Mealybug Population Dynamics: A Comparative Analysis of Sampling Methods for Saccharicoccus sacchari and Heliococcus summervillei in Sugarcane (Saccharum sp. Hybrids).

This research is focused on a comparative field-based study of the population dynamics and sampling methods of two mealybug species, Saccharicoccus sacchari (Cockerell, 1895) (Hemiptera: Coccomorpha, Pseudococcidae) and Heliococcus summervillei (Brookes, 1978) (Hemiptera: Coccomorpha, Pseudococcidae), in sugarcane (Saccharum sp. hybrids) (f. Poaceae) over consecutive growing seasons. The research monitored and compared the above- and belowground populations and seasonal abundance of these two mealybug species in sugarcane fields in Far North Queensland, with non-destructive sampling techniques of yellow sticky traps, pan traps, and stem traps, and destructive sampling of the whole leaf and whole plant. The results indicated that S. sacchari (n = 29,137) was more abundant and detected throughout the growing season, with population peaks in the mid-season, while H. summervillei (n = 2706) showed peaks of the early-season activity. S. sacchari is primarily located on sugarcane stems and roots, compared to H. summervillei, which is located on leaves and roots. The whole-leaf collection and stem trap were the most effective sampling techniques for quantification of H. summervillei and S. sacchari, respectively. This study enhanced the understanding of S. sacchari and the first-ever record of H. summervillei on sugarcane in Australia and will contribute to the development of more effective pest management strategies.

High Nonunion and Amputations Rates With Either Early Intramedullary Nail Removal or Retention for Tibial Shaft Fracture-Related Infections.

OBJECTIVES: To compare debridement, antibiotics, and implant retention (DAIR) and intramedullary nail (IMN) removal with subsequent strategy for fracture stabilization in the treatment of tibia fracture-related infections (FRIs) occurring within 90 days of initial IMN placement. DESIGN: Retrospective case-control. SETTING: Four academic, Level 1 trauma centers. PATIENTS: Sixty-six patients who subsequently received unplanned operative treatment for FRI diagnosed within 90 days of initial tibia IMN. INTERVENTION: DAIR versus IMN removal pathways. MAIN OUTCOME MEASUREMENTS: Fracture union. RESULTS: Twenty-eight patients (42.4%) were treated with DAIR and 38 (57.6%) via IMN removal with subsequent strategy for fracture stabilization. Mean follow-up was 16.3 months. At final follow-up, ultimate bone healing was achieved in 75.8% (47/62), whereas 24.2% (15/62) had persistent nonunion or amputation. No significant difference was observed in ultimate bone healing ( P = 0.216) comparing DAIR and IMN removal. Factors associated with persistent nonunion or amputation were time from injury to initial IMN ( P < 0.001), McPherson systemic host grade B ( P = 0.046), and increasing open-fracture grade, with Gustilo-Anderson IIIB/IIIC fractures being the worst ( P = 0.009). Fewer surgeries after initial FRI treatment were positively associated with ultimate bone healing ( P = 0.029). CONCLUSIONS: Treatment of FRI within 90 days of tibial IMN with DAIR or IMN removal with subsequent strategy for fracture stabilization results in a high rate, nearly 1 in 4, of persistent nonunion or amputation, with neither appearing superior for improving bone healing outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Renewal of cocaine seeking using social and nonsocial contextual stimuli.

RATIONALE: Various nonsocial cues have been used as stimuli to examine the contextual control of drug seeking behavior, but little is known about the role of social stimuli. OBJECTIVES: This study determined if renewal of cocaine seeking is differentially controlled using a context consisting of either a social peer and/or house light illumination. METHODS: In Experiment 1, male and female rats trained to self-administer cocaine in the presence of a same-sex social peer and house light illumination (context A). Following self-administration, rats were randomly assigned to either an AAA (control) or ABA (renewal) group for extinction. For AAA rats, extinction consisted of the same context A as self-administration; for ABA rats, extinction occurred without the peer or house light (context B). Following extinction, renewal of cocaine seeking occurred by testing the peer alone, house light alone, and the peer + house light combination. Experiment 2 was conducted to ensure that the house light alone was sufficiently salient to produce renewal. RESULTS: Both experiments showed that rats acquired cocaine self-administration and extinguished lever pressing. In Experiment 1, the ABA group renewed cocaine seeking to the peer and peer + house light, but not to the house light alone. In Experiment 2, ABA rats renewed cocaine seeking to the house light alone, indicating it was sufficiently salient to produce renewal. The AAA group did not show renewal in either experiment. CONCLUSION: Social peers serve as powerful stimuli that can overshadow nonsocial visual stimuli in the renewal of cocaine seeking.

