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Background and Purpose: The κ opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide κ-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a κ-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour.Experimental Approach: Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPγS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55°C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily κ-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP).Key Results: The two isomers showed similar affinity and selectivity for κ receptors (K(i)  30-35 nM) as well as κ receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent κ-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity.Conclusions and Implications: The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief κ opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse. [ABSTRACT FROM AUTHOR]

Perturbation of dopamine transmission has been implicated as a contributing factor in HIV-1 associated neurocognitive disorders with concurrent methamphetamine (METH) abuse. We have demonstrated that the HIV-1 protein, transactivator of transcription (Tat), decreases dopamine transport through inhibition of vesicular monoamine transporter2 (VMAT2). This study determined the effects of Tat protein on METH-inhibited VMAT2 function and METH-conditioned place preference (CPP). In vitro exposure of isolated mouse whole brain vesicles to recombinant Tat 1-86 or METH displayed a concentration-dependent inhibition of the vesicular [ 3 H]Dopamine uptake, in which a combination of Tat and METH induced a greater reduction of dopamine uptake compared to Tat or METH alone. In vivo, the maximal velocity (V max ) of vesicular [ 3 H]Dopamine uptake was decreased in inducible Tat transgenic (iTat-tg) mice harvested after treatment with either 21-day doxycycline (Dox) or 14-day METH (3 mg/kg, i.p., daily), whereas these mice treated with both Dox and METH displayed an additive reduction of the V max compared to either Tat or METH alone. Moreover, Dox-induced Tat expression increased METH-CPP in an exposure-dependent manner, with iTat-tg mice demonstrating a 2.3-fold potentiation of METH-CPP compared with Tat null control mice upon administration of Dox for 14 days. Furthermore, a 7-day administration of Dox reinstated extinguished METH-CPP. Collectively, these results suggest a synergistic effect of Tat protein and METH on inhibition of VMAT2-mediated DA transport, potentially contributing to potentiation of METH-CPP in iTat-tg mice., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest with the contents of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Birmingham Hip Resurfacing (BHR) has emerged as a compelling and innovative alternative to total hip arthroplasty (THA), especially among young, active patients. However, the Minimal Clinically Important Difference (MCID) and the Patient Acceptable Symptom State (PASS) thresholds have not yet been determined for patients undergoing BHR. Therefore, the current study aimed to (1) determine the MCID and PASS thresholds for both the Hip disability and Osteoarthritis Outcome Score (HOOS)-Pain and HOOS physical function shortform (PS), for patients who underwent BHR; and (2) identify factors influencing the achievement of MCID and PASS for HOOS-Pain and HOOS-PS., Methods: Prospectively collected data from patients undergoing BHR was analyzed. Patients with osteoarthritis and completed preoperative and 1-year postoperative PROMs were included. Distribution-based and anchored-based approaches were used to estimate MCID and PASS, respectively. The optimal cut-off point for PASS thresholds was calculated using the Youden index., Results: MCID for HOOS-Pain and PS were calculated to be 9.2 and 9.3, respectively. The PASS threshold for HOOS-Pain and PS were ≥ 77.7 and ≥ 87.3, respectively. The current study identified several factors affecting postoperative achievement of thresholds. Baseline Mental Component Summary (MCS) scores were a predictor for achieving MCID for postoperative HOOS-Pain, achieving MCID for postoperative HOOS-PS, achieving PASS for postoperative HOOS-Pain, and achieving PASS for postoperative HOOS-PS. Furthermore, baseline HOOS-Pain was a significant predictor for achieving MCID for postoperative HOOS-PS, achieving PASS for postoperative HOOS-Pain, and achieving PASS for postoperative HOOS-PS., Conclusions: MCID and PASS thresholds were established for HOOS-Pain and PS domains following BHR with most patients achieving these clinically meaningful benchmarks. Additionally, several factors affecting achievement of MCID and PASS were identified, including modifiable risk factors that may allow clinicians to implement optimization strategies and further improve outcomes., (© 2024. The Author(s).)

The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named C6guano . Presently, to improve systemic activity of this ligand, we used structure-based design, identifying a new ligand named RO76 where the flexible alkyl linker and polar guanidine guano group is swapped with a benzyl alcohol, and the sodium site is targeted indirectly through waters. A cryoEM structure of RO76 bound to the μOR-G i complex confirmed that RO76 interacts with the sodium site residues through a water molecule, unlike C6guano which engages the sodium site directly. Signaling assays coupled with APEX based proximity labeling show binding in the sodium pocket modulates receptor efficacy and trafficking. In mice, RO76 was systemically active in tail withdrawal assays and showed reduced liabilities compared to those of morphine. In summary, we show that targeting water molecules in the sodium binding pocket may be an avenue to modulate signaling properties of opioids, and which may potentially be extended to other G-protein coupled receptors where this site is conserved., Competing Interests: The authors declare the following competing financial interest(s): S.M. is a cofounder of Sparian Biosciences. R.O.D. holds equity in Septerna, Inc. Other authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The µ-opioid receptor (µOR) is a well-established target for analgesia 1 , yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl 2 , a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Obesity has been identified as a risk factor for postoperative complications in patients undergoing total hip arthroplasty (THA). This study aimed to investigate patient-reported outcomes, pain, and satisfaction as a function of body mass index (BMI) class in patients undergoing THA., Methods: 1736 patients within a prospective observational study were categorized into BMI classes. Pre- and postoperative Hip disability and Osteoarthritis Outcome Score for Joint Replacement (HOOS JR), satisfaction, and pain scores were compared by BMI class using one-way ANOVA., Results: Healthy weight patients reported the highest preoperative HOOS JR (56.66 ± 13.35) compared to 45.51 ± 14.45 in Class III subjects. Healthy weight and Class III patients reported the lowest (5.65 ± 2.01) and highest (7.06 ± 1.98, p < 0.0001) preoperative pain, respectively. Changes in HOOS JR scores from baseline suggest larger improvements with increasing BMI class, where Class III patients reported an increase of 33.7 ± 15.6 points at 90 days compared to 26.1 ± 17.1 in healthy weight individuals (p = 0.002). Fewer healthy weight patients achieved the minimal clinically important difference (87.4%) for HOOS JR compared to Class II (96.5%) and III (94.7%) obesity groups at 90 days postoperatively. Changes in satisfaction and pain scores were largest in the Class III patients. Overall, no functional outcomes varied by BMI class postoperatively., Conclusion: Patients of higher BMI class reported greater improvements following THA. While risk/benefit shared decision-making remains a personalized requirement of THA, this study highlights that utilization of BMI cutoff may not be warranted based on pain and functional improvement., (© 2024. The Author(s).)

