Developing a European longitudinal and interprofessional curriculum for clinical reasoning.

Clinical reasoning is a complex and crucial ability health professions students need to acquire during their education. Despite its importance, explicit clinical reasoning teaching is not yet implemented in most health professions educational programs. Therefore, we carried out an international and interprofessional project to plan and develop a clinical reasoning curriculum with a train-the-trainer course to support educators in teaching this curriculum to students. We developed a framework and curricular blueprint. Then we created 25 student and 7 train-the-trainer learning units and we piloted 11 of these learning units at our institutions. Learners and faculty reported high satisfaction and they also provided helpful suggestions for improvements. One of the main challenges we faced was the heterogeneous understanding of clinical reasoning within and across professions. However, we learned from each other while discussing these different views and perspectives on clinical reasoning and were able to come to a shared understanding as the basis for developing the curriculum. Our curriculum fills an important gap in the availability of explicit clinical reasoning educational materials both for students and faculty and is unique with having specialists from different countries, schools, and professions. Faculty time and time for teaching clinical reasoning in existing curricula remain important barriers for implementation of clinical reasoning teaching.

Digital patient-centred learning in medical education: A national learning platform with virtual patients as part of the DigiPaL project.

Background: Due to the coronavirus pandemic, the medical faculties in the Federal Republic of Germany converted their curricula to digital formats on a large scale and very quickly in spring 2020 as an emergency measure. At the same time, a start was made on the nationwide exchange of digital teaching/learning materials via the online platform "LOOOP share" in order to save local resources. Among other things, virtual patient cases (VP) were shared across faculties for case-based learning, through which students can acquire clinical decision-making skills. Objectives: Within the framework of the cooperation project "National Learning Platforms for Digital Patient-Related Learning in Medical Studies" (DigiPaL), the usability of VPs for students and teachers should be improved, and the spectrum of disease patterns that are covered by VPs should be systematically expanded. Results: With the participation of many locations, a total of 150 VPs were developed by 96 case authors from 16 faculties, in addition to the existing 403 VPs. The thematic selection was made on the basis of criteria oriented to the National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). After completion, these VPs were also made available to all faculties for free use via "LOOOP share" and the CASUS learning platform. Discussion: Even after the pandemic, these developed VPs should be available to the faculties and thus make a lasting contribution to improve medical training in Germany - especially in light of digital teaching formats being expressly advocated on the basis of the adapted current Medical Licensure Act (ÄApprO). A possible application is interdisciplinary learning of clinical decision-making with the help of blended learning formats within the framework of a longitudinal curriculum. The large number of involved colleagues and faculties shows that the nationally coordinated development of VPs across faculties was commonly seen as useful.

Potentiation of morphine antinociception and inhibition of diabetic neuropathic pain by the multi-chemokine receptor antagonist peptide RAP-103.

AIMS: We determined the ability of the multi-chemokine receptor (CCR2/CCR5/CCR8) antagonist RAP-103 to modulate pain behaviors in an acute model of surgical pain, with and without an added opioid (morphine), and by itself in a chronic model of Streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: Pain behaviors were assessed by mechanical and thermal tests in rats. Cytokine and chemokine biomarkers in sciatic nerve and spinal cord were assessed by in situ qPCR. KEY FINDINGS: In the incisional pain assay, RAP-103 (0.01-1 mg/kg, i.p.) alone had no antiallodynic effect post-surgery. RAP-103 (0.5 mg/kg) when co-administered with morphine (0.5-5 mg/kg), reduced the ED50 of morphine from 3.19 mg/kg to 1.42 mg/kg. In a DPN model, rats exhibited persistent mechanical and cold allodynia. Oral administration of RAP-103 (0.5-0.02 mg/kg/day) resulted in a complete reversal of established hypersensitivity in DPN rats (P < .001), which gradually returned to pain hypersensitivity after the cessation of the treatment. The mRNA expression of cytokines, IL-1ß, TNFα; chemokines CCL2, CCL3; and chemokine receptors CCR2 and CCR5 in DPN rat sciatic nerve, but not spinal cord, were significantly increased. RAP-103 resulted in significant reductions in sciatic nerve expression of IL-1ß, TNFα and CCL3 in STZ-induced diabetic rats with trends toward lower levels for CCL2 and CCR5, while CCR2 was unchanged. SIGNIFICANCE: In acute pain, co-administration of RAP-103 with morphine provided the same antinociceptive effect with a reduced dose of morphine, reducing opioid side-effects and risks. RAP-103 by itself is an effective non-opioid antinociceptive treatment for diabetic neuropathic pain.

