Future malaria environmental suitability in Africa is sensitive to hydrology.

Changes in climate shift the geographic locations that are suitable for malaria transmission because of the thermal constraints on vector Anopheles mosquitos and Plasmodium spp. malaria parasites and the lack of availability of surface water for vector breeding. Previous Africa-wide assessments have tended to solely represent surface water using precipitation, ignoring many important hydrological processes. Here, we applied a validated and weighted ensemble of global hydrological and climate models to estimate present and future areas of hydroclimatic suitability for malaria transmission. With explicit surface water representation, we predict a net decrease in areas suitable for malaria transmission from 2025 onward, greater sensitivity to future greenhouse gas emissions, and different, more complex, malaria transmission patterns. Areas of malaria transmission that are projected to change are smaller than those estimated by precipitation-based estimates but are associated with greater changes in transmission season lengths.

Use of THRIVE for Apneic Oxygenation in Transoral Laser Microlaryngeal Surgery: A Scoping Review.

OBJECTIVES: Trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) has demonstrated utility in extending the apneic window in the perioperative setting. Its benefits in facilitating tubeless anesthesia are recognized during elective laryngotracheal surgeries. The use of THRIVE and administering higher fractional inspired oxygen concentrations in laser laryngeal surgery (LLS) remains controversial due to the theoretical risk of airway fires. A scoping review of the literature describing institutional experiences with THRIVE during LLS was conducted. DATA SOURCES AND REVIEW METHODS: A systematic scoping review of the literature was performed including PubMed, Medline, Embase, Scopus, JBI EBP Database, and Cochrane Library from inception to April 2023. RESULTS: From the 472 articles identified in our review, nine articles were included representing 271 cases. THRIVE was used for preoxygenation and to maintain apneic oxygenation during LLS. Different institutional practices related to THRIVE parameters and intraoperative modifications during lasing were described in the literature, including cessation of THRIVE, reduction of FiO2 to 30%, and continuous 100% FiO2 oxygenation. One study described a brief ignition of the coating of a KTP laser fiber without injury to the patient. No adverse patient outcomes have been documented in the literature with THRIVE during LLS. CONCLUSION: THRIVE is a safe and effective form of tubeless anesthesia and apneic oxygenation during LLS, with no adverse patient safety events reported in the literature. Key determinants to maintain safety include optimal patient and team selection, effective surgeon-anesthetist cooperation, and institutional protocols that govern intraoperative practice. Laryngoscope, 2024.

Treatment with dextroamphetamine decreases the reacquisition of cocaine self-administration: Consistency across social contexts.

RATIONALE: A return to cocaine use following abstinence frequently occurs in a social context, and the presence of other individuals using cocaine may contribute to the likelihood of use. Previous studies have reported that chronic d-amphetamine treatment decreases cocaine self-administration in laboratory animals and reduces a return to cocaine use following abstinence in humans. OBJECTIVE: The purpose of this study was to examine the effects of chronic d-amphetamine treatment on the reacquisition of cocaine use in rats self-administering cocaine in different social contexts. METHODS: Male and female rats were implanted with intravenous catheters and trained to self-administer cocaine during daily 6-hr sessions. After 14 days, cocaine self-administration was extinguished by substituting saline for the cocaine stimulus. At this time, rats were randomized to receive chronic treatment with either d-amphetamine or saline. After 9 days of extinction, cocaine was again made available during daily 6-hr sessions. At this time, rats were further randomized into three social conditions: (1) rats continued self-administering cocaine in isolation, (2) rats self-administered cocaine in the presence of a same-sex partner that also self-administered cocaine, or (3) rats self-administered cocaine in the presence of a same-sex partner that did not have access to cocaine. Daily treatment with d-amphetamine or saline continued for the duration of reacquisition testing. RESULTS: Chronic treatment with d-amphetamine decreased cocaine intake during reacquisition, but these effects were not influenced by the social context. No sex differences were observed. CONCLUSION: These data support previous studies reporting that d-amphetamine decreases cocaine intake and demonstrate its efficacy across social contexts.

Toolbox of individual-level interventions against online misinformation.