Objectives: HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the dopamine transporter (DAT) have been shown to reverse Tat-induced DAT dysfunction. We hypothesized that a novel DAT allosteric modulator, SRI-30827, would counteract Tat-induced potentiation of cocaine reward., Methods: Doxycycline (Dox)-inducible Tat transgenic (iTat-tg) mice and their G-tg (Tat-null) counterparts were tested in a cocaine conditioned place preference (CPP) paradigm. Mice were treated 14 days with saline, or Dox (100 mg/kg/day, i.p.) to induce Tat protein. Upon induction, mice were place conditioned two days with cocaine (10 mg/kg/day) after a 1-h daily intracerebroventricular (i.c.v.) pretreatment with SRI-30827 (1 nmol) or a vehicle control, and final place preference assessed as a measure of cocaine reward., Results: Dox-treatment significantly potentiated cocaine-CPP in iTat-tg mice over the response of saline-treated control littermates. SRI-30827 treatment eliminated Tat-induced potentiation without altering normal cocaine-CPP in saline-treated mice. Likewise, SRI-30827 did not alter cocaine-CPP in both saline- and Dox-treated G-tg mice incapable of expressing Tat protein., Conclusions: These findings add to a growing body of evidence that allosteric modulation of DAT could provide a promising therapeutic intervention for patients with comorbid HIV-1 and cocaine use disorder (CUD)., Competing Interests: Competing interests: The authors state no conflict of interest with the contents of this article.

» Bone health optimization (BHO) has become an increasingly important consideration in orthopaedic surgery because deterioration of bone tissue and low bone density are associated with poor outcomes after orthopaedic surgeries.» Management of patients with compromised bone health requires numerous healthcare professionals including orthopaedic surgeons, primary care physicians, nutritionists, and metabolic bone specialists in endocrinology, rheumatology, or obstetrics and gynecology. Therefore, achieving optimal bone health before orthopaedic surgery necessitates a collaborative and synchronized effort among healthcare professionals.» Patients with poor bone health are often asymptomatic and may present to the orthopaedic surgeon for reasons other than poor bone health. Therefore, it is imperative to recognize risk factors such as old age, female sex, and low body mass index, which predispose to decreased bone density.» Workup of suspected poor bone health entails bone density evaluation. For patients without dual-energy x-ray absorptiometry (DXA) scan results within the past 2 years, perform DXA scan in all women aged 65 years and older, all men aged 70 years and older, and women younger than 65 years or men younger than 70 years with concurrent risk factors for poor bone health. All women and men presenting with a fracture secondary to low-energy trauma should receive DXA scan and bone health workup; for fractures secondary to high-energy trauma, perform DXA scan and further workup in women aged 65 years and older and men aged 70 years and older.» Failure to recognize and treat poor bone health can result in poor surgical outcomes including implant failure, periprosthetic infection, and nonunion after fracture fixation. However, collaborative healthcare teams can create personalized care plans involving nutritional supplements, antiresorptive or anabolic treatment, and weight-bearing exercise programs, resulting in BHO before surgery. Ultimately, this coordinated approach can enhance the success rate of surgical interventions, minimize complications, and improve patients' overall quality of life., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/B48)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED 50 (and 95% confidence interval) of 0.70 (0.52-0.97) mg/kg i.p . mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p. ) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED 50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.

Case: This is a case of a 71-year-old female patient with recurrent instability and complex hip abductor deficiency after total hip arthroplasty (THA) who was treated successfully with an abductor reconstruction with gluteal transfer with mesh reconstruction. The patient returned to nonassisted ambulation with no further THA dislocations at the 1-year follow-up., Conclusion: Abductor deficiencies after THA are complex and have a high potential for long-term disability if not properly diagnosed and treated. A modified gluteal transfer with mesh reconstruction and distal fixation with cerclage cable allowed for sustained restoration of functional hip abduction and stability after revision THA., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C208)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

The macrocyclic tetrapeptide CJ-15,208 ( cyclo [Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides' opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [ 35 S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2'-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP.

Background: Previous studies have indicated a close link between the inflammatory response, exacerbated by circadian disruption and psychostimulants such as cocaine and methamphetamine (METH). Indicators of this inflammation include cortisol and acute-phase proteins (APPs) like C-reactive protein (CRP), complement C3 (C3), and serum amyloid A (SAA). The connection between these inflammation markers and circulating mitochondrial DNA (mtDNA) has been gaining attention. However, the specific influence of cocaine and METH on APP, cortisol, and mtDNA levels in mice with disturbed circadian rhythm has yet to be explored, which is the main aim of this research., Methods: In our study, we employed 10-12-week-old male C57BL/6J mice, which underwent an imposed 6-h phase advance every six days for a total of eight cycles. This process led to the formation of mice with disrupted circadian rhythm and sleep disorders (CRSD). We administered 11 dosages of cocaine and METH 15 mg/kg and 20 mg/kg, respectively to these CRSD mice over the course of 22 days. Quantitative assessments of CRP, C3, SAA, cortisol, and cell-free circulating mtDNA were conducted using enzyme-linked immunosorbent assay (ELISA), Western Blot, and quantitative real-time polymerase chain reaction (qRT-PCR) techniques., Results: The experiment revealed that disruption in circadian rhythm alone or cocaine or METH on their own increased CRP, C3, SAA, and cortisol levels in comparison with the control group. CRSD mice, exposed to cocaine and METH, showed a significant rise in CRP, C3, and SAA, while those without exposure remained stable. We also found a reduction in circulating cell-free mtDNA in all CRSD mice, regardless of cocaine and METH exposure., Conclusions: The findings of our study affirm that the levels of CRP, C3, SAA, and cortisol, which reflect inflammation, are enhanced by circadian disruption, cocaine, and METH, and these levels show a strong correlation with the content of circulating cell-free mtDNA. Furthermore, it also shows the potential link between the disruption of the circadian clock and the inflammatory response triggered by cocaine and METH., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare that they do not have any potential competing interests., (© 2023 The Authors.)

