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Purpose The ACOSOG Z0011 (Z11) trial assessed the benefit of axillary dissection (ALND) for breast cancer patients with sentinel lymph node (SLN) metastases; however, Z11 excluded patients with ≥ 3 positive SLNs. We analyzed trends in ALND omission in patients with ≥ 3 positive SLNs. Methods Women with ≥ 3 positive SLNs who underwent breast-conserving surgery (BCS) or mastectomy between 2018–2020 in the National Cancer Database were included using SLN codes initiated in 2018. Patients with stage IV disease, recurrent breast cancer, and who underwent neoadjuvant chemotherapy were excluded. A multivariable logistic regression model was utilized to determine the proportion who received ALND and factors associated with ALND omission. A subgroup analysis was performed among patients who met the remainder of the Z11 inclusion criteria (BCS, T1/T2 breast cancer). Results We identified 3654 patients with ≥ 3 positive SLNs. ALND was omitted in 37% of patients, and omission significantly increased from 2018 to 2020 (29% vs 41%, p

Lizards and spiders are natural adversaries, yet little is known of adaptations that lizards might possess for dealing with the venomous defences of spider prey. In the Western USA, two lizard species ( Elgaria multicarinata and Sceloporus occidentalis ) are sympatric with and predate western black widow spiders ( Latrodectus hesperus ). The consequences of black widow spider venom (BWSV) can be severe, and are well understood for mammals but unknown for reptiles. We evaluated potential resistance to BWSV in the lizards that consume black widows, and a potentially susceptible species ( Uta stansburiana ) known as prey of widows. We investigated BWSV effects on whole-animal performance (sprint) and muscle tissue at two venom doses compared with control injections. Sprint speed was not significantly decreased in E. multicarinata or S. occidentalis in any treatment, while U. stansburiana suffered significant performance reductions in response to BWSV. Furthermore, E. multicarinata showed minimal tissue damage and immune response, while S. occidentalis and U. stansburiana exhibited increased muscle damage and immune system infiltration in response to BWSV. Our data suggest predator–prey relationships between lizards and spiders are complex, possibly leading to physiological and molecular adaptations that allow some lizards to tolerate or overcome the dangerous defences of their arachnid prey.

Family and twin studies demonstrate that genetic factors determine 20-60% of the vulnerability to opioid use disorder. However, the genes/alleles that mediate the risk of developing addiction-related behaviors, including the sensitivity to the analgesic efficacy of opioids, the development of tolerance, dependence, and escalation of oxycodone taking and seeking, have been ill-defined, thus hindering efforts to design pharmacological interventions to enable precision medicine strategies. Here we characterized oxycodone addiction-like behaviors in heterogeneous stock (HS) rats, that show high genetic diversity that mimics the high genetic variability in humans. HS rats were allowed to self-administer oxycodone for two h/daily for four days (ShA) and then moved to 12h/daily (LgA) for 14 days. Animals were screened for motivation to self-administer oxycodone using a progressive-ratio (PR) schedule of reinforcement and for the development of withdrawal-induced hyperalgesia and tolerance to the analgesic effects of oxycodone using the von-Frey and tail immersion tests, respectively. To reduce cohort-specific effects, we used cohorts of 46-60 rats and normalized the response level within cohorts using a Z-score. To take advantage of the four opioid-related behaviors and further identify subjects that are consistently vulnerable vs. resilient to compulsive oxycodone use, we computed an Addiction Index by averaging normalized responding (Z-scores) for the four behavioral tests. Results showed high individual variability between vulnerable and resilient rats, likely to facilitate the detection of gene variants associated with vulnerable vs. resilient individuals. Such data will have considerable translational value for designing follow-up studies in humans.