Cell polarity signalling at the birth of multicellularity: What can we learn from the first animals.

The innovation of multicellularity has driven the unparalleled evolution of animals (Metazoa). But how is a multicellular organism formed and how is its architecture maintained faithfully? The defining properties and rules required for the establishment of the architecture of multicellular organisms include the development of adhesive cell interactions, orientation of division axis, and the ability to reposition daughter cells over long distances. Central to all these properties is the ability to generate asymmetry (polarity), coordinated by a highly conserved set of proteins known as cell polarity regulators. The cell polarity complexes, Scribble, Par and Crumbs, are considered to be a metazoan innovation with apicobasal polarity and adherens junctions both believed to be present in all animals. A better understanding of the fundamental mechanisms regulating cell polarity and tissue architecture should provide key insights into the development and regeneration of all animals including humans. Here we review what is currently known about cell polarity and its control in the most basal metazoans, and how these first examples of multicellular life can inform us about the core mechanisms of tissue organisation and repair, and ultimately diseases of tissue organisation, such as cancer.

Resporulation of Calcium Alginate Encapsulated Metarhizium anisopliae on Metham®-Fumigated Soil and Infectivity on Larvae of Tenebrio molitor.

Metarhizium anisopliae infects and kills a large range of insects and is a promising biocontrol agent to manage soil insects, such as wireworm in sweetpotato. The presence of other soil microbes, which exhibit competitive fungistasis, may inhibit the establishment of M. anisopliae in soil. Microbially depleted soil, for example, sterilized soil, has been shown to improve the resporulation of the fungus from nutrient-fortified M. anisopliae. Prior to planting, sweetpotato plant beds can be disinfected with fumigants, such as Metham®, to control soil-borne pests and weeds. Metham® is a broad-spectrum soil microbial suppressant; however, its effect on Metarhizium spp. is unclear. In the research presented here, fungal resporulation was examined in Metham®-fumigated soil and the infectivity of the resulting granule sporulation was evaluated on mealworm, as a proxy for wireworm. The fungal granules grown on different soil treatments (fumigated, field and pasteurized soil) resporulated profusely (for example, 4.14 × 107 (±2.17 × 106) conidia per granule on fumigated soil), but the resporulation was not significantly different among the three soil treatments. However, the conidial germination of the resporulated granules on fumigated soil was >80%, which was significantly higher than those on pasteurized soil or field soil. The resporulated fungal granules were highly infective, causing 100% insect mortality 9 days after the inoculation, regardless of soil treatments. The results from this research show that the fungal granules applied to soils could be an infective inoculant in sweetpotato fields in conjunction with soil fumigation. Additional field studies are required to validate these results and to demonstrate integration with current farming practices.

Testing and Optimizing Guided Thinking Tasks to Promote Physical Activity: Protocol for a Randomized Factorial Trial.

BACKGROUND: Insufficient physical activity is associated with various health risks; however, most current physical activity interventions have critical barriers to scalability. Delivering interventions via technology and identifying active and inert components in early-phase development are ways to build more efficient and scalable interventions. We developed a novel intervention to promote physical activity that targets 3 brief guided thinking tasks, separately and in combination, using brief audio recordings: (1) episodic future thinking (EFT), (2) positive affective imagery (PAI), and (3) planning. OBJECTIVE: The aim of this GeT (Guided Thinking) Active study is to optimize a scalable guided thinking intervention to promote physical activity using principles of the Multiphase Optimization Strategy (MOST). Mechanism-focused analyses will inform which components are optimal candidates for inclusion in an intervention package and which need refinement. METHODS: We will enroll 192 participants randomized to receive intervention components delivered via an audio recording that they will listen to prior to weekly in-lab physical activity sessions. Participants in the high dose conditions will also be instructed to listen to the audio recording 4 additional days each week. We will evaluate effects of the components on physical activity over 6 weeks in a 2 (EFT vs recent thinking) × 2 (PAI vs neutral imagery) × 2 (planning vs no planning) × 2 (dose: 5×/week vs 1×/week) full factorial randomized trial. RESULTS: The National Cancer Institute funded this study (R21CA260360) on May 13, 2021. Participant recruitment began in February 2022. Data analysis will begin after the completion of data collection. CONCLUSIONS: The GeT Active study will result in a scalable, audio-recorded intervention that will accelerate progress toward the full development of guided thinking interventions to promote physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT05235360; https://clinicaltrials.gov/ct2/show/NCT05235360. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40908.