Background: Decreased cost associated with same-day discharge (SDD) total knee arthroplasty (TKA) has led to an increased interest in this topic. The purpose of this study is to investigate whether there is a population of TKA patients in which SDD has similar rates of 30-day complications compared to patients discharged on postoperative day 1 or 2., Methods: Using the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2018, 6,327 TKA patients who had a SDD (length of stay [LOS] = 0) were matched to TKA patients who had an LOS of 1 or 2 days. All SDD patients were successfully matched 1:1 using the morbidity probability variable (a composite variable of demographics, comorbidities, and laboratory values). Patients were divided into quartiles based on their morbidity probability. Bivariate logistic regressions were then used to compare any complication and major complication rates in the SDD quartiles to the corresponding quartiles with an LOS of 1 or 2 days., Results: When comparing the 1st quartiles (healthiest), there was no difference between the cohorts in any complication (odds ratio [OR] = 0.960, 95% CI 0.552-1.670, P = .866) and major complications (OR = 0.999, 95% CI = 0.448-2.231, P = .999). The same was observed in quartile 2 (any complications: OR = 1.161, 95% CI = 0.720-1.874, P = .540). Comparing the third quartiles, there was an increase in all complications with SDD (OR = 1.784, 95% CI = 1.125-2.829, P = .014), but no difference in major complications (OR = 1.635, 95% CI = 0.874-3.061, P = .124). Comparing the fourth quartiles (least healthy), there was an increase in all complications (OR = 1.384, 95% CI = 1.013-1.892, P = .042) and major complications (OR = 1.711, 95% CI = 1.048-2.793, P = .032) with SDD., Conclusion: The unhealthiest 50% of patients in this study who underwent SDD TKA were at an increased risk of having any complication, calling into question the current state of patient selection for SDD TKA., Level of Evidence: III., (Copyright © 2022 Elsevier Inc. All rights reserved.)

New strategies facilitate the design of cyclic peptides which can penetrate the brain. We have designed a bicyclic peptide, OL-CTOP, composed of the sequences of a selective μ-opioid receptor antagonist, CTOP (f- cyclo (CYwOTX)T) (X = penicillamine, Pen; O = ornithine) and odorranalectin, OL (YASPK- cyclo (CFRYPNGVLAC)T), optimized its solid-phase synthesis and demonstrated its ability for nose-to-brain delivery and in vivo activity. The differences in reactivity of Cys and Pen thiol groups protected with trityl and/or acetamidomethyl protecting groups toward I 2 in different solvents were exploited for selective disulfide bond formation on the solid phase. Both the single step and the sequential strategy applied to macrocyclization reactions generated the desired OL-CTOP, with the sequential strategy yielding a large quantity and better purity of crude OL-CTOP. Importantly, intranasally (i.n.s.) administered OL-CTOP dose-dependently antagonized the analgesic effect of morphine administered to mice through the intracerebroventricular route and prevented morphine-induced respiratory depression. In summary, the results demonstrate the feasibility of our solid-phase synthetic strategy for the preparation of the OL-CTOP bicyclic peptide containing two disulfide bonds and reveal the potential of odorranalectin for further modifications and the targeted delivery to the brain.