RationaleCurrent medications for opioid use disorder include buprenorphine, methadone, and naltrexone. While these medications show significant efficacy in reducing craving and opioid use, there are substantial individual differences in response to these treatments in humans. The reason for such difference is poorly known.ObjectivesHere, we tested the hypothesis that similar individual differences may be observed in a large population of heterogenous stock rats, that have been bred to maximize genetic diversity, using a behavioral paradigm relevant to opioid use disorder.MethodsOver 500 rats were given intermittent (4d/week) and extended access (12h/day) to oxycodone self-administration for 14 sessions to establish oxycodone dependence and escalation of intake. We then measured the effect of buprenorphine (0.5mg/kg), methadone (3mg/kg) and naltrexone (3mg/kg) on the motivation to self-administer oxycodone by using a progressive ratio schedule of reinforcement.ResultsWe found that naltrexone and buprenorphine significantly decreased motivation to oxycodone rewards. While naltrexone reduced oxycodone intake in both males and females, systemic administration with buprenorphine reduced progressive ratio responses only in males. Methadone reduced motivation to oxycodone self-administration in nearly 25% of the population, without reaching statical significance. Our results showed that the efficacy of these medications depends on the severity of addiction like behaviors, indicated by the addiction index.ConclusionsThese results demonstrate individual differences in response to medications to treat opioid use disorder in a genetically diverse population of rats.

Asymmetric surface acoustic waves have been shown useful in separating particles and cells in many microfluidics designs, mostly notably sessile microdroplets. However, no one has successfully extracted target particles or cells for later use from such samples. We present a novel omnidirectional spiral surface acoustic wave (OSSAW) design that exploits a new cut of lithium niobate, 152 Y-rotated, to rapidly rotate a microliter sessile drop to ∼10 g, producing efficient multi-size particle separation. We further extract the separated particles for the first time, demonstrating the ability to target specific particles, for example, platelets from mouse blood for further integrated point-of-care diagnostics. Within ∼5 s of surface acoustic wave actuation, particles with diameter of 5 μm and 1 μm can be separated into two portions with a purity of 83% and 97%, respectively. Red blood cells and platelets within mouse blood are further demonstrated to be separated with a purity of 93% and 84%, respectively. These advancements potentially provide an effective platform for whole blood separation and point-of-care diagnostics without need for micro or nanoscale fluidic enclosures.

Quasiracemates – materials consisting of pairs of near enantiomers – form crystalline motifs that mimic the inversion relationships observed for their racemic counterparts. Recent investigations from our group explored a family of chiral (N-benzoyl)methylbenzylamines to understand the structural boundary of cocrystallization. This investigation extends these earlier studies to include naphthylamide quasiracemates, where the molecular framework is ∼20% larger by volume than the previous diarylamides. A family of naphthylamides was prepared where the pendant functional group differs incrementally in size (i.e., H to C6H5) to give 55 possible unique pairs of racemic and quasiracemic combinations. Data collected from these materials using X-ray crystallography, thermal analysis methods and lattice energy calculations offer important insight into how a spatially larger naphthylamide molecular framework promotes greater structural variance of substituents during the pairwise assembly of quasienantiomers.

Lizards and spiders are natural adversaries, yet little is known of adaptations that lizards might possess for dealing with the venomous defenses of spider prey. In the Western USA, two lizard species (Elgaria multicarinata and Sceloporus occidentalis) are sympatric with and predate western black widow spiders (Latrodectus hesperus). The consequences of black widow spider venom (BWSV) can be severe, and are well understood for mammals but unknown for reptiles. We evaluated potential resistance to BWSV in the lizards that consume black widows, and a potentially susceptible species (Uta stansburiana) known as prey of widows. We investigated BWSV effects on whole-animal performance (sprint) and muscle tissue at two venom doses compared to control injections. Sprint speed was not significantly decreased in E. multicarinata or S. occidentalis in any treatment, while U. stansburiana suffered significant performance reductions in response to BWSV. Furthermore, E. multicarinata showed minimal tissue damage and immune response, while S. occidentalis and U. stansburiana exhibited increased muscle damage and immune system infiltration in response to BWSV. Our data suggest predator–prey relationships between lizards and spiders are complex, possibly leading to physiological and molecular adaptations that allow some lizards to tolerate or overcome the dangerous defenses of their arachnid prey.

Lizards and spiders are natural adversaries, yet little is known of adaptations that lizards might possess for dealing with the venomous defenses of spider prey. In the Western USA, two lizard species (Elgaria multicarinata and Sceloporus occidentalis) are sympatric with and predate western black widow spiders (Latrodectus hesperus). The consequences of black widow spider venom (BWSV) can be severe, and are well understood for mammals but unknown for reptiles. We evaluated potential resistance to BWSV in the lizards that consume black widows, and a potentially susceptible species (Uta stansburiana) known as prey of widows. We investigated BWSV effects on whole-animal performance (sprint) and muscle tissue at two venom doses compared to control injections. Sprint speed was not significantly decreased in E. multicarinata or S. occidentalis in any treatment, while U. stansburiana suffered significant performance reductions in response to BWSV. Furthermore, E. multicarinata showed minimal tissue damage and immune response, while S. occidentalis and U. stansburiana exhibited increased muscle damage and immune system infiltration in response to BWSV. Our data suggest predator–prey relationships between lizards and spiders are complex, possibly leading to physiological and molecular adaptations that allow some lizards to tolerate or overcome the dangerous defenses of their arachnid prey.