The spread of misinformation through media and social networks threatens many aspects of society, including public health and the state of democracies. One approach to mitigating the effect of misinformation focuses on individual-level interventions, equipping policymakers and the public with essential tools to curb the spread and influence of falsehoods. Here we introduce a toolbox of individual-level interventions for reducing harm from online misinformation. Comprising an up-to-date account of interventions featured in 81 scientific papers from across the globe, the toolbox provides both a conceptual overview of nine main types of interventions, including their target, scope and examples, and a summary of the empirical evidence supporting the interventions, including the methods and experimental paradigms used to test them. The nine types of interventions covered are accuracy prompts, debunking and rebuttals, friction, inoculation, lateral reading and verification strategies, media-literacy tips, social norms, source-credibility labels, and warning and fact-checking labels.

Friends or Foes: Fundamental Principles of Th-Organic Scaffold Chemistry Using Zr-Analogs as a Guide.

The fundamental interest in actinide chemistry, particularly for the development of thorium-based materials, is experiencing a renaissance owing to the recent and rapidly growing attention to fuel cycle reactors, radiological daughters for nuclear medicine, and efficient nuclear stockpile development. Herein, we uncover fundamental principles of thorium chemistry on the example of Th-based extended structures such as metal-organic frameworks in comparison with the discrete systems and zirconium extended analogs, demonstrating remarkable over two-and-half-year chemical stability of Th-based frameworks as a function of metal node connectivity, amount of defects, and conformational linker rigidity through comprehensive spectroscopic and crystallographic analysis as well as theoretical modeling. Despite exceptional chemical stability, we report the first example of studies focusing on the reactivity of the most chemically stable Th-based frameworks in comparison with the discrete Th-based systems such as metal-organic complexes and a cage, contrasting multicycle recyclability and selectivity (>97%) of the extended structures in comparison with the molecular compounds. Overall, the presented work not only establishes the conceptual foundation for evaluating the capabilities of Th-based materials but also represents a milestone for their multifaceted future and foreshadows their potential to shape the next era of actinide chemistry.

Durable transgene expression and efficient re-administration after rAAV2.5T-mediated fCFTRΔR gene delivery to adult ferret lungs.

The dosing interval for effective recombinant adeno-associated virus (rAAV)-mediated gene therapy of cystic fibrosis lung disease remains unknown. Here, we assessed the durability of rAAV2.5T-fCFTRΔR-mediated transgene expression and neutralizing antibody (NAb) responses in lungs of adult wild-type ferrets. Within the first 3 months following rAAV2.5T-fCFTRΔR delivery to the lung, CFTRΔR transgene expression declined ∼5.6-fold and then remained stable to 5 months at ∼26% the level of endogenous CFTR. rAAV NAbs in the plasma and bronchoalveolar lavage fluid (BALF) peaked at 21 days, coinciding with peak ELISpot T cell responses to AAV capsid peptides, after which both responses declined and remained stable at 4-5 months post dosing. Administration of reporter vector rAAV2.5T-gLuc (gaussia luciferase) at 5 months following rAAV2.5T-fCFTRΔR dosing gave rise to similar levels of gLuc expression in the BALF as observed in age-matched reporter-only controls, demonstrating that residual BALF NAbs were functionally insignificant. Notably, the second vector administration led to a 2.6-fold greater ELISpot T cell response and ∼2.3-fold decline in fCFTRΔR mRNA and vector genomes derived from the initial rAAV2.5T-fCFTRΔR administration, suggesting selective destruction of transduced cells from the first vector dose. These findings provide insights into humoral and cellular immune response to rAAV that may be useful for optimizing gene therapy to the cystic fibrosis lung.

Trans-nasal Humidified Rapid Insufflation Ventilatory Exchange (THRIVE) and its Utility in Otolaryngology, Head and Neck Surgery: A Literature Review.