Implementing Remote Collaboration in a Virtual Patient Platform: Usability Study.

BACKGROUND: Learning with virtual patients is highly popular for fostering clinical reasoning in medical education. However, little learning with virtual patients is done collaboratively, despite the potential learning benefits of collaborative versus individual learning. OBJECTIVE: This paper describes the implementation of student collaboration in a virtual patient platform. Our aim was to allow pairs of students to communicate remotely with each other during virtual patient learning sessions. We hypothesized that we could provide a collaborative tool that did not impair the usability of the system compared to individual learning and that this would lead to better diagnostic accuracy for the pairs of students. METHODS: Implementing the collaboration tool had five steps: (1) searching for a suitable software library, (2) implementing the application programming interface, (3) performing technical adaptations to ensure high-quality connections for the users, (4) designing and developing the user interface, and (5) testing the usability of the tool in 270 virtual patient sessions. We compared dyad to individual diagnostic accuracy and usability with the 10-item System Usability Scale. RESULTS: We recruited 137 students who worked on 6 virtual patients. Out of 270 virtual patient sessions per group (45 dyads times 6 virtual patients, and 47 students working individually times 6 virtual patients minus 2 randomly selected deleted sessions) the students made successful diagnoses in 143/270 sessions (53%, SD 26%) when working alone and 192/270 sessions (71%, SD 20%) when collaborating (P=.04, η2=0.12). A usability questionnaire given to the students who used the collaboration tool showed a usability score of 82.16 (SD 1.31), representing a B+ grade. CONCLUSIONS: The collaboration tool provides a generic approach for collaboration that can be used with most virtual patient systems. The collaboration tool helped students diagnose virtual patients and had good overall usability. More broadly, the collaboration tool will provide an array of new possibilities for researchers and medical educators alike to design courses for collaborative learning with virtual patients.

Why is it so difficult to implement a longitudinal clinical reasoning curriculum? A multicenter interview study on the barriers perceived by European health professions educators.

BACKGROUND: Effective clinical reasoning is a core competency of health professionals that is necessary to assure patients' safety. Unfortunately, adoption of longitudinal clinical reasoning curricula is still infrequent. This study explores the barriers that hinder the explicit teaching of clinical reasoning from a new international perspective. METHODS: The context of this study was a European project whose aim is to develop a longitudinal clinical reasoning curriculum. We collected data in semi-structured interviews with responders from several European countries who represent various health professions and have different backgrounds, roles and experience. We performed a qualitative content analysis of the gathered data and constructed a coding frame using a combined deductive/inductive approach. The identified themes were validated by parallel coding and in group discussions among project members. RESULTS: A total of 29 respondents from five European countries participated in the interviews; the majority of them represent medicine and nursing sciences. We grouped the identified barriers into eight general themes: Time, Culture, Motivation, Clinical Reasoning as a Concept, Teaching, Assessment, Infrastructure and Others. Subthemes included issues with discussing errors and providing feedback, awareness of clinical reasoning teaching methods, and tensions between the groups of professionals involved. CONCLUSIONS: This study provides an in-depth analysis of the barriers that hinder the teaching of explicit clinical reasoning. The opinions are presented from the perspective of several European higher education institutions. The identified barriers are complex and should be treated holistically due to the many interconnections between the identified barriers. Progress in implementation is hampered by the presence of reciprocal causal chains that aggravate this situation. Further research could investigate the perceptual differences between health professions regarding the barriers to clinical reasoning. The collected insights on the complexity and diversity of these barriers will help when rolling out a long-term agenda for overcoming the factors that inhibit the implementation of clinical reasoning curricula.

Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression.

AIMS: We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated. MAIN METHODS: One, two or four CRAs (AMD3100/CXCR4, maraviroc/CCR5, RS504393/CCR2 orAZD8797/CX3CR1) were used in combination with sub-analgesic doses of morphine, all given systemically. Pain was assessed using the rat CWTF test or formalin injection into the paw of mice scored by licking. Respiration and oxygen saturation were measured in rats using a MouseOX® Plus - pulse oximeter. KEY FINDINGS: In the CWTF test, a sub-maximal dose of morphine in combination with maraviroc alone, maraviroc plus AMD3100, or with the four chemokine receptor antagonists, produced synergistic increases in antinociception. In the formalin test, the combination of four CRAs plus a sub-maximal dose of morphine resulted in increased antinociception in both male and female mice. AMD3100 had an additive effect with morphine in both sexes. Coadministration of CRAs with morphine did not potentiate the opioid respiratory depressive effect. SIGNIFICANCE: These results support the conclusion that combinations of CRAs can increase the potency of sub-analgesic doses of morphine analgesia without increasing respiratory depression. The results support an "opioid sparing" strategy for alleviation of pain using reduced doses of opioids in combination with CRAs to achieve maximal analgesia.

A Cannabinoid 2-Selective Agonist Inhibits Allogeneic Skin Graft Rejection In Vivo.

Previous work from our laboratory showed that a CB2 selective agonist, O-1966, blocked the proliferative response of C57BL/6 mouse spleen cells exposed to spleen cells of C3HeB/FeJ mice in vitro in the mixed lymphocyte reaction (MLR). The MLR is widely accepted as an in vitro correlate of in vivo grant rejection. Mechanisms of the immunosuppression induced by the cannabinoid were explored, and it was shown that O-1966 in this in vitro assay induced CD25+Foxp3+ Treg cells and IL-10, as well as down-regulated mRNA for CD40 and the nuclear form of the transcription factors NF-κB and NFAT in T-cells. The current studies tested the efficacy of O-1966 in prolonging skin grafts in vivo. Full thickness flank skin patches (1-cm2) from C3HeB/FeJ mice were grafted by suturing onto the back of C57BL/6 mice. O-1966 or vehicle was injected intraperitoneally into treated or control groups of animals beginning 1 h pre-op, and then every other day until 14 days post-op. Graft survival was scored based on necrosis and rejection. Treatment with 5 mg/kg of O-1966 prolonged mean graft survival time from 9 to 11 days. Spleens harvested from O-1966 treated mice were significantly smaller than those of vehicle control animals based on weight. Flow cytometry analysis of CD4+ spleen cells showed that O-1966 treated animals had almost a 3-fold increase in CD25+Foxp3+ Treg cells compared to controls. When dissociated spleen cells were placed in culture ex vivo and stimulated with C3HeB/FeJ cells in an MLR, the cells from the O-1966 treated mice were significantly suppressed in their proliferative response to the allogeneic cells. These results support CB2 selective agonists as a new class of compounds to prolong graft survival in transplant patients.

Adaptation of an international virtual patient collection to the COVID-19 pandemic.

The COVID-19 pandemic posed new global challenges for teaching. We met these challenges as an international collaboration by adapting a collection of virtual patients for clinical reasoning training to this novel context.

Automatic analysis of summary statements in virtual patients - a pilot study evaluating a machine learning approach.