Peer-induced cocaine seeking in rats: Comparison to nonsocial stimuli and role of paraventricular hypothalamic oxytocin neurons.

The purpose of this study was to determine if social vs nonsocial cues (peer vs light/tone) can serve as discriminative stimuli to reinstate cocaine seeking. In addition, to assess a potential mechanism, an oxytocin (OT) promoter-linked hM3Dq DREADD was infused into the paraventricular nucleus of the hypothalamus to determine whether peer-induced cocaine seeking is decreased by activation of OT neurons. Male rats underwent twice-daily self-administration sessions, once with cocaine in the presence of one peer (S+) and once with saline in the presence of a different peer (S-). Another experiment used similar procedures, except the discriminative stimuli were nonsocial (constant vs flashing light/tone), with one stimulus paired with cocaine (S+) and the other paired with saline (S-). A third experiment injected male and female rats with OTp-hM3Dq DREADD or control virus into PVN and tested them for peer-induced reinstatement of cocaine seeking following clozapine (0.1 mg/kg). Although acquisition of cocaine self-administration was similar in rats trained with either peer or light/tone discriminative stimuli, the latency to first response was reduced by the peer S+, but not by the light/tone S+. In addition, the effect of the conditioned stimulus was overshadowed by the peer S+ but not by the light/tone S+. Clozapine blocked the effect of the peer S+ in rats receiving the OTp-hM3Dq DREADD virus, but not in rats receiving the control virus. These results demonstrate that a social peer can serve as potent trigger for drug seeking and that OT in PVN modulates peer-induced reinstatement of cocaine seeking.

Involvement of the ghrelin system in the maintenance of oxycodone self-administration: converging evidence from endocrine, pharmacologic and transgenic approaches.

Ghrelin, an orexigenic hormone, has emerged as a critical biological substrate implicated in drug reward. However, the response of the ghrelin system to opioid-motivated behaviors and the role of ghrelin in oxycodone self-administration remain to be studied. Here, we investigated the reciprocal interactions between the endogenous ghrelin system and oxycodone self-administration behaviors in rats and the role of the ghrelin system in brain stimulation reward (BSR) driven by optogenetic stimulation of midbrain reward circuits in mice. Oxycodone self-administration significantly elevated plasma ghrelin, des-acyl ghrelin and growth hormone and showed no effect on plasma LEAP2, a newly identified endogenous ghrelin receptor (GHS-R1a) antagonist. Oxycodone self-administration produced significant decreases in plasma gastric inhibitory polypeptide and insulin. Acquisition of oxycodone self-administration significantly upregulated GHS-R1a mRNA levels in dopamine neurons in the ventral tegmental area (VTA), a brain region critical in drug reward. Pretreatment with JMV2959, a selective GHS-R1a antagonist, dose-dependently reduced oxycodone self-administration and decreased the breakpoint for oxycodone under a progressive ratio reinforcement in Long-Evans rats. The inhibitory effects of JMV2959 on oxycodone self-administration is selectively mediated by GHS-R1a as JMV2959 showed a similar effect in Wistar wildtype but not in GHS-R knockout rats. JMV2959 pretreatment significantly inhibited BSR driven by selective stimulation of VTA dopamine neurons, but not by stimulation of striatal GABA neurons projecting to the VTA in mice. These findings suggest that elevation of ghrelin signaling by oxycodone or oxycodone-associated stimuli is a causal process by which oxycodone motivates oxycodone drug-taking and targeting the ghrelin system may be a viable treatment approach for opioid use disorders.

Topical Oral and Intranasal Antiviral Agents for Coronavirus Disease 2019 (COVID-19).

