Temperature-induced mobility in octacalcium phosphate impacts crystal symmetry: water dynamics studied by NMR crystallography.

Octacalcium phosphate (OCP, Ca8(PO4)4(HPO4)2·5H2O) is a notable calcium phosphate due to its biocompatibility, making it a widely studied material for bone substitution. It is known to be a precursor of bone mineral, but its role in biomineralisation remains unclear. While the structure of OCP has been the subject of thorough investigations (including using Rietveld refinements of X-ray diffraction data, and NMR crystallography studies), important questions regarding the symmetry and H-bonding network in the material remain. In this study, it is shown that OCP undergoes a lowering of symmetry below 200 K, evidenced by 1H, 17O, 31P and 43Ca solid-state NMR experiments. Using ab initio molecular-dynamics (MD) simulations and gauge including projected augmented wave (GIPAW) DFT calculations of NMR parameters, the presence of rapid motions of the water molecules in the crystal cell at room temperature is proved. This information leads to an improved description of the OCP structure at both low and ambient temperatures, and helps explain long-standing issues of symmetry. Remaining challenges related to the understanding of the structure of OCP are then discussed.

Rural service coordination programming for women using substances and their families.

BACKGROUND: Women experiencing substance use during their pregnancies or after the birth of a child report being fearful of losing their children based on care, stigmatized when seeking assistance, and barriers to care such as having to provide the same information to different providers, and having to repeat their lived experiences with substance use in detail. Particularly these service barriers can be confusing, complicated, and difficult to follow, which could lead to non-compliance or not seeking services. OBJECTIVES: We evaluated components of a service coordination program for women experiencing substance use, their children, and larger families who help with caregiving. We examined stakeholder interest in the program, feasibility providing services over time, and initial program effectiveness. DESIGN: Participant enrollment and outcomes as well as service coordination activities provided over a 4-year period was gathered across three demonstration site locations (a birthing hospital, reunification program, and home visiting program). METHODS: Program information was gathered from needs assessment data, health survey data from enrolled caregivers and infants, training evaluations, and budget recordings of direct aid. In this mixed method design, we examined potential differences between baseline and the last assessment for women and children enrolled in the program. We also utilized univariate analyses of variance to examine the main effects of maternal and infant characteristics on final maternal and infant outcomes. RESULTS: Three sites enrolled 182 women and families for program services. Patient navigators provided direct aid, training, goal setting, and service coordination and planning. Families remained in the program, on average, 655 days and were satisfied with the services received. Respondents thought the program elements were easy to implement within the rural setting. The program effectively addressed basic needs, violence (p < 0.001; η2 = 0.34 (0.05-0.53)), infant development (p < 0.02; η2 = 0.51 (0.13-0.61)), and maternal depression (p < 0.05; η2 = 0.9 (0.00-0.22)). Select outcomes did differ by site. CONCLUSION: A service coordination model utilizing a patient navigator role to coordinate client services coupled with an approach that serves the infant and caregiver needs was feasible and desirable by all stakeholders within a rural setting. Service coordination effectively impacted select caregiver and infant outcomes.

Study using various reports from women who have, or still are, using substances, their family members, and providers about a service coordination structure designed to complement existing services for women and families in the rural setting.Why was the study done? Services for women who have, or still use, substances and their families are limited in rural settings. When they do exist, they are often disjointed, duplicative, and difficult to navigate. We hypothesized that a service coordination program with a key role available to help families navigate services would improve caregiver and family outcomes in many areas.What did the researchers do? The research team identified specific services offered in one program over the past five years. The program was given to women and families who had infants two years or younger and lived in rural communities. Caregivers and providers offered feedback about their experiences in the program. Caregiver and infant health were assessed and used to see if the program had a positive impact.What did researchers find? 182 families successfully enrolled in the program and stayed involved for an average of two years. Families and providers thought the program was easy to provide and navigate. They valued the role of the patient navigator and money offered to pay for essentials, if needed, was thought to be a key benefit, especially during COVID.What do the findings mean? Families may experience greater benefits from services if they have support for daily needs, when crises occur, someone to help navigate multiple services, and access to information when needed. These services are easy to provide and could be offered in rural communities.

Sol-moiety: Discovery of a water-soluble prodrug technology for enhanced oral bioavailability of insoluble therapeutics.

