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Background: Balance between benefits and harms of using opioids for the management of chronic noncancer pain (CNCP) must be carefully considered on a case-by-case basis. There is no one-size-fits-all approach that can be executed by prescribers and clinicians when considering this therapy., Aim: The aim of this study was to identify barriers and facilitators for prescribing opioids for CNCP through a systematic review of qualitative literature., Methods: Six databases were searched from inception to June 2019 for qualitative studies reporting on provider knowledge, attitudes, beliefs, or practices pertaining to prescribing opioids for CNCP in North America. Data were extracted, risk of bias was rated, and confidence in evidence was graded., Results: Twenty-seven studies reporting data from 599 health care providers were included. Ten themes emerged that influenced clinical decision making when prescribing opioids. Providers were more comfortable to prescribe opioids when (1) patients were actively engaged in pain self-management, (2) clear institutional prescribing policies were present and prescription drug monitoring programs were used, (3) long-standing relationships and strong therapeutic alliance were present, and (4) interprofessional supports were available. Factors that reduced likelihood of prescribing opioids included (1) uncertainty toward subjectivity of pain and efficacy of opioids, (2) concern for the patient (e.g., adverse effects) and community (i.e., diversion), (3) previous negative experiences (e.g., receiving threats), (4) difficulty enacting guidelines, and (5) organizational barriers (e.g., insufficient appointment duration and lengthy documentation)., Conclusions: Understanding barriers and facilitators that influence opioid-prescribing practices offers insight into modifiable targets for interventions that can support providers in delivering care consistent with practice guidelines., Competing Interests: The authors have no conflicts of interest to report., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Context: This study is a systematic review of interventions to improve adherence to guideline recommendations for prescribing opioids for chronic noncancer pain., Evidence Acquisition: Investigators searched CINAHL, Embase, MEDLINE, PsycINFO, the Cochrane Library, and Joanna Briggs Institute Evid Based Pract database from inception until June 3, 2019. Interventional studies to improve adherence to recommendations made by opioid guidelines for chronic noncancer pain in North America were eligible if outcomes included adherence to guideline recommendations or change in quantity of opioids prescribed. Data were extracted independently and in duplicate. Quantitative synthesis was performed using random effects meta-analysis. Confidence in evidence was determined using the Grades of Recommendation, Assessment, Development, and Evaluation., Evidence Synthesis: A total of 20 studies (8 controlled and 12 prospective cohort) involving 1,491 providers and 72 clinics met inclusion. Interventions included education, audit and feedback, interprofessional support, shared decision making, and multifaceted strategies. Multifaceted interventions improved the use of urine drug testing (n=2, or =2.31, 95% CI=1.53, 3.49, z=3.98, p<0.01; high-certainty evidence), treatment agreements (n=2, or =1.96, 95% CI=1.47, 2.61, z=4.56, p<0.01; moderate-certainty evidence), and mental health screening (n=2, 2.57-fold, 95% CI=1.56, 4.24, z=2.32, p=0.02; low-certainty evidence) when prescribing opioids for chronic noncancer pain. Very low-certainty evidence suggests that several interventions improved the use of treatment agreements, urine drug testing, and prescription drug monitoring programs., Conclusions: Mostly very low-certainty evidence supports a number of interventions for improving adherence to risk management strategies when prescribing opioids for chronic noncancer pain; however, the effect on patient important outcomes (e.g., overdose, addiction, death) is uncertain., (Copyright © 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: This review quantified prescriber adherence to opioid prescribing guidelines for chronic noncancer pain (CNCP)., Method: We searched CINAHL, Embase, MEDLINE, PsycINFO, the Cochrane Library, and the Joanna Briggs Institute EBP Database from inception until June 3, 2019. Studies that focused on provider adherence to opioids guidelines for CNCP in North America were eligible. Four reviewers screened studies, extracted data, and assessed study quality., Results: Thirty-eight studies were eligible, comprising 17 cross-sectional studies ( n = 11,835 providers) and 22 chart reviews ( n = 22,512 patients). Survey data indicated that adherence was 49% (95% CI [40, 59]) for treatment agreements, 33% (95% CI [19%, 47%]) for urine drug testing, 48% (95% CI [26%, 71%]) for consultation with drug monitoring program, 57% (95% CI [35%, 79%]) for assessing risk of aberrant medication-taking behavior, and 61% (95% CI [35%, 87%]) for mental health screening. Chart review data indicated that the proportion of patients with documentation was 40% (95% CI [29, 51]) for treatment agreements, 41% (95% CI [32%, 50%]) for urine drug testing, 40% (95% CI [2%, 78%]) for consultation with drug monitoring program, 41% (95% CI [20%, 64%]) for assessing risk of aberrant medication-taking behavior, and 22% (95% CI [9%, 33%]) for mental health screening. Year of publication, practice guideline referenced, and risk of bias explained significant heterogeneity. No study evaluated whether nonadherence to recommendations reflected well-justified deviations to care., Conclusions: Adherence to guideline recommendations for opioids for CNCP is low. It is unclear whether nonadherence reflects thoughtful deviations in care. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Introduction: Approximately one-third of adults with chronic pain also report clinically relevant levels of depression. Internet-delivered psychological therapies such as Cognitive Behavioural Therapy (iCBT) and Acceptance and Commitment Therapy (iACT) have been developed to overcome barriers of access to services and ensure the timely delivery of care. The objective of this trial is to collect data on feasibility, acceptability and range of probable effect sizes for iCBT and iACT interventions tailored towards the treatment of depression and chronic pain using a randomised controlled patient-preference design., Methods and Analysis: Community dwelling adults with chronic non-cancer pain (CNCP) and major depression will be recruited from pain clinics and primary care providers in Newfoundland and Labrador, Canada. The study is a randomised controlled patient-preference trial. Eligible patients will be randomly assigned to a 'preference' or 'no-preference' arm during the first step of randomisation and to intervention or control in the second step of randomisation. Two interventions (ie, iCBT or iACT) will be evaluated relative to attention control. iCBT and iACT involve the completion of 7-weekly online modules augmented with one session of motivational enhancement and weekly therapy sessions. Primary outcomes include (1) feasibility and acceptability parameters and (2) change in symptoms of depression. Secondary outcomes include pain, physical function, emotional function and quality of life. We will recruit 60 participants and examine the range of effect sizes obtained from the trial but will not conduct significance testing as per recommendations for behavioural trial development., Ethics and Dissemination: Ethics was approved by the provincial Health Research Ethics Board. Dissemination of results will be published in a peer-reviewed academic journal and presented at scientific conferences., Trial Registration Number: NCT04009135., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Alternatively activated macrophages (AAMs) have key roles in the immune response to a variety of gastrointestinal helminths such as Heligmosomoides bakeri and Nippostrongylus brasiliensis. In addition, AAMs have been implicated in the resolution of infection-induced pathology in Schistosoma mansoni infection. AAMs exert their activity in part via the enzyme arginase-1 (Arg1), which hydrolyses L-arginine into urea and ornithine, and can supply precursor substrate for proline and polyamine production. Trichuris muris is a worm that resides in the large intestine with resistance being characterized by a Th2 T-cell response, which drives alternatively activated macrophage production in the local environment of the infection. To investigate the role of AAMs in T. muris infection, we used independent genetic and pharmacologic models of arginase deficiency. In acute infection and Th2-dominated immunity, arginase-deficient models expelled worms normally. Macrophage-Arg1-deficient mice showed cytokine and antibody levels comparable to wild-type animals in acute and chronic infection. We also found no role for AAMs and Arg1 in infection-induced pathology in the response to T. muris in either chronic (Th1 dominated) or acute (Th2 dominated) infections. Our data demonstrate that, unlike other gastrointestinal helminths, Arg1 expression in AAMs is not essential for resistance to T. muris in effective resolution of helminth-induced inflammation., (© 2011 Blackwell Publishing Ltd.)

