g., sandstone), but low-silica-content materials (<2 % quartz) such as limestone and lime mortar are also used. A combination of short sample duration and low silica content makes the quantification of worker exposure to respirable crystalline silica (RCS) difficult. This problem will be further compounded by the introduction of lower occupational exposure standards for RCS. The objective of this work was to determine whether higher-flow samplers might be an effective tool in characterizing lower RCS concentrations. A short study was performed to evaluate the performance of three high-flow samplers (FSP10, CIP10-R, and GK2.69) using side-by-side sampling with low-flow samplers (SIMPEDS and 10-mm nylon cyclones) for RCS exposure measurement at a restoration stonemasonry field site. A total of 19 side-by-side sample replicates for each high-flow and low-flow sampler pair were collected from work tasks involving limestone and sandstone. RESULTS: Most of the RCS (quartz) masses collected with the high-flow-rate samplers were above the limit of detection (62 % to 84 %) relative to the low-flow-rate samplers (58 % to 78 %). The average of the respirable mass concentration ratios for CIP10-R/SIMPEDS, GK2.69/10-mm nylon, FSP10/SIMPEDS, and FSP10/10-mm nylon pairs and the range of the quartz concentration ratios for the CIP10-R/SIMPEDS, CIP10-R/10-mm nylon, GK2.69/10-mm nylon, FSP10/SIMPEDS, and FSP10/10-mm nylon pairs included unity with an average close to unity, indicating no likely difference between the reported values for each sampler. Workers reported problems related to the weight of the sampling pumps for the high-flow-rate samplers. Respirable mass concentration data suggest that the high-flow-rate samplers evaluated would be appropriate for sampling respirable dust concentrations during restoration stone work. Results from the comparison of average quartz concentration ratios between high-and low-flow samplers suggest that the higher mass collected by the high-flow-rate samplers did not interfere with the quartz measurement. A sig-nificant portion of the data collected with the high-flow-rate samplers (>82 %) were greater than the limit of detection, which indicates that these samplers are suitable for quantifying exposures, even with low-quartz materials.

HIV and the decriminalization of sex work in New Zealand.

The decriminalization of sex work in New Zealand will protect the rights of sex workers and improve their working conditions and general well-being. It will also improve HIV prevention programs. In this article, which is based on a presentation at a "learning from practice" session at the conference, Catherine Healy describes the situation prior to decriminalization, and discusses the features of the new law and accompanying guidelines.