BACKGROUND: The ability to compose a concise summary statement about a patient is a good indicator for the clinical reasoning abilities of healthcare students. To assess such summary statements manually a rubric based on five categories - use of semantic qualifiers, narrowing, transformation, accuracy, and global rating has been published. Our aim was to explore whether computer-based methods can be applied to automatically assess summary statements composed by learners in virtual patient scenarios based on the available rubric in real-time to serve as a basis for immediate feedback to learners. METHODS: We randomly selected 125 summary statements in German and English composed by learners in five different virtual patient scenarios. Then we manually rated these statements based on the rubric plus an additional category for the use of the virtual patients' name. We implemented a natural language processing approach in combination with our own algorithm to automatically assess 125 randomly selected summary statements and compared the results of the manual and automatic rating in each category. RESULTS: We found a moderate agreement of the manual and automatic rating in most of the categories. However, some further analysis and development is needed, especially for a more reliable assessment of the factual accuracy and the identification of patient names in the German statements. CONCLUSIONS: Despite some areas of improvement we believe that our results justify a careful display of the computer-calculated assessment scores as feedback to the learners. It will be important to emphasize that the rating is an approximation and give learners the possibility to complain about supposedly incorrect assessments, which will also help us to further improve the rating algorithms.

Blended learning: ten tips on how to implement it into a curriculum in healthcare education.

Blended learning is a meaningful combination of online and face-to-face teaching and learning. In this article we summarize relevant aspects of this format and provide ten tips for educators and curriculum developers on implementing a blended learning curriculum in healthcare education. These general tips are derived from our experience and the available literature and cover the planning and implementation process.

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments.

(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated ß-arrestin recruitment assays). "Body" and "tail" interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address" can be considered the "body" of the hydromorphone molecule and the "message" delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/µ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Chemokine Receptor Antagonists in Combination with Morphine as a Novel Strategy for Opioid Dose Reduction in Pain Management.

INTRODUCTION: Although opioids are widely prescribed for pain, in many circumstances, they have only modest efficacy. Preclinical studies have shown that chemokines, immune mediators released during tissue injury and inflammation, can desensitize opioid receptors and block opioid analgesia by a process termed "heterologous desensitization." The present studies tested the hypothesis that in evoked pain, certain chemokine receptor antagonists (CRAs), given with a submaximal dose of morphine, would result in enhanced morphine potency. METHODS: Three rodent pain assays were used: incisional pain in rats, the cold-water tail flick test in rats, and the formalin test in mice. The FDA-approved, commercially available CRAs, maraviroc and AMD3100, were used. They block the chemokine receptors and ligands, CCR5/CCL5 (RANTES) and CXCR4/CXCL4 (SDF-1α), respectively. RESULTS: In the incisional pain assay, it was found that the combination of a single CRA, or of both CRAs, with morphine significantly shifted the morphine dose-response curve to the left, as much as 3.3-fold. In the cold-water tail flick and formalin tests, significant increases of the antinociceptive effects of morphine were also observed when combined with CRAs. CONCLUSIONS: These results support the potential of a new "opioid-sparing" approach for pain treatment, which combines CRAs with reduced doses of morphine.

Treatment of signs and symptoms of the common cold using EPs 7630 - results of a meta-analysis.

The efficacy of Pelargonium sidoides preparation EPs 7630 in the common cold (CC) was assessed by performing meta-analyses of randomized, double-blind, placebo-controlled trials. Mean differences (MD) and risk ratios (RR) with their 95% confidence intervals (CI) were computed. Five trials with a total of 833 patients were included. All trials had a treatment period of ten days with visits at days 3, 5, and 10 after baseline and used a ten-symptom Cold Intensity Score (CIS) as the primary outcome. Significant differences favoring EPs 7630 were observed for total CIS reduction (day 5: MD = -2·30; 95%CI = -4·12,-0·49; day 10: MD = -1·16; 95%CI = -2·22,-0·10), proportion of patients with substantial improvement (day 5: RR = 1·73; day 10: RR = 1·06) and complete remission (day 5: RR = 2·52; day 10: RR = 2·13). Subjects treated with EPs 7630 missed fewer days at work, used less paracetamol and had an improved sleep quality. No serious adverse reactions to EPs 7630 were reported. The results support the efficacy of EPs 7630 in adults with CC.

Opioid-sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors.