Though conceptually attractive, the use of water-soluble prodrug technology to enhance oral bioavailability of highly insoluble small molecule therapeutics has not been widely adopted. In large part, this is due to the rapid enzymatic or chemical hydrolysis of prodrugs within the gastrointestinal tract, resulting in drug precipitation and no overall improvement in oral bioavailability relative to standard formulation strategies. We reasoned that an optimal water-soluble prodrug could be attained if the rate of prodrug hydrolysis were reduced to favor drug absorption rather than drug precipitation. In doing so, the rate of hydrolysis provides a pharmacokinetic control point for drug delivery. Herein, we report the discovery of a water-soluble promoiety (Sol-moiety) technology to optimize the oral bioavailability of highly insoluble small molecule therapeutics, possessing various functional groups, without the need for sophisticated, often toxic, lipid or organic solvent-based formulations. The power of the technology is demonstrated with marked pharmacokinetic improvement of the commercial drugs enzalutamide, vemurafenib, and paclitaxel. This led to a successful efficacy study of a water-soluble orally administered prodrug of paclitaxel in a mouse pancreatic tumor model.

Assessment of Perioperative Protamine Reactions in Patients With Fish Allergies: A Retrospective Observational Study.

OBJECTIVES: To retrospectively assess the incidence and severity of perioperative protamine reactions in adult patients with documented history of fish allergy. DESIGN: Retrospective observational study. SETTING: Large academic tertiary referral center. PARTICIPANTS: Adults with fish allergies undergoing surgeries involving protamine, between January 1, 2008, and March 1, 2018. INTERVENTIONS: Perioperative protamine administration in patients with documented fish allergy. MEASUREMENTS AND MAIN RESULTS: Perioperative protamine and anaphylactic reactions were reviewed. A diagnosis of anaphylaxis or protamine reaction was based on clinical suspicion, perioperative events, and postoperative evaluations. Among 214 patients, 2 cases (<1%) of anaphylaxis or protamine reactions occurred. Cardiac procedures were most common (67%). The median intraoperative heparin dosage was 46,000 IU, and the median protamine dosage was 310 mg. Nearly all patients (99%) were admitted to the intensive care unit postoperatively, with a median hospital stay of 6.5 days (interquartile range, 5.2-14.6 days). There were 3 deaths (1%) within 30 days, and 15 (7%) within 1 year. CONCLUSIONS: The study findings suggest that in patients with a history of fish allergy, cross-reactivity with protamine is unlikely, as anaphylaxis and/or protamine reactions were rare in this patient population in the perioperative environment. Based on these findings, this study does not recommend avoiding protamine solely based on a history of fish allergy when heparin reversal is required during surgery.

Effects of xylazine on naloxone-precipitated fentanyl withdrawal in male and female rats.

PURPOSE: The combination of fentanyl and xylazine (i.e., "tranq-dope") was recently declared an emerging national health threat in the United States. Given the recency of this development, very little is known regarding the behavioral pharmacology of fentanyl-xylazine combinations. The purpose of this study was to characterize the somatic and affective withdrawal symptoms of this drug combination. METHODS: Male and female Long Evans rats were given twice daily (08:00 and 20:00) subcutaneous injections of fentanyl, xylazine, or combined fentanyl-xylazine for five days. On the sixth (testing) day, rats were given a final injection at 08:00. Four hours later, rats were injected intraperitoneally with either saline or a naloxone challenge before behavioral observation. Somatic withdrawal was examined using the Gellert-Holtzman scale and anxiety-like behavior was examined using the elevated plus maze. RESULTS: Naloxone administration did not induce somatic or affective symptoms in rats treated with fentanyl alone, a low dose of xylazine alone, or a high dose of xylazine alone. Naloxone induced somatic but not affective withdrawal symptoms in rats treated with both fentanyl and xylazine. CONCLUSION: Chronic co-exposure to fentanyl and xylazine produces an opioid-like somatic withdrawal syndrome at doses that are not apparent with either drug alone. These results corroborate clinical reports that xylazine worsens fentanyl withdrawal and suggest that novel interventions may be required to treat withdrawal from fentanyl-xylazine combinations in humans.

Sensitivity of Mild Hydrothermal Synthesis to the Reaction Conditions: Targeting Mixed-Metal Hexagonal Tungsten Bronze Fluorides AxM2+xM3+(1-x)F3 to Investigate Their Magnetic Behavior.