IntroductionSubstance use disorders (SUDs) take an enormous toll on US Veterans and civilians alike. Existing empirically supported interventions vary by substance and demonstrate only moderate efficacy. Non-invasive brain stimulation represents an innovative treatment for SUDs, yet aspects of traditional neurostimulation may hinder its implementation in SUD populations. Synchronised transcranial magnetic stimulation (sTMS) uses rotating rare earth magnets to deliver low-field stimulation synchronised to an individual’s alpha peak frequency that is safe for at-home administration. The current trial aims to assess the acceptability and feasibility of sTMS, as well as the safety of at-home sTMS administration for substance-disordered Veterans.Methods and analysisSixty Veterans in substance treatment at the Providence Veterans Affairs will be randomised to receive 6 weeks of active or sham sTMS treatment. Eligibility will be confirmed by meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for an alcohol, cocaine or opioid use disorder. Daily supervised sTMS treatment will occur either in clinic or at home through video monitoring. Clinical and self-report assessments will be completed at baseline, end of treatment and 1-month follow-up. Urine drug screening will occur once per week during the treatment phase. Primary outcomes include treatment adherence/retention and satisfaction to evaluate sTMS feasibility and acceptability in Veterans with SUDs. The safety of at-home sTMS administration will be assessed via adverse event monitoring.Ethics and disseminationThe sTMS device received a significant risk determination for at-home use by the Food and Drug Administration in July 2021. Ethics approval was obtained in August 2021 from the Providence Veterans Affairs institutional review board and research and development committee. Data collection began in September 2021 and is planned to continue through December 2023. Findings will be disseminated at national conferences and in peer-reviewed journals. Results will serve to inform the development of large-scale clinical trials of sTMS efficacy for substance-disordered Veterans.Trial registration numberClinicalTrials.gov Registry (NCT04336293).

520 Background: Patients with estrogen receptor (ER)- positive breast cancer and high-risk 21-gene recurrence score (RS) assay results benefit from chemotherapy, however some patients choose to decline chemotherapy. We evaluated factors associated with chemotherapy refusal by older women with high RS breast cancer and investigated the association of chemotherapy refusal with mortality. Methods: We used the National Cancer Database (2010-2017) to retrospectively identify women aged ≥65 years with ER-positive, HER2-negative, high RS (≥26) breast cancer. Women with Charlson Comorbidity Index ≥1, stage III or IV disease, or any unknown variables were excluded. Women with high RS who refused chemotherapy were compared to women with high RS who received chemotherapy. Refusal trends were analyzed using the Cochrane Armitage test. Factors associated with chemotherapy refusal were evaluated with a multivariable regression model. Overall survival (OS) by age and by treatment were evaluated with Kaplan-Meier and Cox proportional hazards modeling. Results: 6827 women met study criteria; 5449 (80%) received chemotherapy and 1378 (20%) refused. Relative to those who received chemotherapy, those who refused chemotherapy were older (median age 71 vs 69 years; p < 0.05), more often insured with Medicare (83% vs 80%; p = 0.05), were diagnosed more recently (2014-2017 vs 2010-2013, 67% vs 61%; p < 0.05), had lower grade tumors (grade 1 or 2 vs grade 3, 57% vs 48%; p < 0.05), more frequently had progesterone receptor-positive tumors (68% vs 63%; p < 0.05), and received radiation less frequently (67% vs 71%; p < 0.05). Chemotherapy refusal was significantly associated with increasing age (age 75-79 vs 65-74 OR 1.61, CI 1.4-1.85; age ≥80 vs 65-74 OR 3.24, CI 2.76-3.79) and more recent year of diagnosis (2014-2017 vs 2010-2013; OR 1.3 CI 1.14-1.48). Chemotherapy refusal was significantly associated with decreased 5-year OS for patients aged 65-74 years (92% vs 95%; p < 0.05) and patients aged 75-79 years (85% vs 92%; p < 0.05), but not for those aged ≥80 years (84% vs 91%; p = 0.07). Overall, when controlling for patient factors, hazard of death with chemotherapy refusal was significantly increased (HR 1.12, CI 1.04-1.2), but was not increased for women aged ≥80 years when stratified by age. Conclusions: Among healthy women aged ≥65 with high genomic risk ER-positive breast cancer, chemotherapy refusal increased with increasing age. Chemotherapy refusal was significantly associated with decreased OS in women aged 65-79, but did not impact OS in women aged ≥80. Lower use of chemotherapy in women ≥80 may demonstrate pragmatic decision-making between physicians and patients. Furthermore, the routine use of genomic assays may not be appropriate in this age group. More research is needed to determine why women aged 65-79 refuse chemotherapy, and whether patients remain satisfied with these choices.