BACKGROUND AND PURPOSE: Much of the opioid epidemic arose from abuse of prescription opioid drugs. This study sought to determine if the combination of a cannabinoid with an opioid could produce additive or synergistic effects on pain, allowing reduction in the opioid dose needed for maximal analgesia. EXPERIMENTAL APPROACH: Pain was assayed using the formalin test in mice and the carrageenan assay in rats. Morphine and two synthetic cannabinoids were tested: WIN55,212-2 (WIN), which binds to both CB1 and CB2 receptors, and possibly TRPV1 channels; and GP1a, which has activity at CB2 receptors and is reported to inhibit fatty acid amide hydrolase, thus raising levels of endogenous cannabinoids. KEY RESULTS: Morphine in combination with WIN in the formalin test gave synergistic analgesia. Studies with selective antagonists showed that WIN was acting through CB1 receptors. Morphine in combination with GP1a in the formalin test was sub-additive. In the carrageenan test, WIN had no added effect when combined with morphine, but GP1a with morphine showed enhanced analgesia. Both WIN and Gp1a used alone had analgesic activity in the formalin pain test, but not in the carrageenan pain test. CONCLUSIONS AND IMPLICATIONS: The ability of a cannabinoid to produce an additive or synergistic effect on analgesia when combined with morphine varies with the pain assay and may be mediated by CB1 or CB2 receptors. These results hold the promise of using cannabinoids to reduce the dose of opioids for analgesia in certain pain conditions.

Coadministration of Chemokine Receptor Antagonists with Morphine Potentiates Morphine's Analgesic Effect on Incisional Pain in Rats.

Crossdesensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if coadministration of chemokine receptor antagonists (CRAs) with morphine would enhance the analgesic potency of morphine on incisional pain in rats. Animals underwent incisional surgery on the left hind paw and pain responses were evaluated using von Frey filaments at various time points postsurgery between 15 and 360 minutes and daily between 24 and 72 hours. Dose-response curves for morphine, maraviroc (a CCR5 antagonist), and AMD3100 (a CXCR4 antagonist) alone were established. While morphine significantly reduced pain in a time- and dose-dependent manner, maraviroc and AMD3100 had no effect by themselves. Coadministration of either maraviroc or AMD3100 with morphine significantly increased morphine's analgesic effect on incisional pain, shifting the dose-response curve to the left 2.3- and 1.8-fold, respectively. Coadministration of both CRAs with morphine significantly shifted further the morphine dose-response curve to the left 3.3-fold. The effect of treatments on mRNA levels in the draining popliteal lymph node for a panel of chemokines and cytokines showed that message for many of these mediators was upregulated by the incision, and the combination of morphine with the CRAs markedly downregulated them. The data show that combining morphine with CRAs potentiates morphine's analgesic effect on incisional pain. Thus, the same analgesic effect of morphine alone can be achieved with lower doses of morphine when combined with CRAs. Using morphine in lower doses could reduce unwanted side effects and possibly block development of tolerance and dependence.

Impact of Virtual Patients as Optional Learning Material in Veterinary Biochemistry Education.

Biochemistry and physiology teachers from veterinary faculties in Hannover, Budapest, and Lublin prepared innovative, computer-based, integrative clinical case scenarios as optional learning materials for teaching and learning in basic sciences. These learning materials were designed to enhance attention and increase interest and intrinsic motivation for learning, thus strengthening autonomous, active, and self-directed learning. We investigated learning progress and success by administering a pre-test before exposure to the virtual patients (vetVIP) cases, offered vetVIP cases alongside regular biochemistry courses, and then administered a complementary post-test. We analyzed improvement in cohort performance and level of confidence in rating questions. Results of the performance in biochemistry examinations in 2014, 2015, and 2016 were correlated with the use of and performance in vetVIP cases throughout biochemistry courses in Hannover. Surveys of students reflected that interactive cases helped them understand the relevance of basic sciences in veterinary education. Differences between identical pre- and post-tests revealed knowledge improvement (correct answers: +28% in Hannover, +9% in Lublin) and enhanced confidence in decision making ("I don't know" answers: -20% in Hannover, -7.5% in Lublin). High case usage and voluntary participation (use of vetVIP cases in Hannover and Lublin >70%, Budapest <1%; response rates in pre-test 72% and post-test 48%) indicated a good increase in motivation for the subject of biochemistry. Despite increased motivation, there was only a weak correlation between performance in final exams and performance in the vetVIP cases. Case-based e-learning could be extended and generated cases should be shared across veterinary faculties.

