Continuous renal replacement therapy and survival in acute liver failure: A systematic review and meta-analysis.

OBJECTIVE: Acute liver failure (ALF) is a rare syndrome leading to significant morbidity and mortality. An important cause of mortality is cerebral edema due to hyperammonemia. Different therapies for hyperammonemia have been assessed including continuous renal replacement therapy (CRRT). We conducted a systematic review and meta-analysis to determine the efficacy of CRRT in ALF patients. MATERIALS AND METHODS: We searched MEDLINE, EMBASE, Cochrane Library, and Web of Science. Inclusion criteria included adult patients admitted to an ICU with ALF. Intervention was the use of CRRT for one or more indications with the comparator being standard care without the use of CRRT. Outcomes of interest were overall survival, transplant-free survival (TFS), mortality and changes in serum ammonia levels. RESULTS: In total, 305 patients underwent CRRT while 1137 patients did not receive CRRT. CRRT was associated with improved overall survival [risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70-0.99, p-value 0.04, I2 = 50%] and improved TFS (RR 0.65, 95% CI 0.49-0.85, p-value 0.002, I2 = 25%). There was a trend towards higher mortality with no CRRT (RR 1.24, 95% CI 0.84-1.81, p-value 0.28, I2 = 37%). Ammonia clearance data was unable to be pooled and was not analyzable. CONCLUSION: Use of CRRT in ALF patients is associated with improved overall and transplant-free survival compared to no CRRT.

Synthesis of Cystine-Stabilised Dicarba Conotoxin EpI: Ring-Closing Metathesis of Sidechain Deprotected, Sulfide-Rich Sequences.

Recombinant peptide synthesis allows for large-scale production of peptides with therapeutic potential. However, access to dicarba peptidomimetics via sidechain-deprotected sequences becomes challenging with exposed Lewis basicity presented by amine and sulfur-containing residues. Presented here is a combination of strategies which can be used to deactivate coordinative residues and achieve high-yielding Ru-catalyzed ring-closing metathesis. The chemistry is exemplified using α-conotoxin EpI, a native bicyclic disulfide-containing sequence isolated from the marine conesnail Conus episcopatus. Replacement of the loop I disulfide with E/Z-dicarba bridges was achieved with high conversion via solution-phase ring-closing metathesis of the unprotected linear peptide after simple chemoselective oxidation and ion-exchange masking of problematic functionality. Metathesis was also attempted in green solvent choices to further improve the sustainability of dicarba peptide synthesis.

Development and preliminary validation of computationally efficient and detailed 50th percentile female human body models.

OBJECTIVE: No vehicle testing standard (physical or computational) employs a mid-sized female human surrogate, despite discrepancies related to injury outcomes for female occupants amongst all vehicle users. We detail the design and preliminary validation of 50th percentile female (F50) computational human body models (HBMs) based on Global Human Body Models Consortium (GHBMC) models. METHOD: Data for the target geometry was collected as part of the initial generation of GHBMC models. Imaging, surface data, and 15 anthropomorphic measures from a living female subject (60.8 kg and 1.61 m) served as the baseline for model development. Due to the role rib cage geometry plays in biomechanical loading, rib cage morphology from secondary retrospective data was leveraged to identify an average female rib cage based on gross anatomical features. A female rib cage was selected from an existing dataset closest to the mean depth, height, and width of the set, considering only those aged 20 - 50 years. The selected subject among this secondary set also exhibited a 7th rib angle and sternum angle within 5% of the mean measurements, and within the range of previously reported studies. The GHBMC 5th percentile, small female detailed (high biofidelity) and simplified (computationally efficient) models were morphed to match the F50 subject body surface, selected bones, and mean rib cage using established thin plate spline techniques. The models were validated vs. previously published literature studies with an emphasis on rib cage response. Model data was compared to 47 channels of experimental data across four biomechanical hub simulations, two sled test simulations (one of which included all female PMHS), and two robustness simulations to test stability. Model results were mass scaled to the average of the reported corridors. Objective evaluation was conducted using CORA. IRB approval was obtained for all prospective and retrospective data collected or used. The target rib cage was selected from retrospective image data used in prior studies (n = 339 chest CT scans). RESULTS: The morphed HBMs closely matched the target geometry. The detailed and simplified models had masses and element counts of 61.2 kg and 61.8 kg, and 2.8 million and 0.3 million, respectively. The mass difference is due to a coarser mesh in the simplified model. The simplified model ran 23 times faster than the detailed model on the same hardware. Each model exhibited stability in robustness tests, and the average CORA scores were 0.80 and 0.72 in the detailed and simplified models, respectively. The models performed well in frontal impacts against PMHS corridors after mass scaling. CONCLUSIONS: Numerous recent studies underscore poorer injury outcomes for female vehicle occupants compared to males. While such outcomes are multifactorial, the average female models introduced in this work offer a novel tool within a widely used family of HBMs to reduce the outcome gap in terms of injury for all drivers. HBMs can be deployed in safety studies or in future regulatory requirements faster and more economically than a resized or newly designed ATDs aimed at the same target population.