The synthesis of five quaternary hexagonal tungsten bronze (HTB) fluorides, AxM2+xM3+(1-x)F3, (A = Cs and Rb; M2+ = Co2+, Ni2+, and Zn2+; and M3+ = V3+) via a mild hydrothermal route is reported. The crystal structures and compositions were determined using a combination of single-crystal X-ray diffraction, Rietveld refinement of powder X-ray diffraction data, and inductively coupled plasma optical emission spectroscopy analysis. This study highlights the sensitivity of the mild hydrothermal method on the reaction temperature, solvent system, and quantity of starting reagents that directly influence the selective synthesis of kinetically stabilized fluoride materials, including hydrated fluorides, ß-pyrochlores, and HTB. The magnetic susceptibility and isothermal magnetization data for all five compounds were collected, which revealed the existence of a strong antiferromagnetic component in these phases. The presence of the Kagome layer in the structure results in geometrical frustration and leads to frustration indexes ranging from 7 to 13 for these compounds.

Inhalation of SP-101 Followed by Inhaled Doxorubicin Results in Robust and Durable hCFTRΔR Transgene Expression in the Airways of Wild-Type and Cystic Fibrosis Ferrets.

Cystic fibrosis (CF) is a serious genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approved small molecule therapies benefit the majority of people with CF (pwCF), but unfortunately not all. Gene addition offers a mutation agnostic treatment option for all pwCF. SP-101 is an adeno-associated virus gene therapy vector (AAV2.5T) that has been optimized for efficient human airway cell transduction, and that contains a functional and regulated shortened human CFTR minigene (hCFTRΔR) with a small synthetic promoter/enhancer. To understand SP-101 airway distribution, activity, and the associated immune response, in vivo studies were performed in wild-type and CF ferrets. After single dose inhaled delivery of SP-101, followed by single dose inhaled doxorubicin (an AAV transduction augmenter) or saline, SP-101 vector genomes were detected throughout the respiratory tract. hCFTRΔR mRNA expression was highest in ferrets also receiving doxorubicin and persisted for the duration of the study (13 weeks). Pre-existing mucus in the CF ferrets did not present a barrier to effective transduction. Binding and neutralizing antibodies to the AAV2.5T capsid were observed regardless of doxorubicin exposure. Only a portion of ferrets exhibited a weak T-cell response to AAV2.5T and no T-cell response was seen against hCFTRΔR. These data strongly support the continued development of inhaled SP-101, followed by inhaled doxorubicin, for the treatment of CF.

SP-101, A Novel Adeno-Associated Virus Gene Therapy for the Treatment of Cystic Fibrosis, Mediates Functional Correction of Primary Human Airway Epithelia From Donors with Cystic Fibrosis.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation-agnostic option for treatment. SP-101 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a human CFTR minigene, hCFTRΔR, and is being investigated as an inhalation treatment for people with CF. To further understand SP-101 activity, in vitro studies were performed in human airway epithelia (HAE) derived from multiple CF and non-CF donors. SP-101 restored CFTR-mediated chloride conductance, measured via Ussing chamber assay, at a multiplicity of infection (MOI) as low as 5E2 in the presence of doxorubicin, a small molecule known to augment AAV transduction. Functional correction of CF HAE increased with increasing MOI and doxorubicin concentration and correlated with increasing cell-associated vector genomes and hCFTRΔR mRNA expression. Tropism studies using a fluorescent reporter vector and single-cell mRNA sequencing of SP-101-mediated hCFTRΔR mRNA demonstrated broad expression in all cell types after apical transduction, including secretory, ciliated, and basal cells. In summary, SP-101, particularly in combination with doxorubicin, shows promise for a novel CF treatment strategy and strongly supports continued development.

Embracing Robotics in Microsurgery: Robotic-Assisted Deep Inferior Epigastric Perforator Flap Breast Reconstruction.

The integration of robotic-assisted surgery (RAS) has transformed various surgical disciplines, including more recently plastic surgery. While RAS has gained acceptance in multiple specialties, its integration in plastic surgery has been gradual, challenging traditional open methods. Robotic-assisted deep inferior epigastric perforator (DIEP) flap breast reconstruction is a technique aimed at overcoming drawbacks associated with the traditional open DIEP flap approach. These limitations include a relatively large fascial incision length, potentially increasing rates of postoperative pain, abdominal bulge, hernia rates, and core weakening. The robotic-assisted DIEP flap technique emerges as an innovative and advantageous approach in fascial-sparing abdominal autologous breast reconstruction. While acknowledging certain challenges such as increased operative time, ongoing refinements are expected to further improve the overall surgical experience, optimize results, and solidify the role of robotics in advancing reconstructive microsurgical procedures in plastic surgery. Herein, the authors provide an overview of robotic surgery in the context of plastic surgery and its role in the DIEP flap harvest for breast reconstruction.