A Clinical Reasoning Tool for Virtual Patients: Design-Based Research Study.

BACKGROUND: Clinical reasoning is a fundamental process medical students have to learn during and after medical school. Virtual patients (VP) are a technology-enhanced learning method to teach clinical reasoning. However, VP systems do not exploit their full potential concerning the clinical reasoning process; for example, most systems focus on the outcome and less on the process of clinical reasoning. OBJECTIVES: Keeping our concept grounded in a former qualitative study, we aimed to design and implement a tool to enhance VPs with activities and feedback, which specifically foster the acquisition of clinical reasoning skills. METHODS: We designed the tool by translating elements of a conceptual clinical reasoning learning framework into software requirements. The resulting clinical reasoning tool enables learners to build their patient's illness script as a concept map when they are working on a VP scenario. The student's map is compared with the experts' reasoning at each stage of the VP, which is technically enabled by using Medical Subject Headings, which is a comprehensive controlled vocabulary published by the US National Library of Medicine. The tool is implemented using Web technologies, has an open architecture that enables its integration into various systems through an open application program interface, and is available under a Massachusetts Institute of Technology license. RESULTS: We conducted usability tests following a think-aloud protocol and a pilot field study with maps created by 64 medical students. The results show that learners interact with the tool but create less nodes and connections in the concept map than an expert. Further research and usability tests are required to analyze the reasons. CONCLUSIONS: The presented tool is a versatile, systematically developed software component that specifically supports the clinical reasoning skills acquisition. It can be plugged into VP systems or used as stand-alone software in other teaching scenarios. The modular design allows an extension with new feedback mechanisms and learning analytics algorithms.

Ethanol in herbal medicinal products for children : Data from pediatric studies and pharmacovigilance programs.

Herbal medicinal products are indispensable in children, e. g., in functional gastrointestinal diseases and coughs and colds, especially when available in liquid dosing forms for which dosing can be adapted ideally to different age groups. Despite being generally accepted as safe, the ethanol content of many of these products, necessary for Galenic reasons, has raised questions regarding their safety. Therefore, safety data from more than 50,000 children in noninterventional pediatric studies with these products, as well as data from routine clinical use in several million children, were assessed. No evidence of the involvement of the ethanol content in any adverse drug reactions was found. This allows us to conclude that these herbal medicinal products are safe in the age groups for which they are authorized or registered and that the present labeling is adequate to allow for their safe use in the pediatric population.

Heroin inhibits HIV-restriction miRNAs and enhances HIV infection of macrophages.

Although opioids have been extensively studied for their impact on the immune system, limited information is available about the specific actions of opioids on intracellular antiviral innate immunity against HIV infection. Thus, we investigated whether heroin, one of the most abused drugs, inhibits the expression of intracellular HIV restriction microRNA (miRNA) and facilitates HIV replication in macrophages. Heroin treatment of macrophages enhanced HIV replication, which was associated with the downregulation of several HIV restriction miRNAs. These heroin-mediated actions on the miRNAs and HIV could be antagonized by naltrexone, an opioid receptor antagonist. Furthermore, the in vitro negative impact of heroin on HIV-associated miRNAs was confirmed by the in vivo observation that heroin addicts had significantly lower levels of macrophage-derived HIV restriction miRNAs than those in the control subjects. These in vitro and in vivo findings indicate that heroin use compromises intracellular anti-HIV innate immunity, providing a favorable microenvironment for HIV survival in the target cells.