With the largest viral loads in both symptomatic and asymptomatic patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) present in the oral and nasal cavities, agents that act on these two areas have the potential for large therapeutic and prophylactic benefit. A literature review was conducted to elucidate the possible agents useful in treatment of SARS-CoV-2. These agents were evaluated for their current applications, adverse reactions, their current state of study, and any future considerations in their management of coronavirus disease 2019 (COVID-2019). Our review has found that, while there are many promising agents with proven efficacy in their in-vitro efficacy against SARS-CoV-2, more clinical trials and in-vivo studies, as well as safety trials, must be conducted before these agents can be effectively implemented.

Optogenetic brain-stimulation reward: A new procedure to re-evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter-Cre mice.

Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self-stimulation (ICSS) (oICSS) to re-examine the abuse potential of cannabinoids in mice. A specific adeno-associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light-sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)-Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical "sigmoidal"-shaped stimulation-response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose-dependently enhanced oICSS and shifted stimulation-response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ9 -tetrahydrocannabinol (Δ9 -THC), but not cannabidiol, dose-dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212-2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose-dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR-11 produced a cocaine-like increase, AM-2201 produced a Δ9 -THC-like reduction, while 5F-AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB1 Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2 Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB1 R and/or CB2 R in different populations of neurons in the brain may underlie the observed actions.

Transmission of Metarhizium anisopliae and Beauveria bassiana to adults of Kuschelorhynchus macadamiae (Coleoptera: Curculionidae) from infected adults and conidiated cadavers.

Kuschelorhynchus macadamiae is a major pest of macadamias in Australia, causing yield losses of up to 15%. Our previous studies have shown the weevil is susceptible to Beauveria bassiana and Metarhizium anisopliae. The aim of this study was to investigate horizontal transmission of both fungal species to healthy weevils from both infected adults and weevil cadavers. In a confined environment the mortality of healthy adults caused by the transmission of conidia from live fungus-infected adults was < 50%. Under similar experimental conditions, the mortality of healthy adults reached 100% when exposed to conidiated cadavers. However, when conidiated cadavers were used in more spacious environments (insect cages), the mortality of adults was < 80%. Using scanning electron microscopy, it was observed that all healthy adults had conidia attached to all external parts of the body. This suggests that although the conidia were readily transferred to the adults, the lower mortality in the larger insect cages could be the result of an unfavourable environmental factor such as low humidity. The presence of conidia attached to all the adults indicated that they did not show any discriminatory behaviour such as avoidance of conidiated cadavers infected by these two fungal species. The results from this study show that there is potential for enhanced control of adult K. macadamiae via transmission from either fungus-infected adults or conidiated cadavers and this could strengthen sustainable pest management in macadamias.

Virtual Interviews at Graduate Medical Education Training Programs: Determining Evidence-Based Best Practices.

The COVID-19 pandemic has had a profound impact on the nation's health care system, including on graduate medical education (GME) training programs. Traditionally, residency and fellowship training program applications involve in-person interviews conducted on-site, with only a minority of programs offering interviews remotely via a virtual platform. However, in light of the COVID-19 pandemic, it is anticipated that most interviews will be conducted virtually for the 2021 application cycle and possibly beyond. Therefore, GME training programs need to prepare for the transition to virtual interviews using evidence-based practices. At the University of California, San Francisco, a multidisciplinary task force was convened to review existing literature about virtual interviews and determine best practices. This article summarizes these findings, first discussing the advantages and disadvantages of the virtual interview format and then providing evidence-based best practices for GME training programs. Specifically, the authors make the following recommendations: develop a detailed plan for the interview process, consider using standardized interview questions, recognize and respond to potential biases that may be amplified with the virtual interview format, prepare your own trainees for virtual interviews, develop electronic materials and virtual social events to approximate the interview day, and collect data about virtual interviews at your own institution. With adequate preparation, the virtual interview experience can be high yield, positive, and equitable for both applicants and GME training programs.

Integration of Entomopathogenic Fungi into IPM Programs: Studies Involving Weevils (Coleoptera: Curculionoidea) Affecting Horticultural Crops.