Negating coordinative cysteine and methionine residues during metathesis of unprotected peptides.

Ru-Alkylidene catalysed olefin metathesis generates metabolically stable cystine bridge peptidomimetics with defined geometry. Deleterious coordinative bonding to the catalyst by sulfur-containing functionality found in cysteine and methionine residues can be negated by in situ and reversible oxidation of thiol and thioether functionality, as disulfides and S-oxides respectively, to facilitate high yielding ring-closing and cross metathesis of bioorthogonally protected peptides.

Advances in Design and Development of Lumi-Solve: A Novel Drug-Eluting Photo-Angioplasty Device.

PURPOSE: The Lumi-Solve photo-angioplasty drug eluting balloon catheter (DEBc) may afford safety advantages over current DEBc. Lumi-Solve utilises the guidewire (GW) port and lumen to deliver fibre-optic UV365nm light to the angioplasty balloon which may be problematic. We explore and evaluate alternative Lumi-Solve design options to circumvent fibre-optic use of the GW port and lumen which may enhance efficacy and clinical utility. METHODS: Effects of guidewire shadowing (GWS) on visible and UV365nm light transmission were evaluated and modelled in-silico. To evaluate the effect of a dedicated intra-balloon fibre-optic port, modified angioplasty balloons and sections of translucent polyethylene terephthalate (PET) GW port tubing were utilised. Investigation of the effect of GWS on chemical and biological photo-activation of balloon surface drug was performed utilising LCMS analysis and inhibition of histone deacetylase activity (HDACi) was measured in human umbilical vein endothelial cells (HUVEC). RESULTS: Parallel fibre-optic and GW port configurations generated a GWS of approximately 18.0% of the evaluable balloon surface area and attenuated both visible and UV light intensity by 20.0-25.0% and reduced chemical photo-activation of balloon surface drug and HDACi by at least 40-45%. Alternative fibre-optic port configurations including a spiral design significantly mitigated GWS effects on UV light transmission. CONCLUSIONS: To avoid use of the GW port and its associated complications a dedicated third port and lumen for the Lumi-Solve fibre-optic may be required. To maximize balloon surface chemical and biological photo-activation, non-parallel, intra-balloon, fibre-optic lumen trajectories, including a spiral design may be useful.

Intrapulmonary and Intracardiac Shunts in Adult COVID-19 Versus Non-COVID Acute Respiratory Distress Syndrome ICU Patients Using Echocardiography and Contrast Bubble Studies (COVID-Shunt Study): A Prospective, Observational Cohort Study.

OBJECTIVES: Studies have suggested intrapulmonary shunts may contribute to hypoxemia in COVID-19 acute respiratory distress syndrome (ARDS) with worse associated outcomes. We evaluated the presence of right-to-left (R-L) shunts in COVID-19 and non-COVID ARDS patients using a comprehensive hypoxemia workup for shunt etiology and associations with mortality. DESIGN: Prospective, observational cohort study. SETTING: Four tertiary hospitals in Edmonton, Alberta, Canada. PATIENTS: Adult critically ill, mechanically ventilated, ICU patients admitted with COVID-19 or non-COVID (November 16, 2020, to September 1, 2021). INTERVENTIONS: Agitated-saline bubble studies with transthoracic echocardiography/transcranial Doppler ± transesophageal echocardiography assessed for R-L shunts presence. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were shunt frequency and association with hospital mortality. Logistic regression analysis was used for adjustment. The study enrolled 226 patients (182 COVID-19 vs 42 non-COVID). Median age was 58 years (interquartile range [IQR], 47-67 yr) and Acute Physiology and Chronic Health Evaluation II scores of 30 (IQR, 21-36). In COVID-19 patients, the frequency of R-L shunt was 31 of 182 COVID patients (17.0%) versus 10 of 44 non-COVID patients (22.7%), with no difference detected in shunt rates (risk difference [RD], -5.7%; 95% CI, -18.4 to 7.0; p = 0.38). In the COVID-19 group, hospital mortality was higher for those with R-L shunt compared with those without (54.8% vs 35.8%; RD, 19.0%; 95% CI, 0.1-37.9; p = 0.05). This did not persist at 90-day mortality nor after adjustment with regression. CONCLUSIONS: There was no evidence of increased R-L shunt rates in COVID-19 compared with non-COVID controls. R-L shunt was associated with increased in-hospital mortality for COVID-19 patients, but this did not persist at 90-day mortality or after adjusting using logistic regression.