Visual Abstract, The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc. Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.

BackgroundThe morbidity and mortality attributed to injecting drug use is a substantial contributor to any study on causes of premature death. Understanding the extent of this may be limited by difficulties in observing and recording outcomes over several decades. Historic studies have recorded information in a period when blood borne virus and drug deaths were a smaller proportion or, in the cases of Hepatitis C and HIV/AIDS, absent from National mortality figures.Design and settingA cohort of people who had, ever, injected drugs was established over a prolonged period of observation in one, community based, medical practice in Edinburgh (UK). Outcomes were measured in the clinical situation and by accessing death certificates from national, UK, registers.FindingsCauses of death in a cohort of 794 people who inject drugs (PWIDs) varied over time, some conditions relating to single pathological diagnoses and others were more complicated, multimorbid, and cumulative over time. HIV/AIDS was a striking cause of death until 1995 when antiviral chemotherapy was introduced. Drug related deaths (mainly overdose) remained a significant cause of death and death due to alcohol, respiratory, cardiovascular and cancer (mainly lung) increased over time. A wide range of other causes including suicide and violence and trauma were recorded.ConclusionsMortality resulting from present or historic drug use may be underestimated in current recoding systems, which largely record deaths from overdose or a single pathological event in an acute situation. The range of conditions causing or contributing to premature death is enormous reflecting multiple risks associated with drug use.

Background It is unclear whether the addition of chemoradiation (CRT) to adjuvant chemotherapy (CT) following upfront resection of pancreatic ductal adenocarcinoma (PDAC) provides any benefit. While some studies have suggested a benefit to combined modality therapy (CMT) (adjuvant CT plus CRT), it is not clear if this benefit was related to increased CT usage in patients who received CMT. We sought to clarify the use of CMT in patients who underwent upfront resection of PDAC. Methods Patients with non-metastatic PDAC were retrospectively identified from the linked SEER-Medicare database. Those who underwent upfront resection were identified and divided into two cohorts – patients who received adjuvant CT and patients who received adjuvant CMT. Cohorts were compared. Univariate analysis described patient characteristics. Kaplan-Meier and multivariable Cox proportional hazards modeling were used to estimate overall survival (OS). Results 3555 patients were identified; 856 (24%) received CT and 573 (16%) received CMT. The median number of CT doses was 11 for both groups. Patients who received CMT were younger, diagnosed in the earlier time frame, and had fewer comorbidities. The median OS was 21 months and 18 months for those treated with CMT and CT ( P < .0001), respectively, but when stratified by nodal status, the association with improved OS in the CMT cohort was only observed in node-positive patients. On multivariable analysis, receipt of CMT and removal of >15 lymph nodes decreased the risk of death ( P < .05). Discussion Receipt of CMT following upfront resection for PDAC was associated with improved survival, which was confined to node-positive patients. The role of adjuvant CMT in PDAC with nodal metastases warrants further study.

Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h–28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1–11d), and returned to pre-abstinence levels during protracted abstinence (17–27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naive (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8 h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse.