Weevils are significant pests of horticultural crops and are largely managed with insecticides. In response to concerns about negative impacts of synthetic insecticides on humans and the environment, entomopathogenic fungi (EPF) have been developed as an alternative method of control, and as such appear to be "ready-made" components of integrated pest management (IPM) programs. As the success of pest control requires a thorough knowledge of the biology of the pests, this review summarises our current knowledge of weevil biology on nut trees, fruit crops, plant storage roots, and palm trees. In addition, three groups of life cycles are defined based on weevil developmental habitats, and together with information from studies of EPF activity on these groups, we discuss the tactics for integrating EPF into IPM programs. Finally, we highlight the gaps in the research required to optimise the performance of EPF and provide recommendations for the improvement of EPF efficacy for the management of key weevils of horticultural crops.

Mental Health and Self-Care Practices Among Dental Hygienists.

Purpose: Occupational stress and burn-out among dental hygienists may produce a decrease in overall mental health and well-being. The purpose of this study was to determine prevalence of mental health concerns as well as perceived stressors and self-care strategies among dental hygienists in Oregon.Methods: Dental hygienists belonging to the Oregon Dental Hygienists' Association were invited to participate in an electronic survey. The validated and pilot tested-survey consisted of 28 items that addressed experiences with stress, mental health issues and coping mechanisms. Descriptive and inferential statistics were used to analyze the data.Results: Of the email invitations that were successfully delivered (n=251), 83 dental hygienists volunteered to participate (n=83), for a 33% response rate. Difficulty maintaining work-life balance (35%, n=28), dysfunctional work teams (34%, n=28), and not enough time in the work schedule (65%, n=54) were the most common stressors. Respondents who worked ≥20 hours per week were more likely to attribute their daily stress primarily or entirely to work (p=0.009). Self-care methods included exercise, quiet time, spending time with loved ones, and self-care activities. Only 21% of respondents (n=17) reported that they received information or training on stress management and or burn-out in as part of their dental hygiene education.Conclusion: Symptoms linked to depression and anxiety are common among dental hygienists in Oregon. Stress management education and training should be incorporated in dental hygiene educational programs to prepare graduates to effectively manage the stressors that may lead to burn-out. Additional research should be conducted on a national level to gain a more representative sample.

Mathematical interventions for students with autism spectrum disorder: Recommendations for practitioners.

Students with extensive support needs (ESN; i.e., autism spectrum disorder, intellectual disability, or both), have the ability to learn a variety of mathematical skills when taught using scientifically validated strategies (e.g., Bouck, Satsangi, Taber-Doughty, & Courtney, 2014; Creech-Galloway, Collins, Knight, & Bausch, 2013; Root, Browder, Saunders, & Lo, 2017). The urgency of teaching grade-aligned, mathematical standards to this population has significantly increased in the past two decades. Yet, in order to teach grade-aligned mathematics to individuals with disabilities, teachers need access to scientifically validated strategies that can be effective with this heterogeneous population. This article extends work by Fleury and colleagues (2014) by expanding their findings of interventions to teach academic content to students with ASD. We hope practitioners can use this article as a starting point when selecting scientifically validated interventions to teach mathematics to students with ESN. We highlight mathematics interventions from a variety of recent literature reviews of mathematics interventions for students with ASD, ID, or both to provide guidance for practitioners of what we know works for which students under what conditions. This article also seeks to bridge research to practice by offering recommendations for math educators serving students with disabilities in heterogeneous classrooms.

Intranasal Antiviral Drug Delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review.

OBJECTIVE: To provide a state of the art review of intranasal antiviral drug delivery and to discuss current applications, adverse reactions, and future considerations in the management of coronavirus disease 2019 (COVID-19). DATA SOURCES: PubMed, Embase, and Clinicaltrials.gov search engines. REVIEW METHODS: A structured search of the current literature was performed of dates up to and including April 2020. Search terms were queried as related to topics of antiviral agents and intranasal applications. A series of video conferences was convened among experts in otolaryngology, infectious diseases, public health, pharmacology, and virology to review the literature and discuss relevant findings. CONCLUSIONS: Intranasal drug delivery for antiviral agents has been studied for many years. Several agents have broad-spectrum antiviral activity, but they still require human safety and efficacy trials prior to implementation. Intranasal drug delivery has potential relevance for future clinical trials in the settings of disease spread prevention and treatment of SARS-CoV-2 and other viral diseases. IMPLICATIONS FOR PRACTICE: Intranasal drug delivery represents an important area of research for COVID-19 and other viral diseases. The consideration of any potential adverse reactions is paramount.