Presence of postlaryngectomy pseudodiverticulum on barium swallow does not affect early dietary progression.

BACKGROUND: The presence of a pseudodiverticulum of the anterior pharyngeal wall, or prominent "pharyngeal bar," is a well-known phenomenon that occurs following total laryngectomy, which can be visualized by nasolaryngoscopy or videofluoroscopy. Among the different techniques of pharyngeal reconstruction, there is higher incidence following primary vertical multilayered closure. It has been postulated to cause dysphagia and lack of dietary progression despite a paucity of data. However, the direct impact of pseudodiverticulum is less clear and anecdotally its presence and severity does not necessarily correlate with dysphagia. METHODS: A retrospective case series was performed of all consecutive patients who underwent total laryngectomy or laryngopharyngectomy between 2015 and 2022 at two tertiary head and neck institutions. All patients underwent routine videofluoroscopy postoperatively for swallow assessment. The presence of pseudodiverticulum on postoperative contrast swallow study was recorded to investigate the relationship with patient's ability to tolerate oral intake at 3 months discharge from the hospital. RESULTS: Of 50 laryngectomized patients (mean age 63.8 ± 10.0, 86% male), the main closure techniques were primary vertical (n = 9, 18%), primary T-closure (n = 14, 28%), and flap reconstruction (n = 27, 54%). Pseudodiverticulum was identified in 19 cases (38%). 43 patients underwent primary surgery and 30 had adjuvant radiotherapy. The presence of pseudodiverticulum was significantly associated with vertical primary closure versus non-vertical (T-closure or flap reconstruction) techniques (χ2 (df 1) = 7.4, p = 0.007, OR = 5.7, 95% CI 1.3-24.7). Pseudodiverticulum was not associated with an increased inability to tolerate solid intake or full diet compared to patients without pseudodiverticulum. 26.3% of patients with pseudodiverticulum were on full diet compared to 25.8% of patients without. The vertical closure technique showed no difference in ability to maintain solid intake compared with non-vertical closure; however, no patients were on full diet. Only one patient in the pseudodiverticulum group required surgical management during the study period for retention. CONCLUSION: The presence of a pseudodiverticulum does not appear to be significantly associated with a need for postoperative dietary modification. The authors postulate that postlaryngectomy dysphagia is multifactorial with sensorimotor aperistalsis of the pharynx and cricopharyngeal stenosis. While a pseudodiverticulum is a common phenomenon, patients did not require modification of diet at higher rates than those without, and they seldom require intervention.

Flux Synthesis of Alkaline-Earth Lanthanide Borates as Potential Nuclear Waste Forms.

Neodymium is typically considered the best surrogate for trivalent americium and can be used to identify Am3+ containing materials that are likely to form. We have explored the alkaline-earth lanthanide borate phase space using alkaline-earth halide/carbonate fluxes. This resulted in the synthesis of new compounds AE5Ln(BO3)4X (AE = Ca, Sr; Ln = Pr, Nd, Eu, Tb; X = Cl, Br) and AE3Ln2(BO3)4 (AE = Sr, Ba; Ln = Pr, Nd) as well as the synthesis of two compounds of Ba8Ln2(BO3)6(B2O5) (Ln = Eu, Tb) crystallizing in a new structure type. Ba8Ln2(BO3)6(B2O5) crystallizes in the space group P21/n with lattice parameters a = 8.6002(3) Å, b = 7.9245(3) Å, c = 17.6697(7) Å, and ß = 91.3560(10)° for the Eu analogue, and the structure contains isolated LnO8 polyhedra connected into a framework by BO3 and B2O5 units. The fluorescence emission spectra of AE5Ln(BO3)4X (AE = Ca, Sr; Ln = Eu, Tb; X = Cl, Br) and Ba8Ln2(BO3)6(B2O5) (Ln = Eu, Tb) are reported.

Redox-Active Carboranyl Diphosphine as an Electron and Proton Transfer Agent.

In this work, we report the first example of the PCET reactivity for a boron cluster compound, the zwitterionic nido-carboranyl diphosphonium derivative 7-P(H)tBu2-10-P(H)iPr2-nido-C2B10H10. This main-group reagent efficiently transfers two electrons and two protons to quinones to yield hydroquinones and regenerate a neutral closo-carboranyl diphosphine, 1-PtBu2-2-PiPr2-closo-C2B10H10. As we have previously reported the conversion of this closo-carboranyl diphosphine into the zwitterionic nido- derivative upon reaction with main group hydrides, the transformation reported herein represents a complete synthetic cycle for the metal-free reduction of quinones, with the redox-active carboranyl diphosphine scaffold acting as a mediator. The proposed mechanism of this reduction, based on pKa determination, electrochemical studies, and kinetic isotope effect determination, involves the electron transfer from the nido- cluster to the quinone coupled with the delivery of protons.