Purpose: With the advent of practice changes surrounding preoperative patient optimization and postoperative protocols, a marked reduction has been reported in blood transfusion rates following total hip arthroplasty (THA). Thus, the purpose of this study was to examine differences in the prevalence of preoperative anemia, thrombocytopenia, elevated international normalized ratio (INR), bleeding disorders, and pre- and postoperative blood transfusions over the last decade., Methods: From 2011 to 2018, the American College of Surgeons National Quality Improvement Program database was queried for all primary THA procedures (n = 208,796). The following continuous variables were examined using analysis of variance: preoperative hematocrit (HCT), platelet count, and INR. The following categorical variables were analyzed by chi-squared tests: anemia (HCT < 35.5% for females and < 38.5% for males), thrombocytopenia (platelet count < 150,000/µL), INR > 2.0, bleeding disorders, preoperative transfusions, and postoperative transfusions., Results: There were decreases in preoperative anemia (2011: 16.2%; 2018: 11.4%, p < 0.001) and postoperative transfusions (2011: high = 22.2%; 2018: low = 1.3%, p < 0.001). Statistically significant but clinically irrelevant changes were observed in preoperative HCT (2011: low = 40.3, 2018: high = 41.1, p < 0.001), platelet count (2011: low = 248,700; 2018: high = 250,100, p < 0.001), thrombocytopenia (2011: high = 4.9%; 2018: low = 4.3%, p = 0.036), INR > 2.0 (2011: high = 1.1%; 2018: low = 0.7%, p = 0.001), bleeding disorders (2011: high = 2.9%; 2018: low = 2.0%, p < 0.001), and preoperative transfusions (2011: high = 0.2%; 2018: low = 0.1%, p = 0.007)., Conclusion: Large decreases in the number of patients with preoperative anemia and those receiving postoperative blood transfusion were observed during the study period. Future investigation is needed to ascertain whether this is due to patient optimization, practice changes, "cherry-picking" of healthy patients, or a combination of these factors., Level of Evidence: III., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose 1 . Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site 2 found in µOR 3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp 2.50 residue in the Na + site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G i subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G z efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G i , G o and G z subtypes and arrestins, thus modulating their in vivo pharmacology., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Cocaine abuse increases the incidence of HIV-1-associated neurocognitive disorders. We have demonstrated that HIV-1 transactivator of transcription (Tat) allosterically modulates dopamine (DA) reuptake through the human DA transporter (hDAT), potentially contributing to Tat-induced cognitive impairment and potentiation of cocaine conditioned place preference (CPP). This study determined the effects of a novel allosteric modulator of DAT, SRI-32743, on the interactions of HIV-1 Tat, DA, cocaine, and [ 3 H]WIN35,428 with hDAT in vitro. SRI-32743 (50 nM) attenuated Tat-induced inhibition of [ 3 H]DA uptake and decreased the cocaine-mediated dissociation of [ 3 H]WIN35,428 binding in CHO cells expressing hDAT, suggesting a SRI-32743-mediated allosteric modulation of the Tat-DAT interaction. In further in vivo studies utilizing doxycycline-inducible Tat transgenic (iTat-tg) mice, 14 days of Tat expression significantly reduced the recognition index by 31.7% in the final phase of novel object recognition (NOR) and potentiated cocaine-CPP 2.7-fold compared to responses of vehicle-treated control iTat-tg mice. The Tat-induced NOR deficits and potentiation of cocaine-CPP were not observed in saline-treated iTat-tg or doxycycline-treated G-tg (Tat-null) mice. Systemic administration (i.p.) of SRI-32743 prior to behavioral testing ameliorated Tat-induced impairment of NOR (at a dose of 10 mg/kg) and the Tat-induced potentiation of cocaine-CPP (at doses of 1 or 10 mg/kg). These findings demonstrate that Tat and cocaine interactions with DAT may be regulated by compounds interacting at the DAT allosteric modulatory sites, suggesting a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The multifaceted effects of socioeconomic status on healthcare outcomes can be difficult to quantify. The Area Deprivation Index (ADI) quantifies a socioeconomic disadvantage with higher scores indicating more disadvantaged groups. The present study aimed to describe the ADI distribution for primary total hip arthroplasty (THA) patients stratified by patient demographics and to characterize the association of ADI with healthcare utilization (discharge disposition and length of stay [LOS]), 90-day emergency department (ED) visits, and 90-day all cause readmissions., Methods: Two thousand three hundred and ninety one patients who underwent primary elective THA over a 13-month period were included. A multivariable binary logistic regression analysis with outcomes of nonhome discharge, prolonged LOS (>3 days), 90-day ED visits, and 90-day readmission were performed using predictors of ADI, gender, race, smoking status, body mass index, insurance status, and Charlson comorbidity index. Plots of restricted cubic splines were used to graph associations between ADI as a continuous variable and the outcomes of interest using odds ratios., Results: In the multivariable regression model, there were statistically significant higher odds of nonhome discharge (OR, 1.82; 95% CI, 1.19-2.77, P = .005) for individuals in the 61-80 ADI quintile as compared to the reference group of 21-40. Individuals in the highest ADI quintile, 81-100, had the greatest odds of nonhome discharge (OR, 2.20; 95% CI, 1.39-3.49, P < .001) and prolonged LOS (OR, 1.91, 95% CI, 1.28-2.84, P = .001)., Conclusions: Higher ADI is associated with an increased healthcare utilization within 90 days of THA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Disturbances in the circadian rhythm alter the normal sleep-wake cycle, which increases vulnerability to drug abuse. Drug abuse can disrupt several homeostatic processes regulated by the circadian rhythm and influence addiction paradigms, including cravings for cocaine. The relationship between circadian rhythm and cocaine abuse is complex and bidirectional, and disruption impacts both brain function and metabolic profiles. Therefore, elucidating the impact of circadian rhythm changes and cocaine abuse on the human metabolome may provide new insights into identifying potential biomarkers. We examine the effect of cocaine administration with and without circadian rhythm sleep disruption (CRSD) on metabolite levels and compare these to healthy controls in an in vivo study. A metabolomics analysis is performed on the control, CRSD, cocaine, and CRSD with cocaine groups. Plasma metabolite concentrations are analyzed using a liquid chromatography electrochemical array platform. We identify 242 known metabolites compared to the control; 26 in the CRSD with cocaine group, 4 in the CRSD group, and 22 in the cocaine group are significantly differentially expressed. Intriguingly, in the CRSD with cocaine treatment group, the expression levels of uridine monophosphate (p < 0.008), adenosine 5′-diphosphate (p < 0.044), and inosine (p < 0.019) are significantly altered compared with those in the cocaine group. In summary, alterations in purine and pyrimidine metabolism provide clues regarding changes in the energy profile and metabolic pathways associated with chronic exposure to cocaine and CRSD.

The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use.

➢: Periprosthetic acetabular fractures are uncommon and infrequently the focus of studies., ➢: Acetabular fractures are occasionally recognized postoperatively when patients report unremitting groin pain weeks after surgery., ➢: The widespread use of cementless acetabular cups might lead to a higher number of fractures than are clinically detectable., ➢: Appropriate recognition, including mindfulness of preoperative patient and surgical risk factors, is critical to the successful management of acetabular complications., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/A850)., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

HIV is a major global public threat burdening society, yet the exact mechanism of HIV pathogenesis needs to be elucidated. In the era of epigenetic therapy, N-terminal acetylation (Nt-acetylation) changes induced by viral infection might play a critical role in virus-host interactions in HIV infection. The mitochondrial epigenetic mechanism, predominantly Nt acetylation, holds HIV immunopathogenesis and is vastly unexplored. The challenge is to single out the specific pathological role of NAT changes in HIV-associated neurodegeneration. Therefore, this nano review aims to shine light on Nt acetylation in HIV pathogenesis, which we believe can lead to effective future therapeutic strategies against HIV-associated neurodegeneration., (© 2022. The Author(s).)

Wildfire dynamics are changing around the world and understanding their effects on ecological communities and landscapes is urgent and important. We report detailed food webs for unburned, low-to-moderate and high severity burned habitats three years post-fire in the Eldorado National Forest, California. The cumulative cross-habitat food web contains 3,084 ontogenetic stages (nodes) or plant parts comprising 849 species (including 107 primary producers, 634 invertebrates, 94 vertebrates). There were 178,655 trophic interactions between these nodes. We provide information on taxonomy, body size, biomass density and trophic interactions under each of the three burn conditions. We detail 19 sampling methods deployed across 27 sites (nine in each burn condition) used to estimate the richness, body size, abundance and biomass density estimates in the node lists. We provide the R code and raw data to estimate summarized node densities and assign trophic links., (© 2022. The Author(s).)