High-flow nasal oxygen (HFNO) therapy is extensively used in critical care units for spontaneously breathing patients. Trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) is a method of apnoeic oxygenation with continuous nasal delivery of warmed, humidified oxygen at high-flow rates up to 70L/min. THRIVE extends the apnoeic window before desaturation occurs so that tubeless anaesthesia is possible. The advent of THRIVE has had a monumental impact on anaesthetic practice, with a diverse range of clinical applications and it has been incorporated into difficult airway guidelines. THRIVE has many applications in otolaryngology and head and neck surgery. It is used as a pre-oxygenation tool during induction in both anticipated and unanticipated difficult airway scenarios and as a method of oxygenation for tubeless anaesthesia in elective laryngotracheal and hypopharyngeal surgeries and during emergence from anaesthesia. In this scoping review of the literature, we aim to provide an overview on the utility of THRIVE in otolaryngology, including the underlying physiologic principles, current indications and limitations, and its feasibility and safety in different surgical contexts and specific population groups.

Early Results in Total Replacement of the Distal Radioulnar Joint.

BACKGROUND: Pathology of the distal radioulnar joint (DRUJ) including instability and arthritis presents a challenge for hand and upper extremity surgeons. Surgical options include a Darrach procedure and similar resections, soft tissue interposition arthroplasty, and a one-bone forearm. In 2005, a prosthesis for DRUJ arthroplasty was approved for use in the United States. The authors hypothesize that DRUJ arthroplasty will lead to improved pain and range of motion (ROM) with a moderate, but manageable, complication rate. METHODS: A retrospective review of 46 patients who underwent DRUJ arthroplasty by a single private group of hand surgeons was performed. Demographics, complications, postoperative visual analog scale (VAS), and postoperative ROM were obtained and analyzed. RESULTS: The patients were followed up for a mean of 60 weeks. The implant was used both as primary surgical treatment for DRUJ pathology and as salvage for previous failed procedures. Twenty-two percent of patients experienced complications: 15% required revision surgery. No patients were converted to another type of implant, including those who underwent revision surgery. Prominent hardware was the most common indication requiring revision. Patients achieved an improvement in supination of 17° and extension of 5°. They additionally achieved a decrease in average VAS score from 7.1 to 2.3. CONCLUSIONS: Distal radioulnar joint arthroplasty reduces pain and improves ROM in patients with DRUJ pathology with a 22% complication rate. This cohort demonstrates improved pain, modest improvement in ROM, but a 22% complication rate for this implant. Further long-term studies are encouraged.

Perceptions of Wild Pig Impact, Management, and Policy in Alabama.

Successful management of invasive species often requires working across public and private landownerships. A prime example of an invasive species that commonly occurs on privately and publicly owned and managed lands is the wild pig (Sus scrofa). Because of the multitude of negative impacts associated with wild pigs, management must occur across both private and public lands to achieve widespread control and sustained success. However, managing wild pigs across property boundaries is challenging as we know very little about differing management practices and landowner perspectives. To address this knowledge gap, we sought to understand wild pig management efforts on privately owned lands, the perceived economic, ecological, and human health impact of wild pigs, and beliefs related to policy. Generally, stakeholders believe wild pigs have negative impacts on wildlife, the economy, and ecological and public health, however less than half of landowners participate in wild pig control. Furthermore, stakeholders believe that the responsibility of managing and paying for damages associated with wild pigs lies with individual landowners. Our findings suggest that increased efficacy of wild pig control and collaboration between private and public landowners is not only possible but also necessary if wild pig population control is to be regionally successful.

Does type of bone graft matter? A retrospective review of the use of biological bone grafts in patients undergoing elective 1-3 level spinal interbody fusion.

OBJECTIVE: There is a lack of strong evidence for use of expensive bone substitutes. This study compares perioperative data and patient reported quality-of-life outcomes across the varied types of bone graft extenders. The study analyzes the existing Quality and Outcomes Database and evaluates patient reported outcomes for 1-3 level lumbar fusion procedures comparing across different types of biologics bone graft. METHODS: We retrospectively analyzed a prospectively collected data registry. Bone graft implant data were collected and grouped into the following categories: (1) Autograft with basic allograft (2) Enhanced, synthetic, or cellular allograft (3) Use of BMP. Preoperative and 1 year patient reported outcomes and perioperative data from the prospective collected registry were analyzed. RESULTS: There were 384 patients included in this study. There were 168 (43.8%) patients in group 1, 133 (34.6%) patients in group 2, and 83 (21.6%) in group 3. There were no group differences in baseline or 1 year back pain, leg pain, ODI, or EQ-5D. The GLM Repeated Measures results indicate a significant difference within each of the three groups between the preoperative and postoperative measures for back pain, leg pain, ODI, and EQ-5D. The change over time was not significantly different between the groups. CONCLUSIONS: Bone graft extenders are a significant contributor to the cost of lumbar fusion. This study demonstrates no difference in preoperative, and 1 year patient reported outcomes between the three groups. There was no significant difference in rate of reoperations across the three groups.