Studies in vitro and in vivo demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1–overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and membrane/lipid raft localization of postsynaptic density protein 95, NMDA receptor, and tropomyosin receptor kinase B. When subjected to a controlled cortical impact, SynCav1 Tg mice demonstrated preserved hippocampus-dependent fear learning and memory, improved motor function recovery, and decreased brain lesion volume compared with wild-type controls. Neuron-targeted overexpression of Cav-1 in the adult brain prevents hippocampus-dependent learning and memory deficits, restores motor function after brain trauma, and decreases brain lesion size induced by trauma. Our findings demonstrate that neuron-targeted Cav-1 can be used as a novel therapeutic strategy to restore brain function and prevent trauma-associated maladaptive plasticity.—Egawa, J., Schilling, J. M., Cui, W., Posadas, E., Sawada, A., Alas, B., Zemljic-Harpf, A. E., Fannon-Pavlich, M. J., Mandyam, C. D., Roth, D. M., Patel, H. H., Patel, P. M., Head, B. P. Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

The objective of this study was to evaluate the prevalence of two internal parasites (strongylate nematodes and Nematodirus spp.) in white-tailed deer (Odocoileus virginianus) sharing a home range with domestic sheep (Ovis aries), compared to deer likely having minimal contact with sheep. Fecal samples were collected from sheep (n=75), deer (n=99) within 300m of the sheep center, and deer (n=98) located 1.3km away from the livestock center, over a 7-week period during the summer. Sheep had the highest (p

The objective of this study was to evaluate two electric fence configurations in minimizing damage to impatiens (Impatiens walleriana) by white-tailed deer (Odocoileus virginianus). Each of 3 sites consisted of 3 plots (3mx3m), containing 16, evenly spaced impatiens planted on the perimeter of each plot. Plots within each site had a control, single strand and 2-layered electric fence. Control plots had no fencing. Single strand plots had one electrified wire attached to posts at 40 cm height, surrounding the plot. Two-layered electric fence had energized wire attached to posts at 25 cm and 60 cm height, on the perimeter of the plot. A second, single electrified wire was attached to posts at 25 cm height, 1 m to the exterior of the two strand fence. Eight plants within each plot was photographed weekly for 3-weeks. The percentage of total pixels containing plant material in each photo was used to determine changes in plant growth. The percentage of pixels containing impatiens plants was lower (p

Analyses of mammal remains from middle and late Holocene deposits in Floating Island Cave on the arid floor of the Bonneville basin in western North America are presented. Identified specimens consist of various desert mammals, especially leporids, which mirror collections from neighboring sites and provide additional data for one of the most comprehensive Holocene zoogeographic histories in the world. Taphonomic analyses identified large- and especially small-bodied mammal bones that were deposited by both human and non-human predators. Most horizons contained unusually high proportions of burned bones which are often viewed as unambiguous indicators of human subsistence activities. However, analyses of the cave’s deposits and the numbers and extent of burned bone indicate many specimens were charred in situ by post-depositional burning of the dry vegetal-rich fill. We employed abundance index measurements comparing artiodactyls against smaller leporids to investigate potential changes in human subsistence. We calculated two indices to illustrate the effects of non-human bone accumulations on abundance measures; one encompasses only specimens identified to genera and the other discounts scatological bones and other non-human accumulations and includes only bones and bone fragments classified as cultural refuse. When discounting the hundreds of leporid bones deposited by non-human vectors, the analyses show that the remains of leporids (especially hares [Lepus sp.]) are appreciably more abundant than artiodactyls, even during late Holocene periods of increased moisture. Given the dominance of Lepus in regional archaeological collections we argue that hares were not a low-ranked prey item but a low-risk dietary staple pursued throughout Holocene human occupation.

The therapeutic effects of wheel running (WR) during abstinence on reinstatement of ethanol seeking behaviors in rats that self-administered ethanol only (ethanol drinking, ED) or ED with concurrent chronic intermittent ethanol vapor experience (CIE-ED) were investigated. Neuronal activation as well as oligodendroglial and neuroinflammatory factors were measured in the medial prefrontal cortex (mPFC) tissue to determine cellular correlates associated with enhanced ethanol seeking. CIE-ED rats demonstrated escalated and unregulated intake of ethanol and maintained higher drinking than ED rats during abstinence. CIE-ED rats were more resistant to extinction from ethanol self-administration, however, demonstrated similar ethanol seeking triggered by ethanol contextual cues compared to ED rats. Enhanced seeking was associated with reduced neuronal activation, and increased number of myelinating oligodendrocyte progenitors and PECAM-1 expression in the mPFC, indicating enhanced oligodendroglial and neuroinflammatory response during abstinence. WR during abstinence enhanced self-administration in ED rats, indicating a deprivation effect. WR reduced reinstatement of ethanol seeking in CIE-ED and ED rats, indicating protection against relapse. The reduced ethanol seeking was associated with enhanced neuronal activation, reduced number of myelinating oligodendrocyte progenitors, and reduced PECAM-1 expression. The current findings demonstrate a protective role of WR during abstinence in reducing ethanol seeking triggered by ethanol contextual cues and establish a role for oligodendroglia-neuroinflammatory response in ethanol seeking. Taken together, enhanced oligodendroglia-neuroinflammatory response during abstinence may contribute to brain trauma in chronic alcohol drinking subjects and be a risk factor for enhanced propensity for alcohol relapse.

