Buprenorphine for Pain: A Narrative Review and Practical Applications.

Chronic noncancer pain affects about 20% of US adults and can significantly affect function and quality of life. Current guidelines recommend multimodal pain control. Despite risks associated with long-term opioid therapy, opioids are commonly prescribed. Buprenorphine is a partial opioid agonist with an improved safety profile compared to full agonists. Some formulations are approved for chronic pain and others for opioid use disorder. Buprenorphine is an option for patients who use chronic daily opioids for pain. This review summarizes the literature on buprenorphine's efficacy and safety for chronic pain and provides recommendations to generalists on initiation, titration, and monitoring of buprenorphine-based pain treatment. We also discuss a communication approach when considering buprenorphine for pain.

A Video- and Case-Based Curriculum on the Management of Alcohol Use Disorder for Internal Medicine Residents.

Introduction: Alcohol use disorder (AUD) is commonly undertreated. Physicians cite discomfort with AUD medication as a barrier to treatment. While several curricula teach and assess screening and brief interventions, few teach and assess learner knowledge of treatment options. Methods: We created a video- and case-based curriculum for internal medicine residents delivered by 16 internal medicine faculty in three 30-minute sessions at four clinic sites. Learner knowledge, attitudes, and confidence were assessed before and after the curriculum. We used qualitative methods to evaluate learner reflections. We also assessed faculty satisfaction with the curriculum. Results: Of 153 residents receiving the curriculum, 35 (23%) completed both pre- and postsurveys. Median percent correct on knowledge questions improved from 67% pre- to 80% postcurriculum (p < .001). Confidence increased for all three items assessing it, with a notable increase in confidence with pharmacotherapy (2.9 pre- vs. 4.5 postcurriculum on a 7-point Likert scale with high scores indicating greater confidence, p < .001). Positive attitudes toward people with AUD increased from 3.4 pre- to 3.9 postcurriculum (p < .001) on a 7-point Likert scale. Learners continued to express concerns about prescribing logistics, the role of primary care, and management of ongoing use. Thirteen of 16 faculty (83%) completed the postcurricular survey; all said they would be happy to facilitate again. Discussion: Implementation of this curriculum for the management of AUD improved resident knowledge, attitudes, and confidence in AUD treatment. The curriculum was acceptable to faculty and is ideal for programs looking to expand teaching about AUD.

CNS Melioidosis in a Traveler Returning from Cabo, Mexico.

Melioidosis is caused by the gram-negative bacillus Burkholderia pseudomallei, endemic to northern Australia and Southeast Asia. We present a patient who traveled to Mexico, returned to the United States, and developed progressive manifestations of melioidosis, culminating as central nervous system disease. Standard therapy was contraindicated, and a prolonged intensive phase was employed.

Healthcare Proxy Awareness of Suspected Infections in Nursing Home Residents with Advanced Dementia.

OBJECTIVES: To determine healthcare proxy involvement in decision-making regarding infections in individuals with advanced dementia. DESIGN: Prospective cohort study. SETTING: Thirty-five Boston-area nursing homes (NHs). PARTICIPANTS: NH residents with advanced dementia and their proxies (N = 362). MEASUREMENTS: Charts were abstracted monthly (up to 12 months) for documentation of suspected infections and provider-proxy discussions for each episode. Proxies were interviewed within 8 weeks of the infection to determine their awareness and decision-making involvement. Factors associated with proxy awareness and discussion documentation were identified. RESULTS: There were 496 suspected infections; proxies were reached for interview for 395 (80%). Proxy-provider discussions were documented for 207 (52%) episodes, yet proxies were aware of only 156 (39%). Proxies participated in decision-making for 89 (57%) episodes of which they were aware. Proxy awareness was associated with antimicrobial use (adjusted odds ratio (AOR) = 3.43, 95% confidence interval (CI) = 1.94-6.05), hospital transfer (AOR = 3.00, 95% CI = 1.19-7.53), infection within 30 days of death (AOR = 3.32, 95% CI = 1.54-7.18), and fewer days between infection and study interview (AOR = 2.71, 95% CI = 1.63-4.51). Discussion documentation was associated with the resident residing in a dementia special care unit (AOR = 1.71, 95% CI = 1.04-2.80), the resident not on hospice (AOR = 3.25, 95% CI = 1.31-8.02), more provider visits (AOR = 1.71, 95% CI = 1.07-2.75), proxy visits of more than 7 h/wk (AOR = 1.93, 95% CI = 1.02-3.67), and episode within 30 days of death (AOR = 3.99, 95% CI = 1.98-8.02). CONCLUSION: Proxies are unaware of and do not participate in decision-making for most suspected infections that NH residents with advanced dementia experience. Proxy awareness of episodes and documentation of provider-proxy discussions are not congruent.

Measuring peptide translocation into large unilamellar vesicles.