Synthesis and cluster structure distortions of biscarborane dithiol, thioether, and disulfide.

The synthesis and structural characterization of the first sulfur-containing derivatives of the C,C-biscarborane {ortho-C2B10}2 cluster - thiol, thioether, and disulfide - are reported. The biscarboranyl dithiol (1-HS-C2B10H10)2 exhibits an exceedingly long intracluster carbon-carbon bond length of 1.858(3) Å, which is attributed to the extensive interaction between the lone pairs of the thiol groups and the unoccupied molecular orbital of the carborane cluster. The structures of the doubly deprotonated biscarboranyl dithiolate anion (1-S-C2B10H10)22- with various counter cations feature an even longer carbon-carbon bond length of 2.062(10) Å within the cluster along with a short carbon-sulfur bond of 1.660(7) Å, both indicative of significant delocalization of electron density from the sulfur atoms into the cluster.

Return to Sports and Recreational Activities Following Arthroplasty of the Basal Joint of the Thumb: A Retrospective Review.

Purpose: Arthroplasty of the basal, or carpometacarpal, joint of the thumb has been shown to decrease pain, improve strength, improve range of motion, and allow return to work. This study sought to assess whether basal joint arthroplasty also allows for a return to sports and recreational activities. Methods: A survey assessing participation in sports and recreational activities, timing of return to play after surgery, enjoyment, and the presence of pain and limitations was mailed to patients who had undergone an arthroplasty of the basal joint of the thumb over a 3-year period. Results: Of the 333 patients who underwent thumb carpometacarpal arthroplasty, met the criteria, and responded, 73% were able to successfully return to sports and recreational activities, with decreased pain and at the same or increased level of play, frequency of participation, and level of enjoyment for their sport or recreational activity. Patients were more likely to successfully return to sports and recreational activities if they had undergone surgery on their nondominant hand, did not stop their sport or recreational activity before surgery, were able to return within 9 months of surgery, and reported no postoperative limitations. Successful return to sports and recreational activities was not related to age, sex, surgeon, level of play, or the type of sport or recreational activity. Conclusions: Most patients who replied to our survey reported successful return to sports and recreational activities after arthroplasty of the basal joint of the thumb. Type of study/level of evidence: Prognostic IV.

Land cover changes across Greenland dominated by a doubling of vegetation in three decades.

Land cover responses to climate change must be quantified for understanding Arctic climate, managing Arctic water resources, maintaining the health and livelihoods of Arctic societies and for sustainable economic development. This need is especially pressing in Greenland, where climate changes are amongst the most pronounced of anywhere in the Arctic. Ice loss from the Greenland Ice Sheet and from glaciers and ice caps has increased since the 1980s and consequently the proglacial parts of Greenland have expanded rapidly. Here we determine proglacial land cover changes at 30 m spatial resolution across Greenland during the last three decades. Besides the vastly decreased ice cover (- 28,707 km2 ± 9767 km2), we find a doubling in total areal coverage of vegetation (111% ± 13%), a quadrupling in wetlands coverage (380% ± 29%), increased meltwater (15% ± 15%), decreased bare bedrock (- 16% ± 4%) and increased coverage of fine unconsolidated sediment (4% ± 13%). We identify that land cover change is strongly associated with the difference in the number of positive degree days, especially above 6 °C between the 1980s and the present day. Contrastingly, absolute temperature increase has a negligible association with land cover change. We explain that these land cover changes represent local rapid and intense geomorphological activity that has profound consequences for land surface albedo, greenhouse gas emissions, landscape stability and sediment delivery, and biogeochemical processes.