Neurite orientation dispersion and density imaging (NODDI) is an emerging magnetic resonance (MR) diffusion weighted imaging (DWI) technique that permits non-invasive quantitative assessment of neurite density and morphology. NODDI has improved our ability to image neuronal microstructure over conventional techniques such as diffusion tensor imaging (DTI) and is particularly suited for studies of the developing brain as it can measure and characterize the dynamic changes occurring in dendrite cytoarchitecture that are critical to early brain development. Neurodevelopmental alterations to the diffusion tensor have been reported in psychiatric illness, but it remains unknown whether advanced DWI techniques such as NODDI are able to sensitively and specifically detect neurodevelopmental changes in brain microstructure beyond those provided by DTI. We show, in an extension of our previous work with a Disc1 svΔ2 rat genetic model of psychiatric illness, the enhanced sensitivity and specificity of NODDI to identify neurodevelopmental and sex-specific changes in brain microstructure that are otherwise difficult to observe with DTI and further corroborate observed changes in brain microstructure to differences in sex-specific systems-level animal behavior. Together, these findings inform the potential application and clinical translational utility of NODDI in studies of brain microstructure in psychiatric illness throughout neurodevelopment and further, the ability of advanced diffusion weighted imaging methods such as NODDI to examine the role of biological sex and its influence on brain microstructure in psychiatric illness. SIGNIFICANCE STATEMENT This research presents the first demonstration of the ability of NODDI multicompartment diffusion imaging to uncover both neurodevelopmental and sex-specific alterations in brain microstructure in psychiatric illness. We show, in a genetic Disc1 svΔ2 rat model, sex-specific neurodevelopmental patterns of neural microstructural change with NODDI and corresponding evidence of sex differences in behavioral endophenotypes of anxiety, cognition, and general activity. Together, our results support the potential impact and translational utility of NODDI to identify salient neurodevelopmental and sex-specific changes in brain microstructure in psychiatric illness beyond traditional morphometric and diffusion tensor approaches currently employed.

This thesis presents the design and commissioning of a system to characterise the longitudinal beam properties of VELA (Versatile Electron Linear Accelerator) based around a transverse deflecting cavity, and the first measurements made using it. VELA at Daresbury Laboratory consists of an S-band RF photoinjector, which accelerates electrons to approximately 5 MeV/c. VELA was intended as the injector for the CLARA Free Electron Laser test facility. The gun is operated in the ``blow-out'' regime, driven by a laser of pulse length 76 fs rms, with the electron beam distribution formed by the space-charge of the bunch. The transverse deflecting cavity is a 9-cell standing wave S-band cavity and the design was intended to provide 10 fs temporal resolution for the 250 MeV beam from CLARA. This thesis shows how the design of the cavity evolved via beam dynamics simulations to reduce unwanted transverse beam offset and momentum change through the cavity. Bunch length measurements are presented using the deflecting cavity to characterise the ``blow-out'' regime of the gun at bunch charges from 40 fC to 215 pC, and as a function of gun phase and beam momentum. Investigations into measurements of the longitudinal phase space distribution of the beam are also presented.

The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats and neuronal excitability were evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males were associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII and choline acetyltransferase in the DG. Enhanced excitability in females were associated with increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs were associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors.

The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction.