Tryptophan catabolism via the kynurenine pathway is dependent on the enzyme Indoleamine 2,3-dioxygenase (IDO). Expression of IDO is upregulated in a number of inflammatory settings such as wounding and infection, and the resulting local tryptophan depletion may inhibit the replication of intracellular pathogens. Indo gene expression is upregulated in the gut during chronic infection with the mouse whipworm Trichuris muris. We demonstrate an increase in the rate of colonic epithelial cell turnover after inhibition of IDO in T. muris-infected SCID mice, leading to a significant expulsion of parasite burden. We identify the goblet cell as a novel source of IDO and present data revealing a new role for IDO in the regulation of epithelial cell turnover post-infectious challenge., (© 2011 Blackwell Publishing Ltd.)

Parasitic helminths possess surface glycoconjugates that are recognized by the serum collectin molecule, mannose-binding lectin (MBL). Once bound, MBL triggers the lectin pathway of complement. Mice have two MBL, MBL-A and MBL-C. We previously showed that MBL-A deficient (MBL-A(-/-)) mice have enhanced survival of Brugia malayi microfilariae and abrogated microfilariae-specific IgM responses. In this study we show that MBL-A deficiency does not alter immunity to either Trichuris muris or Schistosoma mansoni. However, anti-nematode IgM levels were significantly lower in T. muris infected MBL-A(-/-) than wild-type mice. Interestingly nematode-specific IgG1 and IgG2a levels were higher in MBL-A(-/-) mice. Although, larval schistosomes are surrounded by a complement-sensitive membranous tegument, neither adult worm development, egg output, egg granuloma size nor cellular composition was affected in MBL-A(-/-) mice. In contrast to anti-nematode IgM responses, anti-schistosome IgM (and also IgG1 and IgG2b) responses were unaltered from wild-type mice. Anti-schistosome IgG2a was elevated, while IgG3 was significantly lowered, in MBL-A(-/-) mice. These results suggest that MBL-A is not a necessary component for immunity to either T. muris or S. mansoni helminths, however, MBL-A appears to be necessary for the development of specific IgM responses to nematode antigens.