Clinical research has proven that HIV-positive (HIV + ) individuals with cocaine abuse show behavioral and neurocognitive disorders. Noncoding RNAs (ncRNAs), such as long ncRNAs (lncRNAs) and microRNAs (miRNAs), are known to regulate gene expression in the contexts of HIV infection and drug abuse. However, there are no specific lncRNA or miRNA biomarkers associated with HIV-1 Transactivator of transcription protein (Tat) and cocaine coexposure. In the central nervous system (CNS), astrocytes are the primary regulators of energy metabolism, and impairment of the astrocytic energy supply can trigger neurodegeneration. The aim of this study was to uncover the roles of lncRNAs and miRNAs in the regulation of messenger RNA (mRNA) targets affected by HIV infection and cocaine abuse. Integrative bioinformatics analysis revealed altered expression of 10 lncRNAs, 10 miRNAs, and 4 mRNA/gene targets in human primary astrocytes treated with cocaine and HIV-1 Tat. We assessed the alterations in the expression of two miRNAs, hsa-miR-2355 and hsa-miR-4726-5p; four lncRNAs, LINC01133, H19, HHIP-AS1, and NOP14-AS1; and four genes, NDUFA9, KYNU, HKDC1, and LIPG. The results revealed interactions in the LINC01133-hsa-miR-4726-5p-NDUFA9 axis that may eventually help us understand cocaine- and HIV-1 Tat-induced astrocyte dysfunction that may ultimately result in neurodegeneration., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Both advances in perioperative blood management, anesthesia, and surgical technique have improved transfusion rates following primary total knee arthroplasty (TKA), and have driven substantial change in preoperative blood ordering protocols. Therefore, blood management in TKA has seen substantial changes with the implementation of preoperative screening, patient optimization, and intra- and postoperative advances. Thus, the purpose of this study was to examine changes in blood management in primary TKA, a nationwide sample, to assess gaps and opportunities. The American College of Surgeons National Surgical Quality Improvement Program database was used to identify TKA ( n  = 337,160) cases from 2011 to 2018. The following variables examined, such as preoperative hematocrit (HCT), anemia (HCT <35.5% for females and <38.5% for males), platelet count, thrombocytopenia (platelet count < 150,000/µL), international normalized ration (INR), INR > 2.0, bleeding disorders, preoperative, and postoperative transfusions. Analysis of variances were used to examine changes in continuous variables, and Chi-squared tests were used for categorical variables. There was a substantial decrease in postoperative transfusions from high of 18.3% in 2011 to a low of 1.0% in 2018, ( p  < 0.001), as well as in preoperative anemia from a high of 13.3% in 2011 to a low of 9.5% in 2016 to 2017 ( p  < 0.001). There were statistically significant, but clinically irrelevant changes in the other variables examined. There was a HCT high of 41.2 in 2016 and a low of 40.4 in 2011 to 2012 ( p  < 0.001). There was platelet count high of 247,400 in 2018 and a low of 242,700 in 201 ( p  < 0.001). There was a high incidence of thrombocytopenia of 5.2% in 2017 and a low of low of 4.4% in 2018 ( p  < 0.001). There was a high INR of 1.037 in 2011 and a low of 1.021 in 2013 ( p  < 0.001). There was a high incidence of INR >2.0 of 1.0% in 2012 to 2015 and a low of 0.8% in 2016 to 2018 ( p  = 0.027). There was a high incidence of bleeding disorders of 2.9% in 2013 and a low of 1.8% in 2017 to 2018 ( p  < 0.001). There was a high incidence of preoperative transfusions of 0.1% in 2011 to 2014 and a low of <0.1% in 2015 to 2018 ( p  = 0.021). From 2011 to 2018, there has been substantial decreases in patients receiving postoperative transfusions after primary TKA. Similarly, although a decrease in patients with anemia was seen, there remains 1 out 10 patients with preoperative anemia, highlighting the opportunity to further improve and address this potentially modifiable risk factor before surgery. These findings may reflect changes during TKA patient selection, optimization, or management, and emphasizes the need to further advance multimodal approaches for perioperative blood management of TKA patients. This is a Level III study., Competing Interests: None declared., (Thieme. All rights reserved.)

Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10-45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED 50 (and 95% C.I.) = 14.7 (10.6-20) mg/kg, i.p.) and the formalin assay (ED 50 (and 95% C.I.) = 0.86 (0.44-1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain.