Preoperative Anemia and Postoperative Outcomes in Cardiac Surgery: A Mediation Analysis Evaluating Intraoperative Transfusion Exposures.

BACKGROUND: Preoperative anemia is associated with adverse outcomes in cardiac surgery, yet it remains unclear what proportion of this association is mediated through red blood cell (RBC) transfusions. METHODS: This is a historical observational cohort study of adults undergoing coronary artery bypass grafting or valve surgery on cardiopulmonary bypass at an academic medical center between May 1, 2008, and May 1, 2018. A mediation analysis framework was used to evaluate the associations between preoperative anemia and postoperative outcomes, including a primary outcome of acute kidney injury (AKI). Intraoperative RBC transfusions were evaluated as mediators of preoperative anemia and outcome relationships. The estimated total effect, average direct effect of preoperative anemia, and percent of the total effect mediated through transfusions are presented with 95% confidence intervals and P -values. RESULTS: A total of 4117 patients were included, including 1234 (30%) with preoperative anemia. Overall, 437 of 4117 (11%) patients went on to develop AKI, with a greater proportion of patients having preoperative anemia (219 of 1234 [18%] vs 218 of 2883 [8%]). In multivariable analyses, the presence of preoperative anemia was associated with increased postoperative AKI (6.4% [4.2%-8.7%] absolute difference in percent with AKI, P < .001), with incremental decreases in preoperative hemoglobin concentrations displaying greater AKI risk (eg, 11.9% [6.9%-17.5%] absolute increase in probability of AKI for preoperative hemoglobin of 9 g/dL compared to a reference of 14 g/dL, P < .001). The association between preoperative anemia and postoperative AKI was primarily due to direct effects of preoperative anemia (5.9% [3.6%-8.3%] absolute difference, P < .001) rather than mediated through intraoperative RBC transfusions (7.5% [-4.3% to 21.1%] of the total effect mediated by transfusions, P = .220). Preoperative anemia was also associated with longer hospital durations (1.07 [1.05-1.10] ratio of geometric mean length of stay, P < .001). Of this total effect, 38% (22%, 62%; P < .001) was estimated to be mediated through subsequent intraoperative RBC transfusion. Preoperative anemia was not associated with reoperation or vascular complications. CONCLUSIONS: Preoperative anemia was associated with higher odds of AKI and longer hospitalizations in cardiac surgery. The attributable effects of anemia and transfusion on postoperative complications are likely to differ across outcomes. Future studies are necessary to further evaluate mechanisms of anemia-associated postoperative organ injury and treatment strategies.

A Technique to Enable Efficient Adaptive Radiation Therapy: Automated Contouring of Prostate and Adjacent Organs.

Purpose: The purpose of this work was to investigate the use of a segmentation approach that could potentially improve the speed and reproducibility of contouring during magnetic resonance-guided adaptive radiation therapy. Methods and Materials: The segmentation algorithm was based on a hybrid deep neural network and graph optimization approach that also allows rapid user intervention (Deep layered optimal graph image segmentation of multiple objects and surfaces [LOGISMOS] + just enough interaction [JEI]). A total of 115 magnetic resonance-data sets were used for training and quantitative assessment. Expert segmentations were used as the independent standard for the prostate, seminal vesicles, bladder, rectum, and femoral heads for all 115 data sets. In addition, 3 independent radiation oncologists contoured the prostate, seminal vesicles, and rectum for a subset of patients such that the interobserver variability could be quantified. Consensus contours were then generated from these independent contours using a simultaneous truth and performance level estimation approach, and the deviation of Deep LOGISMOS + JEI contours to the consensus contours was evaluated and compared with the interobserver variability. Results: The absolute accuracy of Deep LOGISMOS + JEI generated contours was evaluated using median absolute surface-to-surface distance which ranged from a minimum of 0.20 mm for the bladder to a maximum of 0.93 mm for the prostate compared with the independent standard across all data sets. The median relative surface-to-surface distance was less than 0.17 mm for all organs, indicating that the Deep LOGISMOS + JEI algorithm did not exhibit a systematic under- or oversegmentation. Interobserver variability testing yielded a mean absolute surface-to-surface distance of 0.93, 1.04, and 0.81 mm for the prostate, seminal vesicles, and rectum, respectively. In comparison, the deviation of Deep LOGISMOS + JEI from consensus simultaneous truth and performance level estimation contours was 0.57, 0.64, and 0.55 mm for the same organs. On average, the Deep LOGISMOS algorithm took less than 26 seconds for contour segmentation. Conclusions: Deep LOGISMOS + JEI segmentation efficiently generated clinically acceptable prostate and normal tissue contours, potentially limiting the need for time intensive manual contouring with each fraction.

Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101).

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Effect of fasedienol (PH94B) pherine nasal spray and steroidal hormones on electrogram responses and autonomic nervous system activity in healthy adult volunteers.

OBJECTIVE: Fasedienol (PH94B) is a pherine compound formulated as a nasal spray that is hypothesized to regulate olfactory-amygdala circuits of fear and anxiety. Fasedienol's effect on the local electrogram of nasal chemosensory neurons (EGNR) and autonomic nervous system (ANS) responses versus steroidal hormones and controls in healthy adults is reported. METHODS: Eight males and 8 females randomly received aerosolized control (propylene glycol) and study drugs (fasedienol, 17ß-estradiol, progesterone, cortisol, and testosterone, 0.4 µg each in propylene glycol) onto the nasal septum mucosal lining at 30-min intervals over 2 sessions. EGNR was continuously monitored; autonomic parameters were recorded before and after administration. RESULTS: Fasedienol significantly increased EGNR amplitude (males: 5.0 vs. 0.6 mV, p < 0.001; females:5.7 vs. 0.6 mV, p < 0.001), and rapidly reduced respiratory rate (p < 0.05), heart rate (p < 0.01), and electrodermal activity (p < 0.05) versus control. EGNR and ANS responses after steroidal hormone administration were similar to control. 81% reported feeling less tense/more relaxed after receiving fasedienol, but not after receiving either control or steroidal hormones. CONCLUSIONS: Intranasal fasedienol, but not control or steroidal hormones, activated EGNR and rapidly reduced ANS responses, consistent with sympatholytic effects. Combined with subjective reports, results suggest fasedienol may provide acute relief in anxiety conditions.

Impact of Share 35 liver transplantation allocation in Australia and New Zealand.

Patients with high model for end-stage liver disease (MELD) scores waiting for liver transplantation in Australia and New Zealand (ANZ) have had limited access to deceased donor livers and therefore binational sharing of livers, for patients with a MELD score ≥35 was introduced in February 2016. Waiting list mortality, post-transplant outcomes and intention-to-treat survival were compared between patients whose MELD score reached 35 on the waiting list between October 2013 and April 2015 (Pre-Share 35 group, n = 23) and patients who were Share 35 listed between February 2016 and May 2022 (Share 35 group, n = 112). There was significantly reduced waiting list mortality in share 35 listed patients in comparison to the pre-Share 35 group (11.7% vs. 52.2%, OR .120 95% CI .044-.328, P < .001). Post-transplant patient and graft survival were not significantly different between the groups (5-year patient survival 82% vs. 84%, P = .991, 5-year graft survival 82% vs. 76%, P = .543). Intention-to-treat survival was superior in the Share 35 group (HR .302, 95% CI .149-.614, P < .001). Introduction of Share 35 in ANZ resulted in a 78% risk reduction in waiting list mortality, equivalent post-transplant survival and an improvement in intention-to-treat survival.

The effects of gonadal hormones on heroin Self-Administration in male gonadectomized rats.

RATIONALE: Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. OBJECTIVES: The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. METHODS: Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75 mg, sc), estradiol (0.0005 or 0.005 mg, sc), progesterone, (0.0125 or 0.125 mg, sc), or their vehicles. After 14 days of chronic treatment, a dose-effect curve was determined for heroin (0.0003-0.03 mg/kg/infusion) over the course of one week. RESULTS: Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125 mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. CONCLUSIONS: These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.