There is an active interest in peptides that readily cross cell membranes without the assistance of cell membrane receptors(1). Many of these are referred to as cell-penetrating peptides, which are frequently noted for their potential as drug delivery vectors(1-3). Moreover, there is increasing interest in antimicrobial peptides that operate via non-membrane lytic mechanisms(4,5), particularly those that cross bacterial membranes without causing cell lysis and kill cells by interfering with intracellular processes(6,7). In fact, authors have increasingly pointed out the relationship between cell-penetrating and antimicrobial peptides(1,8). A firm understanding of the process of membrane translocation and the relationship between peptide structure and its ability to translocate requires effective, reproducible assays for translocation. Several groups have proposed methods to measure translocation into large unilamellar lipid vesicles (LUVs)(9-13). LUVs serve as useful models for bacterial and eukaryotic cell membranes and are frequently used in peptide fluorescent studies(14,15). Here, we describe our application of the method first developed by Matsuzaki and co-workers to consider antimicrobial peptides, such as magainin and buforin II(16,17). In addition to providing our protocol for this method, we also present a straightforward approach to data analysis that quantifies translocation ability using this assay. The advantages of this translocation assay compared to others are that it has the potential to provide information about the rate of membrane translocation and does not require the addition of a fluorescent label, which can alter peptide properties(18), to tryptophan-containing peptides. Briefly, translocation ability into lipid vesicles is measured as a function of the Foster Resonance Energy Transfer (FRET) between native tryptophan residues and dansyl phosphatidylethanolamine when proteins are associated with the external LUV membrane (Figure 1). Cell-penetrating peptides are cleaved as they encounter uninhibited trypsin encapsulated with the LUVs, leading to disassociation from the LUV membrane and a drop in FRET signal. The drop in FRET signal observed for a translocating peptide is significantly greater than that observed for the same peptide when the LUVs contain both trypsin and trypsin inhibitor, or when a peptide that does not spontaneously cross lipid membranes is exposed to trypsin-containing LUVs. This change in fluorescence provides a direct quantification of peptide translocation over time.

Novel histone-derived antimicrobial peptides use different antimicrobial mechanisms.

The increase in multidrug resistant bacteria has sparked an interest in the development of novel antibiotics. Antimicrobial peptides that operate by crossing the cell membrane may also have the potential to deliver drugs to intracellular targets. Buforin 2 (BF2) is an antimicrobial peptide that shares sequence identity with a fragment of histone subunit H2A and whose bactericidal mechanism depends on membrane translocation and DNA binding. Previously, novel histone-derived antimicrobial peptides (HDAPs) were designed based on properties of BF2, and DesHDAP1 and DesHDAP3 showed significant antibacterial activity. In this study, their DNA binding, permeabilization, and translocation abilities were assessed independently and compared to antibacterial activity to determine whether they share a mechanism with BF2. To investigate the importance of proline in determining the peptides' mechanisms of action, proline to alanine mutants of the novel peptides were generated. DesHDAP1, which shows significant similarities to BF2 in terms of secondary structure, translocates effectively across lipid vesicle and bacterial membranes, while the DesHDAP1 proline mutant shows reduced translocation abilities and antimicrobial potency. In contrast, both DesHDAP3 and its proline mutant translocate poorly, though the DesHDAP3 proline mutant is more potent. Our findings suggest that a proline hinge can promote membrane translocation in some peptides, but that the extent of its effect on permeabilization depends on the peptide's amphipathic properties. Our results also highlight the different antimicrobial mechanisms exhibited by histone-derived peptides and suggest that histones may serve as a source of novel antimicrobial peptides with varied properties.

Design of novel histone-derived antimicrobial peptides.

Previous studies have identified several naturally occurring antimicrobial peptides derived from histone proteins. This research aimed to design novel histone-derived antimicrobial peptides (HDAPs). To this end, three novel peptides (DesHDAP1, DesHDAP2, and DesHDAP3) were designed based on a histone-DNA crystal structure and structural properties of buforin II, the best characterized naturally occurring HDAP. Molecular dynamics simulations and circular dichroism spectroscopy were used to further support the predicted structure and potential nucleic acid interactions of these three designed peptides. The antibacterial activity of the three peptides was then verified experimentally against a series of bacterial strains using a radial diffusion assay. One of these peptides is the first known fragment of histone H3 with antibacterial properties. Optical density measurements of bacterial cells exposed to the designed peptides implied that at least two of the novel peptides can induce cell death without causing significant membrane permeabilization, as observed for buforin II. The antibacterial potency of these designed HDAPs does not appear to correlate with their overall alpha-helical content, unlike previous observations for analogs of buforin II. However, the most potent designed peptide, DesHDAP1, shares a markedly similar circular dichroism spectrum with buforin II. These results demonstrate the potential of using histone structures as a framework for designing novel antimicrobial peptides. As well, these studies represent an important starting point for a broader characterization of properties shared by HDAPs.