Background: Evaluating trends and drivers of baseline patient-reported outcome measures (PROMs) is critical to understanding when patients and providers elect to undergo surgery. We aimed to assess the following: (1) 5-year trends in baseline PROMs pre-THA (total hip arthroplasty) stratified by patient determinants; (2) patient factor associated with poor preoperative hip pain/function; (3) phenotypes of combined pain/function PROMs at baseline; and (4) intersurgeon variability in PROM thresholds at surgery., Methods: A prospective cohort of 6,902 primary THAs was enrolled (January 2016 to December 2020). Patient/surgeon details and PROMs were collected at point of care preoperatively. Outcomes included trends (5 years; 20 quarters) in Hip disability and Osteoarthritis Outcome Score (HOOS)-Pain and HOOS-PS (Physical Function Short-Form), stratified by patient demographics. Patients were further classified into phenotype categories of above or equal to median pain/function (P+PS+); below median pain/function (P-PS-); above or equal to median pain but below median function (P+PS-); and below median pain but above or equal to median function (P-PS+)., Results: Baseline HOOS-Pain was consistent across the study period (P-trend = .166), while HOOS-PS demonstrated increasing function (P-trend = .015). Such trends were appreciable in males, females, and White (P-trend < .001, each) but not Black patients (P-trend = .67). Higher odds ratio (OR) of low baseline HOOS-Pain and HOOS-PS were detected among females (HOOS-Pain: OR 1.75, 95% confidence interval [CI] 1.55-1.98, P < .001; HOOS-PS: OR 1.56, 95% CI 1.38-1.77, P < .001), Black patients (HOOS-Pain: OR 1.64, 95% CI 1.35-2.82, P < .001; HOOS-PS: OR 1.59, 95% CI 1.34-1.89, P < .001), and smokers (HOOS-Pain: OR 1.56, 95% CI 1.29-1.89, P < .001; HOOS-PS: OR 1.52, 95% CI 1.25-1.85, P < .001). The P-PS- cohort (32.4%) had lowest age (65.2 ± 11.1 years), highest body mass index (31.6 ± 6.9 kg/m 2 ), females (64.8%), Black (15.8%), and current smokers (12.2%). There was significant intersurgeon preoperative PROM variation in HOOS-Pain and HOOS-PS (P < .001, each)., Conclusion: In contrast to the general population, Black patients have consistently received THA at lower functional levels throughout the 5-year period. Females, smokers, and Black patients were more likely to have poorer pain and function at THA. PROMs assessment as combined pain-function phenotypes may provide a more comprehensive interpretation of patient status preoperatively., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Opioid use disorder (OUD) relapse rates are discouragingly high, underscoring the need for new treatment options. The macrocyclic tetrapeptide natural product CJ-15,208 and its stereoisomer [d-Trp]CJ-15,208 demonstrate kappa opioid receptor (KOR) antagonist activity upon oral administration which prevents stress-induced reinstatement of cocaine-seeking behavior. In order to further explore the structure-activity relationships and expand the potential therapeutic applications of KOR antagonism for the treatment of OUD, we screened a series of 24 analogs of [d-Trp]CJ-15,208 with the goal of enhancing KOR antagonist activity. From this screening, analog 22 arose as a compound of interest, demonstrating dose-dependent KOR antagonism after central and oral administration lasting at least 2.5 h. In further oral testing, analog 22 lacked respiratory, locomotor, or reinforcing effects, consistent with the absence of opioid agonism. Pretreatment with analog 22 (30 mg/kg, p.o.) prevented stress-induced reinstatement of extinguished morphine conditioned place preference and reduced some signs of naloxone-precipitated withdrawal in mice physically dependent on morphine. Collectively, these data support the therapeutic potential of KOR antagonists to support abstinence in OUD and ameliorate opioid withdrawal., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite the success of combined antiretroviral therapy (cART) in reducing viral load, a substantial portion of Human Immunodeficiency Virus (HIV)+ patients report chronic pain. The exact mechanism underlying this co-morbidity even with undetectable viral load remains unknown, but the transactivator of transcription (HIV-Tat) protein is of particular interest. Functional HIV-Tat protein is observed even in cerebrospinal fluid of patients who have an undetectable viral load. It is hypothesized that Tat protein exposure is sufficient to induce neuropathic pain-like manifestations via both activation of microglia and generation of oxidative stress. iTat mice conditionally expressed Tat (1-86) protein in the central nervous system upon daily administration of doxycycline (100 mg/kg/d, i.p., up to 14 days). The effect of HIV-Tat protein exposure on the well-being of the animal was assessed using sucrose-evoked grooming and acute nesting behavior for pain-depressed behaviors, and the development of hyperalgesia assessed with warm-water tail-withdrawal and von Frey assays for thermal hyperalgesia and mechanical allodynia, respectively. Tissue harvested at select time points was used to assess ex vivo alterations in oxidative stress, astrocytosis and microgliosis, and blood-brain barrier integrity with assays utilizing fluorescence-based indicators. Tat protein induced mild thermal hyperalgesia but robust mechanical allodynia starting after 4 days of exposure, reaching a nadir after 7 days. Changes in nociceptive processing were associated with reduced sucrose-evoked grooming behavior without altering acute nesting behavior, and in spinal cord dysregulated free radical generation as measured by DCF fluorescence intensity, altered immunohistochemical expression of the gliotic markers, Iba-1 and GFAP, and increased permeability of the blood-brain barrier to the small molecule fluorescent tracer, sodium fluorescein, in a time-dependent manner. Pretreatment with the anti-inflammatory, indomethacin (1 mg/kg/d, i.p.), the antioxidant, methylsulfonylmethane (100 mg/kg/d i.p.), or the immunomodulatory agent, dimethylfumarate (100 mg/kg/d p.o.) thirty minutes prior to daily injections of doxycycline (100 mg/kg/d i.p.) over 7 days significantly attenuated the development of Tat-induced mechanical allodynia. Collectively, the data suggests that even acute exposure to HIV-1 Tat protein at pathologically relevant levels is sufficient to produce select neurophysiological and behavioral manifestations of chronic pain consistent with that reported by HIV-positive patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry-based proteomic approach to screen potential changes of histone protein modifications in microglia isolated from the brain of control and cisplatin-induced neuropathic pain adult C57BL/6J male mice. We identified several novel microglial histone modifications associated with pain, including statistically significantly decreased histone H3.1 lysine 27 mono-methylation (H3.1K27me1, 54.8% of control) and H3 lysine 56 tri-methylation (7.5% of control), as well as a trend suggesting increased H3 tyrosine 41 nitration. We further investigated the functional role of H3.1K27me1 and found that treatment of cultured microglial cells for 4 consecutive days with 1-10 μM of NCDM-64, a potent and selective inhibitor of lysine demethylase 7A, an enzyme responsible for the demethylation of H3K27me1, dose-dependently elevated its levels with a greater than a two-fold increase observed at 10 μM compared to vehicle-treated control cells. Moreover, pretreatment of mice with NCDM-64 (10 or 25 mg/kg/day, i.p.) prior to cisplatin treatment prevented the development of neuropathic pain in mice. The identification of specific chromatin marks in microglia associated with chronic pain may yield critical insight into the contribution of microglia to the development and maintenance of pain, and opens new avenues for the development of novel nonopioid therapeutics for the effective management of chronic pain., (© 2022 Wiley-VCH GmbH.)

Brain derived neurotrophic factor (BDNF) promotes the growth, differentiation, maintenance and survival of neurons. These attributes make BDNF a potentially powerful therapeutic agent. However, its charge, instability in blood, and poor blood brain barrier (BBB) penetrability have impeded its development. Here, we show that engineered clathrin triskelia (CT) conjugated to BDNF (BDNF-CT) and delivered intranasally increased hippocampal BDNF concentrations 400-fold above that achieved previously with intranasal BDNF alone. We also show that BDNF-CT targeted Tropomyosin receptor kinase B (TrkB) and increased TrkB expression and downstream signaling in iTat mouse brains. Mice were induced to conditionally express neurotoxic HIV Transactivator-of-Transcription (Tat) protein that decreases BDNF. Down-regulation of BDNF is correlated with increased severity of HIV/neuroAIDS. BDNF-CT enhanced neurorestorative effects in the hippocampus including newborn cell proliferation and survival, granule cell neurogenesis, synaptogenesis and increased dendritic integrity. BDNF-CT exerted cognitive-enhancing effects by reducing Tat-induced learning and memory deficits. These results show that CT bionanoparticles efficiently deliver BDNF to the brain, making them potentially powerful tools in regenerative medicine., (© 2022. The Author(s).)