Characterisation of Elevenin-Vc1 from the Venom of Conus victoriae: A Structural Analogue of α-Conotoxins.

Elevenins are peptides found in a range of organisms, including arthropods, annelids, nematodes, and molluscs. They consist of 17 to 19 amino acid residues with a single conserved disulfide bond. The subject of this study, elevenin-Vc1, was first identified in the venom of the cone snail Conus victoriae (Gen. Comp. Endocrinol. 2017, 244, 11-18). Although numerous elevenin sequences have been reported, their physiological function is unclear, and no structural information is available. Upon intracranial injection in mice, elevenin-Vc1 induced hyperactivity at doses of 5 or 10 nmol. The structure of elevenin-Vc1, determined using nuclear magnetic resonance spectroscopy, consists of a short helix and a bend region stabilised by the single disulfide bond. The elevenin-Vc1 structural fold is similar to that of α-conotoxins such as α-RgIA and α-ImI, which are also found in the venoms of cone snails and are antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). In an attempt to mimic the functional motif, Asp-Pro-Arg, of α-RgIA and α-ImI, we synthesised an analogue, designated elevenin-Vc1-DPR. However, neither elevenin-Vc1 nor the analogue was active at six different human nAChR subtypes (α1ß1εδ, α3ß2, α3ß4, α4ß2, α7, and α9α10) at 1 µM concentrations.

Acute Respiratory Distress Syndrome and Shunt Detection With Bubble Studies: A Systematic Review and Meta-Analysis.

Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory injury with multiple physiological sequelae. Shunting of deoxygenated blood through intra- and extrapulmonary shunts may complicate ARDS management. Therefore, we conducted a systematic review to determine the prevalence of sonographically detected shunts, and their association with oxygenation and mortality in patients with ARDS. DATA SOURCES: Medical literature analysis and retrieval system online, Excerpta Medica dataBASE, Cochrane Library, and database of abstracts of reviews of effects databases on March 26, 2021. STUDY SELECTION: Articles relating to respiratory failure and sonographic shunt detection. DATA EXTRACTION: Articles were independently screened and extracted in duplicate. Data pertaining to study demographics and shunt detection were compiled for mortality and oxygenation outcomes. Risk of bias was appraised using the Joanna-Briggs Institute and the Newcastle-Ottawa Scale tools with evidence rating certainty using Grading of Recommendations Assessment, Development and Evaluation methodology. DATA SYNTHESIS: From 4,617 citations, 10 observational studies met eligibility criteria. Sonographic detection of right-to-left shunt was present in 21.8% of patients (range, 14.4-30.0%) among included studies using transthoracic, transesophageal, and transcranial bubble Doppler ultrasonographies. Shunt prevalence may be associated with increased mortality (risk ratio, 1.22; 95% CI, 1.01-1.49; p = 0.04, very low certainty evidence) with no difference in oxygenation as measured by Pao2:Fio2 ratio (mean difference, -0.7; 95% CI, -18.6 to 17.2; p = 0.94, very low certainty). CONCLUSIONS: Intra- and extrapulmonary shunts are detected frequently in ARDS with ultrasound techniques. Shunts may increase mortality among patients with ARDS, but its association with oxygenation is uncertain.

Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond.

The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6-A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.

Is massage an effective intervention in the management of post-operative scarring? A scoping review.