Response of the macadamia seed weevil Kuschelorhynchus macadamiae (Coleoptera: Curculionidae) to Metarhizium anisopliae and Beauveria bassiana in laboratory bioassays.

Macadamia seed weevil, Kuschelorhynchus macadamiae Jennings and Oberprieler, is a major pest of macadamia in eastern Australia, causing yield losses of up to 15%. Current control methods involve two applications of acephate per season but more recently have moved to a single application of indoxacarb, combined with the collection and destruction of fallen nuts that contain developing larvae. As a first step towards reducing the dependence of the industry on synthetic insecticides, we tested six isolates of M. anisopliae, six isolates of B. bassiana and one commercial B. bassiana product (Velifer® biological insecticide) against adult macadamia seed weevil under laboratory conditions. All isolates were pathogenic against adult weevils with M. anisopliae accession ECS1/BRIP 70272 and B. bassiana accession B27/BRIP 70267 causing 97.5% and 92.5% mortality 12 days after being treated at 1 × 107 conidia/mL. Isolates ECS1/BRIP 70272 and B27/BRIP 70267 had the shortest LT50 values of 5.13 days and 5.37 days respectively. The median lethal concentrations (LC50) for ECS1/BRIP 70272 and B27/BRIP 70267 were 1.48 × 105 and 1.65 × 105 conidia/mL respectively. Results of this study indicate that M. anisopliae accession ECS1/BRIP 70272 and B. bassiana accession B27/BRIP 70267 have considerable potential for K. macadamiae control, and should be developed into biological insecticides for integration into macadamia pest management programs.

A new definition of gestational hypertension? New-onset blood pressures of 130 to 139/80 to 89 mm Hg after 20 weeks of gestation.

BACKGROUND: Diagnostic criteria for hypertensive disorders in pregnancy have historically been based on the American Heart Association and American College of Cardiology's definition of hypertension, previously defined as a blood pressure of ≥140/90 mm Hg. With the recent redefinition of hypertension, blood pressures of 130 to 139/80 to 89 mm Hg are now considered abnormal. OBJECTIVE: In this study, we aimed to test whether the new-onset blood pressure elevations of 130 to 139/80 to 89 mm Hg after 20 weeks of gestation in previously normotensive women are associated with increased risk for adverse pregnancy outcomes, specifically the development of hypertensive disorders in pregnancy. STUDY DESIGN: We performed a retrospective cohort study at a single tertiary care center of all women who delivered singleton gestations after 20 weeks of gestation from January 01, 2014, to June 08, 2016. Normotensive patients were defined as having maximum blood pressure of <130/80 mm Hg before 20 weeks of gestation and no previous diagnosis of chronic hypertension. Patients who remained normotensive for the remainder of pregnancy were then compared with patients who developed new-onset blood pressure elevations of 130 to 139/80 to 89 mm Hg after 20 weeks of gestation before delivery admission. The primary outcome was the development of a hypertensive disorder in pregnancy at hospital admission or during delivery. Clinical outcomes were assessed using χ2 test and multivariable logistic regression. RESULTS: Of the 2090 normotensive women from our cohort who were analyzed, 1318 (63.0%) remained normotensive for their entire antenatal course before delivery admission and 772 (37.0%) had new-onset blood pressure elevations between 130 and 139/80 and 89 mm Hg. Women with new-onset blood pressure elevations between 130 and 139/80 and 89 mm Hg after 20 weeks of gestation have a significantly increased risk for developing a hypertensive disorder in pregnancy at admission or during delivery (adjusted relative risk, 2.41; 95% confidence interval, 2.02-2.85) including an almost 3-fold increased risk for preeclampsia with severe features, even after adjusting for confounders. There were no differences in other secondary obstetrical outcomes. CONCLUSION: Normotensive women with new-onset blood pressures elevations between 130 and 139/80 and 89 mm Hg after 20 weeks of gestation are more likely to experience hypertensive disorders in pregnancy and preeclampsia with severe features at or during their delivery hospitalization. These more modest blood pressure elevations may be an early indicator of disease and call into question our current blood pressure threshold for diagnosis of hypertensive disorders in pregnancy.