Native forests on tropical islands have been displaced by non-native species, leading to calls for their transformation. Simultaneously, there is increasing recognition that tropical forests can help sequester carbon that would otherwise enter the atmosphere. However, it is unclear if native forests sequester more or less carbon than human-altered landscapes. At Palmyra Atoll, efforts are underway to transform the rainforest composition from coconut palm (Cocos nucifera) dominated to native mixed-species. To better understand how this landscape-level change will alter the atoll's carbon dynamics, we used field sampling, remote sensing, and parameter estimates from the literature to model the total carbon accumulation potential of Palmyra's forest before and after transformation. The model predicted that replacing the C. nucifera plantation with native species would reduce aboveground biomass from 692.6 to 433.3 Mg C. However, expansion of the native Pisonia grandis and Heliotropium foertherianum forest community projected an increase in soil carbon to at least 13,590.8 Mg C, thereby increasing the atoll's overall terrestrial carbon storage potential by 11.6%. Nearshore sites adjacent to C. nucifera canopy had a higher dissolved organic carbon (DOC) concentration (110.0 μMC) than sites adjacent to native forest (81.5 μMC), suggesting that, in conjunction with an increase in terrestrial carbon storage, replacing C. nucifera with native forest will reduce the DOC exported from the forest into in nearshore marine habitats. Lower DOC levels have potential benefits for corals and coral dependent communities. For tropical islands like Palmyra, reverting from C. nucifera dominance to native tree dominance could buffer projected climate change impacts by increasing carbon storage and reducing coral disease., Competing Interests: The authors have declared that no competing interests exist.

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED 50 (and 95% C.I.) value of 13.2 (7.42-28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

Ligands for kappa opioid receptors (KOR) have potential uses as non-addictive analgesics and for the treatment of pruritus, mood disorders, and substance abuse. These areas continue to have major unmet medical needs. Significant advances have been made in recent years in the preclinical development of novel opioid peptides, notably ones with structural features that inherently impart stability to proteases. Following a brief discussion of the potential therapeutic applications of KOR agonists and antagonists, this review focuses on two series of novel opioid peptides, all-D-amino acid tetrapeptides as peripherally selective KOR agonists for the treatment of pain and pruritus without centrally mediated side effects, and macrocyclic tetrapeptides based on CJ-15,208 that can exhibit different opioid profiles with potential applications such as analgesics and treatments for substance abuse., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom's major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo .

The chronic irreversible regression of cognitive ability and memory function in human immunodeficiency virus (HIV)-associated dementia (HAND) is linked with late-stage HIV infection in the brain. The molecular-level signatures of neuroinflammation and neurodegeneration are linked with dysfunction in HAND patients. Protein expression changes and posttranslational modification are epigenetic cues for dementia and neurodegenerative disease. In this study quantitative proteome analysis was performed to comprehensively elucidate changes in protein profiles in HIV-positive (HIV+) human brains. Frontal and temporal lobes of normal and HIV+ brains were subjected to label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using the data-independent acquisition method. Comprehensive proteomic identification and quantification analysis revealed that 3294 total proteins and 251 proteins were differentially expressed in HIV+ brains; specifically, HIV+ frontal and temporal lobes had 132 and 119 differentially expressed proteins, respectively. Proteomic and bioinformatic analyses revealed protein alterations predominantly in the HIV+ frontal lobe region. The expression of GOLPH3, IMPDH2, DYNLL1, RPL11, and GPNMB proteins was significantly altered in HIV+ frontal lobes compared to that in normal brains. These proteins are associated with metabolic pathways, neurodegenerative disorders, and dementia. These proteomic-level changes may be potential biological markers and therapeutic targets to relieve the dementia-associated symptoms in individuals with HAND.

Background: In revision total knee arthroplasty (TKA), information regarding perioperative mortality risk is essential for careful decision-making. This study aimed to elucidate the (1) overall 30-day mortality rate and (2) 30-day mortality rate stratified by age, comorbidity, and septic vs aseptic failure after revision TKA., Methods: The American College of Surgeons National Surgical Quality Improvement Program was reviewed for all patients undergoing revision TKA from 2011 to 2019. A total of 32,354 patients who underwent TKA were identified and categorized as mortality (n = 115) or mortality-free (n = 32,239). Patient characteristics were compared between cohorts and further stratified by septic and aseptic failure., Results: The overall 30-day mortality rate was 0.36%. The percentage of deaths per age group (normalized per 1000) was 0% (18-29 years), 0% (30-39 years), 0.18% (40-49 years), 0.13% (50-59 years), 0.14% (60-69 years), 0.40% (70-79 years), 1.25% (80-89 years), and 6.93% (90+ years). The percentage of deaths per American Society of Anesthesiologists (ASA) class was 0.30% (ASA 1), 0.06% (ASA 2), 0.39% (ASA 3), 2.41% (ASA 4), and 14.29% (ASA 5). Septic revision ( P < .001), general anesthesia ( P < .001), body mass index ≤ 24.9 ( P < .001), and insulin-dependent diabetes ( P  = .039) were associated with an increased risk of mortality., Conclusions: Increasing age, greater comorbidity burden, underweight or normal body mass index, insulin-dependent diabetes, septic revision, and general anesthesia were all associated with an increased risk of mortality after revision TKA. Notably, 1 in 80 patients aged 80-89 years died after revision TKA compared to 1 in 720 patients aged 60-69 years. Patients who underwent septic revision had a 4-fold increase in mortality compared to aseptic revision. Our stratified assessment of mortality provides a more individualized estimation of risk that can be used for patient counseling in revision TKA., (© 2021 The Authors.)

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH 3 group with phenyl ( 4 ), methyl ( 5 ), or 3'-furanyl [ 6 ( SC13 )] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology. In assays limiting MOR reserve, the G-protein efficacy of all three was comparable to buprenorphine. 6 ( SC13 ) showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning in mice. These results suggest the possibility of activating MOR minimally (G-protein E max ≈ 10%) in cell lines while yet attaining maximal antinociception in vivo with reduced opioid liabilities.