The caecal-dwelling nematode Trichuris muris provides a natural model of human whipworm infection. Resistance to T. muris is dependent on a host Th2 response, and CD4+Th2 cells migrate to the gut-associated lymphoid tissue (GALT) to elicit parasite expulsion. Thus, CD4+T cells infiltrate the caecal lamina propria during infection, along with other leucocyte subsets that are not critical for parasite expulsion, such as eosinophils. Trafficking of leucocytes to the GALT has been shown to be dependent on the alpha4beta7/MAdCAM-1 integrin-addressin interaction. However, where inflammation is present, such as during T. muris infection, redundant mechanisms of leucocyte recruitment may also occur in addition to traditional gut-homing interactions. We utilized an anti-integrin/addressin antibody treatment regime to investigate this redundancy in resistant, T. muris-infected C57BL/6 mice. Where only the alpha4beta7/MAdCAM-1 interaction was blocked, mice remained resistant to T. muris infection, making a Th2 response and both CD4+T cells and eosinophils infiltrated the site of infection. However, in the absence of available alpha4beta7 and alpha4beta1, mice became chronically infected with T. muris and mounted a more Th1-biased immune response. Interestingly, CD4+T cells, but not eosinophils, were able to infiltrate the caecum, showing different levels of redundancy between leucocyte subsets during infection.

Despite a growing understanding of the role of cytokines in immunity to the parasitic helminth Trichuris muris, the local effector mechanism culminating in the expulsion of worms from the large intestine is not known. We used flow cytometry and immunohistochemistry to characterize the phenotype of large intestinal intraepithelial lymphocytes (IEL) and lamina propria leukocytes (LPL) from resistant and susceptible strains of mouse infected with T. muris. Leukocytes accumulated in the epithelium and lamina propria after infection, revealing marked differences between the different strains of mouse. In resistant mice, which mount a Th2 response, the number of infiltrating CD4+, CD8+, B220+, and F4/80+ IEL and LPL was generally highest around the time of worm expulsion from the gut, at which point the inflammation was dominated by CD4+ IEL and F4/80+ LPL. In contrast, in susceptible mice, which mount a Th1 response, the number of IEL and LPL increased more gradually and was highest after a chronic infection had developed. At this point, CD8+ IEL and F4/80+ LPL were predominant. Therefore, this study reveals the local immune responses underlying the expulsion of worms or the persistence of a chronic infection in resistant and susceptible strains of mouse, respectively. In addition, for the first time, we illustrate isolated lymphoid follicles in the large intestine, consisting of B cells interspersed with CD4+ T cells and having a central zone of rapidly proliferating cells. Furthermore, we demonstrate the organogenesis of these structures in response to T. muris infection.

Zinc deficiency dermatitis in a patient on long-term total parenteral nutrition (TPN) with trace-element supplementation is reported, and the therapeutic aspects of zinc deficiency are reviewed. A 36-year-old white man was hospitalized and found to have a small-bowel perforation secondary to internal herniation. Small-bowel resection with end-to-end anastomosis was performed, and TPN supplemented with folic acid, multivitamins, trace elements (including elemental zinc 2 mg/day), and fat was begun. Four months later, the patient developed a moist, erythematous, painful groin rash that did not respond to one month of topical antifungal and topical and intravenous antibacterial treatment. At five months after admission, zinc deficiency was suspected; serum zinc concentration was 85 micrograms/dl (normal = 55-150 micrograms/dl). The total daily zinc dose was increased to 60 mg, and within two days the patient's lesions began to improve. The rash healed within two weeks. Six days after increased zinc therapy was begun, lab tests showed: hair zinc content, 185 micrograms/g (normal = 163 micrograms/g); serum zinc content, 90 micrograms/dl; and erythrocyte zinc content, 1058 micrograms/dl (normal = 1100-1400 micrograms/dl). Signs and symptoms of zinc deficiency, zinc disposition in man, predisposing factors to zinc deficiency, laboratory analysis of zinc nutriture, zinc therapy, and zinc toxicity are discussed. Knowledge of drug use, diet, geographic location, underlying disease, and other patient-specific factors is important in recognizing the patient at risk of developing zinc deficiency. Several tests should be performed to document zinc deficiency. Zinc replacement guidelines are outlined.

Studies on the origin, identification, and characterization of osteoclasts have been difficult. This is in part due to a lack of definitive osteoclast markers and the similarity of these cells in form and function to cells of the mononuclear phagocyte system. To solve this problem, we inoculated isolated chick osteoclasts into mice to generate osteoclast-specific monoclonal antibodies. Supernatants from growth-positive hybridomas were screened by indirect immunofluorescent methods against cultured osteoclasts, monocyte-derived multinucleated giant cells, cultured monocytes, fibroblasts, and limb mesenchyme. Select hybridomas were cloned to produce 375 clones, which were analyzed as described above. Antibody from select clones was also reacted with paraffin sections of bone. In addition, two clones have been analyzed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Antibody binding from an osteoclast-specific clone and a clone reactive with osteoclasts, giant cells, and cultured monocytes (as determined by immunohistochemical assay) was confirmed by antibody-binding and titration curves quantitated by ELISA. The above studies demonstrate that osteoclast specific antigens exist, and that osteoclasts, giant cells, and cultured monocytes share common determinants not found on other cells screened.