BACKGROUND: Scar massage is a widely used treatment modality in hand therapy. This intervention is thoroughly discussed in the literature relating to burns rehabilitation, however, the evidence for its use in treating linear scars following surgery is limited. PURPOSE OF STUDY: To collate the empirical literature on scar massage for the treatment of postsurgical cutaneous scars. STUDY DESIGN: Scoping review. METHODS: Medline, EMBASE, CINAHL, AMED, Scopus, ProQuest Dissertations & Theses Global, and the Joanna Briggs Institute were searched from inception to December 2020. Two researchers used a data extraction tool to record key demographic, intervention and outcome data, and to apply the Oxford Levels of Evidence for each study. RESULTS: Twenty-five studies met the inclusion criteria, reporting on a combined sample of 1515 participants. Only two papers addressed hand or wrist scars (92 participants). While all studies reported favorable outcomes for scar massage, there were 45 different outcome measures used and a propensity towards non-standardized assessment. Intervention protocols varied from a single session to three treatments daily for 6 months. The results from 13 studies were confounded by the implementation of additional rehabilitation interventions. CONCLUSIONS: The overall findings suggest that while there may be benefits to scar massage in reducing pain, increasing movement and improving scar characteristics; there is a lack of consistent research methods, intervention protocols and outcome measures. This scoping review highlights the heterogenous nature of research into scar massage following surgery and supports the need for further research to substantiate its use in the clinical setting.

Trash to Treasure: How Insect Protein and Waste Containers Can Improve the Environmental Footprint of Mosquito Egg Releases.

Release and subsequent establishment of Wolbachia-infected Aedes aegypti in native mosquito populations has successfully reduced mosquito-borne disease incidence. While this is promising, further development is required to ensure that this method is scalable and sustainable. Egg release is a beneficial technique that requires reduced onsite resources and increases community acceptance; however, its incidental ecological impacts must be considered to ensure sustainability. In this study, we tested a more environmentally friendly mosquito rearing and release approach through the encapsulation of diet and egg mixtures and the subsequent utilization of waste containers to hatch and release mosquitoes. An ecologically friendly diet mix was specifically developed and tested for use in capsules, and we demonstrated that using either cricket or black soldier fly meal as a substitute for beef liver powder had no adverse effects on fitness or Wolbachia density. We further encapsulated both the egg and diet mixes and demonstrated no loss in viability. To address the potential of increased waste generation through disposable mosquito release containers, we tested reusing commonly found waste containers (aluminum and tin cans, PET, and glass bottles) as an alternative, conducting a case study in Kiribati to assess the concept's cultural, political, and economic applicability. Our results showed that mosquito emergence and fitness was maintained with a variety of containers, including when tested in the field, compared to control containers, and that there are opportunities to implement this method in the Pacific Islands in a way that is culturally considerate and cost-effective.

Exposure, access and interaction: A global analysis of sponsorship of nursing professional associations.

AIM: To analyse the nature and extent of sponsorship of nursing professional associations and their major scientific conferences. DESIGN: Cross-sectional content analysis. METHODS: Data were extracted from the websites and conference documents of 156 national and international professional nursing associations in 2019 to identify sponsors. Sponsorship prospectuses were analysed to estimate the value and describe the nature of sponsorship arrangements. We analysed sponsorship patterns using social network analysis. RESULTS: Most associations (84/156, 54%) did not report any sponsors. Sponsorship was concentrated among specialty nursing associations in high-income countries. Half of identified sponsors promoted products used in clinical care (50%; 981/1969); the majority represented the medical device industry (69%; 681/981). Top sponsors generally favoured opportunities that promoted interaction with conference attendees. CONCLUSION: Globally, commercial sponsorship of nursing associations is a common, but not the dominant source of support for these activities. Half of sponsors were commercial entities that manufactured or distributed products used during clinical care, which presents a risk of commercial influence over education and ultimately, clinical practice. Sponsors favoured opportunities to interact directly with nurses, determine educational content, or foster continued interaction.

Impact of a dedicated atrial fibrillation clinic on diagnosis-to-ablation time.

Background: Outcomes following catheter ablation (CA) for atrial fibrillation (AF) improve as the diagnosis-to-ablation time (DAT) shortens. Use of a protocol-based integrated care model through a dedicated atrial fibrillation clinic (AFC) may serve to standardize treatment pathways and decrease DAT. Objective: To evaluate the DAT and clinical characteristics of patients with AF referred from an AFC vs a conventional electrophysiology clinic (EC). Methods: Retrospective analysis was completed in consecutive patients undergoing index AF ablation at Riverside Methodist Hospital in 2019 with minimum 1 year follow-up. Patients were categorized based off their CA referral source (AFC vs EC) and where the initial visit following index diagnosis of AF occurred (AFC vs EC). Results: A total of 182 patients (mean age 65 years, 64% male) were reviewed. Patients referred from an AFC (21%) had a median DAT of 342 days (interquartile range [IQR], 125-855 days) compared to patients referred from EC (79%) with a median DAT of 813 days (IQR, 241-1444 days; P = .01). Patients with their index visit following AF diagnosis occurring in the AFC (9%) had significantly shorter median DAT (127 days [IQR, 95-188 days]) compared to EC (91%) (789 days [IQR, 253-1503 days]; P = .002). Patients with DAT <1 year had lower AF recurrence than patients with DAT >1 year (P = .04, hazard ratio = 0.58, 95% confidence interval 0.3418-1.000). Conclusion: DAT is a modifiable factor that may affect CA outcomes. Significant reductions in DAT were observed in patients evaluated through a dedicated AF clinic.

Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter.

Capillary endothelial cells of the human blood-brain barrier (BBB) express high levels of P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2). However, little information is available regarding ATP-binding cassette transporters expressed at the zebrafish BBB, which has emerged as a potential model system. We report the characterization and tissue localization of two genes that are similar to ABCB1, zebrafish abcb4 and abcb5. When stably expressed in HEK293 cells, both Abcb4 and Abcb5 conferred resistance to P-gp substrates; however, Abcb5 poorly transported doxorubicin and mitoxantrone compared to zebrafish Abcb4. Additionally, Abcb5 did not transport the fluorescent P-gp probes BODIPY-ethylenediamine or LDS 751, while they were transported by Abcb4. High-throughput screening of 90 human P-gp substrates confirmed that Abcb4 has an overlapping substrate specificity profile with P-gp. In the brain vasculature, RNAscope probes for abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. The abcb4 probe also colocalized with claudin-5 in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, potentially indicating different functions. The data suggest that zebrafish Abcb4 functionally phenocopies P-gp and that the zebrafish may serve as a model to study the role of P-gp at the BBB.

Physical exercise and catecholamine reuptake inhibitors affect orienting behavior and social interaction in a rat model of attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Design, Development, In Vitro and Preliminary In Vivo Evaluation of a Novel Photo-Angioplasty Device: Lumi-Solve.

PURPOSE: Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class. METHODS: In vitro catheter and contrast media transmission of UV365nm was evaluated spectroscopically. UV365nm conversion of c-MCT-3 to MCT-3 was evaluated chromatographically. Cellular toxicity and HDACi activity of c-MCT-3 ∓UV365nm was evaluated in vitro. In vivo UV365nm conversion of c-MCT-3 to MCT-3 was evaluated in an ovine carotid artery model. RESULTS: Catheter material and dilute contrast media did not attenuate UV365nm transmission or c-MCT-3 activation. c-MCT-3 demonstrated less cellular toxicity than MCT-3 and PTX. UV365nm-activated c-MCT-3 demonstrated HDACi activity. In vivo activation of c-MCT-3 produced MCT-3. CONCLUSIONS: Lumi-Solve, a novel DEBc device developed utilizing a combination of chemical, fibre-optic and catheter based technology platforms, demonstrated potential for targeted delivery of bioactive HDACi to the blood vessel wall supporting direct application to the management of NIH and warranting additional in vivo studies.

Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models.

Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.

Modulation of heroin intake by ovarian hormones in gonadectomized and intact female rats.

RATIONALE: Heroin intake decreases during the proestrus phase of the estrous cycle in female rats. Circulating concentrations of both estradiol and progesterone peak during proestrus, and it is not known which of these hormones, or their combination, are responsible for these effects. OBJECTIVES: The purpose of this study was to determine the effects of estradiol, progesterone, and their combination on heroin self-administration in female rats. METHODS: In Experiment 1, the estrous cycle of intact female rats was tracked daily. If a rat was in proestrus, either the estrogen receptor antagonist, raloxifene, the progesterone receptor antagonist, mifepristone, or their combination was administered 30 min prior to a heroin self-administration session. In Experiment 2, separate groups of ovariectomized female rats were treated chronically with exogenous estradiol, progesterone, estradiol + progesterone, or vehicle, and heroin intake was examined over a 100-fold dose range. RESULTS: In Experiment 1, raloxifene, but not mifepristone, significantly blocked proestrus-associated decreases in heroin intake. In Experiment 2, estrogentreated rats self-administered less heroin than any other group and significantly less heroin than rats treated with progesterone. CONCLUSIONS: These data suggest that (1) estradiol but not progesterone is responsible for proestrus-associated decreases in heroin intake and (2) estradiol decreases heroin intake relative to progesterone. These data differ from those reported previously with stimulants and suggest that estrogen-based pharmacotherapies may be of value to women with opioid use disorder.