The positive reinforcing effects of cocaine and opposite-sex social contact: roles of biological sex and estrus.

RATIONALE: Preclinical studies report that drug use and social contact mutually influence the reinforcing effects of one another. Most of these studies have used same-sex dyads exclusively, and the role of factors related to biological sex and hormonal fluctuations are not well understood. OBJECTIVES: The purpose of this study was to examine the reinforcing effects of cocaine and social contact with an opposite-sex partner in male and female rats, and how these effects are modulated by ovarian hormones. METHODS: Male and female rats were trained in a nonexclusive choice procedure in which cocaine and social contact with an opposite-sex partner were simultaneously available on concurrent progressive ratio schedules of reinforcement. To examine the effects of ovarian hormones related to estrous cycling, Experiment 1 used naturally cycling, gonadally intact females, whereas Experiment 2 used ovariectomized females, and estrus was artificially induced with exogenous hormones. RESULTS: In both experiments, cocaine and social contact functioned as robust reinforcers, and there were no significant effects of biological sex or estrus status of the females. The positive reinforcing effects of both cocaine and social contact increased as a function of cocaine dose, indicating that contingent cocaine administration increases the reinforcing effects of social contact. CONCLUSIONS: These data suggest that cocaine use among opposite-sex partners may enhance factors that contribute to social bonding.

Closed-Loop Infraslow Brain-Computer Interface can Modulate Cortical Activity and Connectivity in Individuals With Chronic Painful Knee Osteoarthritis: A Secondary Analysis of a Randomized Placebo-Controlled Clinical Trial.

Introduction. Chronic pain is a percept due to an imbalance in the activity between sensory-discriminative, motivational-affective, and descending pain-inhibitory brain regions. Evidence suggests that electroencephalography (EEG) infraslow fluctuation neurofeedback (ISF-NF) training can improve clinical outcomes. It is unknown whether such training can induce EEG activity and functional connectivity (FC) changes. A secondary data analysis of a feasibility clinical trial was conducted to determine whether EEG ISF-NF training can significantly alter EEG activity and FC between the targeted cortical regions in people with chronic painful knee osteoarthritis (OA). Methods. A parallel, two-arm, double-blind, randomized, sham-controlled clinical trial was conducted. People with chronic knee pain associated with OA were randomized to receive sham NF training or source-localized ratio ISF-NF training protocol to down-train ISF bands at the somatosensory (SSC), dorsal anterior cingulate (dACC), and uptrain pregenual anterior cingulate cortices (pgACC). Resting state EEG was recorded at baseline and immediate post-training. Results. The source localization mapping demonstrated a reduction (P = .04) in the ISF band activity at the left dorsolateral prefrontal cortex (LdlPFC) in the active NF group. Region of interest analysis yielded significant differences for ISF (P = .008), slow (P = .007), beta (P = .043), and gamma (P = .012) band activities at LdlPFC, dACC, and bilateral SSC. The FC between pgACC and left SSC in the delta band was negatively correlated with pain bothersomeness in the ISF-NF group. Conclusion. The EEG ISF-NF training can modulate EEG activity and connectivity in individuals with chronic painful knee osteoarthritis, and the observed EEG changes correlate with clinical pain measures.

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, 134:4203-4212, 2024.

Identification of highly potent and selective HTRA1 inhibitors.

High temperature requirement A serine peptidase 1 (HTRA1) is a serine protease involved in an array of signaling pathways. It is also responsible for the regulation of protein aggregates via refolding, translocation, and degradation. It has subsequently been found that runaway proteolytic HTRA1 activity plays a role in a variety of diseases, including Age-Related Macular Degeneration (AMD), osteoarthritis, and Rheumatoid Arthritis. Selective inhibition of serine protease HTRA1 therefore offers a promising new strategy for the treatment of these diseases. Herein we disclose structure-activity-relationship (SAR) studies which identify key interactions responsible for binding affinity of small molecule inhibitors to HTRA1. The study results in highly potent molecules with IC50's less than 15 nM and excellent selectivity following a screen of 35 proteases.

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.

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.

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.

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.