Newly Developed Dopamine D3 Receptor Antagonists, R-VK4-40 and R-VK4-116, Do Not Potentiate Cardiovascular Effects of Cocaine or Oxycodone in Rats.

Opioid and cocaine abuse are major public health burdens. Existing medications for opioid use disorder are limited by abuse liability and side effects, whereas no treatments are currently approved in the United States for cocaine use disorder. Dopamine D3 receptor (D3R) antagonists have shown promise in attenuating opioid and cocaine reward and mitigating relapse in preclinical models. However, translation of D3R antagonists to the clinic has been hampered by reports that the D3R antagonists GSK598,809 (5-(5-((3-((1S,5R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)propyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)-4-methyloxazole) and SB-277,011A (2-(2-((1r,4r)-4-(2-oxo-2-(quinolin-4-yl)ethyl)cyclohexyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile) have adverse cardiovascular effects in the presence of cocaine. Recently, we developed two structurally novel D3R antagonists, R-VK4-40 and R-VK4-116, which are highly selective for D3R and display translational potential for treatment of opioid use disorder. Here, we tested whether R-VK4-40 ((R)-N-(4-(4-(2-Chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide) and R-VK4-116 ((R)-N-(4-(4-(3-Chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide) have unwanted cardiovascular effects in the presence of oxycodone, a prescription opioid, or cocaine in freely moving rats fitted with surgically implanted telemetry transmitters. We also examined cardiovascular effects of the D3R antagonist, SB-277,011A, and L-741,626 (1-((1H-indol-3-yl)methyl)-4-(4-chlorophenyl)piperidin-4-ol), a dopamine D2 receptor-selective antagonist, for comparison. Consistent with prior reports, SB-277,011A increased blood pressure, heart rate, and locomotor activity alone and in the presence of cocaine. L-741,626 increased blood pressure and heart rate. In contrast, R-VK4-40 alone dose-dependently reduced blood pressure and heart rate and attenuated oxycodone-induced increases in blood pressure and oxycodone or cocaine-induced increases in heart rate. Similarly, R-VK4-116 alone dose-dependently reduced cocaine-induced increases in blood pressure and heart rate. These results highlight the safety of new D3R antagonists and support the continued development of R-VK4-40 and R-VK4-116 for the treatment of opioid and cocaine use disorders. SIGNIFICANCE STATEMENT: Opioid and cocaine abuse are major public health challenges and new treatments that do not adversely impact the cardiovascular system are needed. Here, we show that two structurally novel dopamine D3 receptor antagonists, R-VK4-40 and R-VK4-116, do not potentiate, and may even protect against, oxycodone- or cocaine-induced changes in blood pressure and heart rate, supporting their further development for the treatment of opioid and/or cocaine use disorders.

Occurrence and diversity of entomopathogenic fungi (Beauveria spp. and Metarhizium spp.) in Australian vineyard soils.

Entomopathogenic Ascomycetes: Hypocreales fungi occur worldwide in the soil; however, the abundance and distribution of these fungi in a vineyard environment is unknown. A survey of Australian vineyards was carried out in order to isolate and identify entomopathogenic fungi. A total of 240 soil samples were taken from eight vineyards in two states (New South Wales and Victoria). Insect baiting (using Tenebrio molitor) and soil dilution methods were used to isolate Beauveria spp. and Metarhizium spp. from all soil samples. Of the 240 soil samples, 60% contained either Beauveria spp. (26%) or Metarhizium spp. (33%). Species of Beauveria and Metarhizium were identified by sequencing the B locus nuclear intergenic region (Bloc) and elongation factor-1 alpha (EFT1) regions, respectively. Three Beauveria species (B. bassiana, B. australis and B. pseudobassiana) and six Metarhizium species (M. guizhouense, M. robertsii, M. brunneum, M. flavoviride var. pemphigi, M. pingshaense and M. majus) were identified. A new sister clade made up of six isolates was identified within B. australis. Two potentially new phylogenetic species (six isolates each) were found within the B. bassiana clade. This study revealed a diverse community of entomopathogenic fungi in sampled Australian vineyard soils.