Background: Acute intoxication caused by binge ethanol drinking is linked to widespread impairments in brain functions. Various alcohol administration paradigms have been used in animals to model the heterogeneous clinical manifestation of intoxication in people. It is challenging to model a procedure that produces "visible intoxication" in rodents; however, manipulation of variables such as route of alcohol administration, time of availability, frequency, and duration and amount of ethanol exposure has achieved some success. In the current study, we employed a modified drinking-in-the-dark model to assess the validity of this model in producing "post-ethanol consumption intoxication" impairments following prolonged repeated daily voluntary "binge" ethanol consumption., Methods: Adult male C57BL/6J mice were allowed a daily 3-h access to non-alcoholic plain or ethanol-containing gel during the dark cycle for a total of 83 days. After the initial 2-month daily DID, ethanol intake patterns were intensely characterized during the next 3 weeks. Immediately following the last DID session (day 83), plain and ethanol gel-consuming mice were then subjected to behavioral tests of locomotor ability and/or anxiety (cylinder, wire grip, open field) followed by blood ethanol concentration measurement., Result: Mice exhibited a relatively consistent ethanol consumption pattern during and across daily access periods. Ethanol intake of individual mice positively correlated with blood ethanol concentration that averaged 61.64 ± 2.84 mg/dL (n = 12). Compared to the plain gel-consuming control mice, ethanol gel mice exhibited significant locomotor impairment as well as anxiety-like behavior, with the magnitude of impairments of key indices well correlated with blood ethanol levels., Conclusion: The gelatin vehicle-based voluntary ethanol drinking-in-the-dark model reliably produced post consumption acute movement impairments as well as anxiety-like behaviors even after 2 months of daily binge ethanol consumption in male mice. Taken together, this mouse binge ethanol model should facilitate the investigation of mechanisms of binge drinking in subjects chronically abusing ethanol and the search for effective novel treatment strategies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human immunodeficiency virus (HIV) infection and the psychostimulant drug cocaine are known to induce epigenetic changes in DNA methylation that are linked with the severity of viral replication and disease progression, which impair neuronal functions. Increasing evidence suggests that changes in DNA methylation and hydroxymethylation occur in mitochondrial DNA (mtDNA) and represent mitochondrial genome epigenetic modifications (mitoepigenetic modifications). These modifications likely regulate both mtDNA replication and gene expression. However, mtDNA methylation has not been studied extensively in the contexts of cocaine abuse and HIV-1 infection. In the present study, epigenetic factors changed the levels of the DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b, the Ten-eleven translocation (TET) enzymes 1, 2, and 3, and mitochondrial DNMTs (mtDNMTs) both in vitro and in vivo . These changes resulted in alterations in mtDNA methylation levels at CpG and non-CpG sites in human primary astrocytes as measured using targeted next-generation bisulphite sequencing (TNGBS). Moreover, mitochondrial methylation levels in the MT-RNR1, MT-ND5, MT-ND1, D-loop and MT-CYB regions of mtDNA were lower in the HIV-1 Tat and cocaine treatment groups than in the control group. In summary, the present findings suggest that mitoepigenetic modification in the human brain causes the mitochondrial dysfunction that gives rise to neuro-AIDS.

Most individuals living with HIV in the USA are over 45 years old and are vulnerable to the combined effects of HIV and aging. Antiretroviral therapies reduce HIV morbidity and mortality but do not prevent HIV trans-activator of transcription (Tat) protein expression or development of HIV-associated neurocognitive disorder (HAND), which may be caused by Tat. Tat-transgenic (Tat-tg) mice are used to study Tat's effects, typically after transgene induction with doxycycline. However, uninduced Tat-tg mice experience transgene leak and model aspects of HAND when aged, including neuroinflammation. We used in vivo 9.4-tesla proton magnetic resonance spectroscopy to compare neurochemistry in aged versus young female and male uninduced Tat-tg mice. Aged Tat-tg mice demonstrated measurable tat mRNA brain expression and had lower medial prefrontal cortex (MPFC) GABA, glutamate, and taurine levels and lower striatal GABA and taurine levels. Females had lower MPFC glutathione and taurine and lower striatal taurine levels. Brain testosterone levels were negatively correlated with age in aged males but not females. Aged mice had cortical abnormalities not previously reported in aged wild-type mice including lower MPFC GABA and taurine levels. As glutathione and taurine levels reflect inflammation and oxidative stress, our data suggest that Tat may exacerbate these processes in aged Tat-tg mice. However, additional studies in controls not expressing Tat are needed to confirm this point and to deconvolve individual effects of age and Tat expression. Sex steroid hormone supplements, which counter climacteric effects, increase taurine levels, and reduce inflammation and oxidative stress, could attenuate some of the brain abnormalities we identified in aged Tat-tg mice., (© 2021. American Aging Association.)

Dry leaves of kratom (mitragyna speciosa) are anecdotally consumed as pain relievers and antidotes against opioid withdrawal and alcohol use disorders. There are at least 54 alkaloids in kratom; however, investigations to date have focused around mitragynine, 7-hydroxy mitragynine (7OH), and mitragynine pseudoindoxyl (MP). Herein, we probe a few minor indole and oxindole based alkaloids, reporting the receptor affinity, G-protein activity, and βarrestin-2 signaling of corynantheidine, corynoxine, corynoxine B, mitraciliatine, and isopaynantheine at mouse and human opioid receptors. We identify corynantheidine as a mu opioid receptor (MOR) partial agonist, whereas its oxindole derivative corynoxine was an MOR full agonist. Similarly, another alkaloid mitraciliatine was found to be an MOR partial agonist, while isopaynantheine was a KOR agonist which showed reduced βarrestin-2 recruitment. Corynantheidine, corynoxine, and mitraciliatine showed MOR dependent antinociception in mice, but mitraciliatine and corynoxine displayed attenuated respiratory depression and hyperlocomotion compared to the prototypic MOR agonist morphine in vivo when administered supraspinally. Isopaynantheine on the other hand was identified as the first kratom derived KOR agonist in vivo . While these minor alkaloids are unlikely to play the majority role in the biological actions of kratom, they represent excellent starting points for further diversification as well as distinct efficacy and signaling profiles with which to probe opioid actions in vivo .

»: Dressing choice following lower-extremity total joint arthroplasty has substantial ramifications for postoperative outcomes and should be carefully made to prevent complications such as periprosthetic joint infection., »: Patient risk factors are essential components in the selection of wound dressings in total joint arthroplasty., »: Traditional dressings are inexpensive per unit; nevertheless, the associated higher complication profile in patients at a high risk for poor wound healing and sequelae-associated costs may outweigh the up-front savings., »: Modern dressings have the potential to yield better safety outcomes and increased patient satisfaction; however, there is a paucity of evidence regarding the ideal interactive dressing., »: Active dressings, such as silver-ion dressings and closed-incisional negative-pressure wound therapy, have shown promising results to reduce surgical site and periprosthetic joint infection, especially in patients at a high risk for poor wound healing following hip and knee total joint arthroplasty., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/A721)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.