Lower impulse control is a known risk factor for drug abuse vulnerability. Chronic experience with illicit drugs is suggested to enhance impulsivity and thereby perpetuate addiction. However, the nature of this relationship (directionality, causality) with regard to alcohol use disorder is unclear. The present study tested the hypothesis that higher impulsivity is observed during chronic intermittent ethanol vapor inhalation (CIE, a model of ethanol dependence) and subsequent abstinence from CIE in adult Wistar rats. Impulsivity was tested using a differential reinforcement of low rates 15 s (DRL15) schedule using either nondrug reward (palatable modified sucrose pellets) or sweetened ethanol. A decrease in the efficiency of earning reinforcers (expressed as % reinforcers/responses) is indicative of a decrease in response inhibition or an increase in impulsivity. The efficiency of reinforcement and amount of reinforcers earned were unaltered in CIE and control animals when the reinforcer was sucrose. When the reinforcer was sweetened ethanol, the efficiency of reinforcement increased in CIE rats compared with controls only during protracted abstinence. Responding for sweetened ethanol under a progressive-ratio schedule was more rapid in CIE rats during protracted abstinence. Contrary to the initial hypothesis, impulsivity did not increase in rats with a history of CIE, instead, it decreased when ethanol was used as the reinforcer. Furthermore, although the efficiency of ethanol reinforcement did not differ between CIE and control animals during CIE, CIE rats escalated the amount of sweetened ethanol consumed, suggesting that behavioral adaptations that are induced by CIE in rats that are tested under a DRL15 schedule appear to be targeted toward the maximization of ethanol intake and thus may contribute to escalation and relapse.

Effects of withdrawal from ethanol drinking in chronic intermittent ethanol vapor (CIE)-exposed dependent rats and air-exposed nondependent rats on proliferation and survival of progenitor cells in the hippocampus and the medial prefrontal cortex (mPFC) were investigated. Rats were injected with 5′-Bromo 2-deoxyuridine 72 h post-CIE to measure proliferation (2 h-old cells) and survival (29-day-old cells) of progenitors born during a time-point previously reported to elicit a proliferative burst in the hippocampus. Hippocampal and mPFC brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B receptor (TrkB) expression were measured 3 h or 21d post-CIE to evaluate neurotrophic signaling during a time point preceding the proliferative burst and survival of newly born progenitors. CIE rats demonstrated elevated drinking compared to nondependent rats and CIE rats maintained elevated drinking following protracted abstinence. Withdrawal from CIE increased BDNF levels in the hippocampus and mPFC, and subsequently increased proliferation in the hippocampus and mPFC compared to nondependent rats and controls. Protracted abstinence from CIE reduced BDNF expression to control levels, and subsequently reduced neurogenesis compared to controls and nondependent rats in the hippocampus. In the mPFC, protracted abstinence reduced BDNF expression to control levels, whereas increased oligodendrogenesis in dependent rats compared to nondependent rats and controls. These results suggest a novel relationship between BDNF and progenitors in the hippocampus and mPFC, in which increased ethanol drinking may alter hippocampal and cortical function in alcohol dependent subjects by altering the cellular composition of newly born progenitors in the hippocampus and mPFC.

The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction.

Study objective Serious adverse outcomes associated with skin and soft tissue infections are uncommon, and current hospitalization rates appear excessive. It would be advantageous to be able to differentiate between patients who require high-level inpatient services and those who receive little benefit from hospitalization. We sought to identify characteristics associated with the need for high-level inpatient care among emergency department patients presenting with skin and soft tissue infections. Methods We conducted a nonconcurrent review of existing records to identify emergency department (ED) patients treated for skin and soft tissue infections. For each case, we recorded the presence or absence of select criteria and whether the patient needed high-level care, defined as ICU admission, operating room surgical intervention, or death as the primary outcome. We applied recursive partitioning to identify the principal criteria associated with high-level care. Results We identified 2,923 patients, including 84 experiencing high-level events. Recursive partitioning identified 6 variables associated with high-level outcomes: abnormal computed tomography, magnetic resonance imaging, or ultrasonographic imaging result; systemic inflammatory response syndrome; history of diabetes; previous infection at the same location; older than 65 years; and an infection involving the hand. One or more of these variables were present in all 84 patients requiring high-level care. Conclusion A limited number of simple clinical characteristics appear to be able to identify skin and soft tissue infection patients who require high-level inpatient services. Further research is needed to determine whether patients who do not exhibit these criteria can be safely discharged from the ED.

Background Exposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. Methods RhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5–7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi–Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5–7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5–7. Results Propofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. Conclusion Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.

Alcoholism is a relapsing disorder with limited treatment options, in part due to our limited understanding of the disease etiology. We have recently shown that increased ethanol-seeking in a behavioral model of relapse in a rat model of alcoholism was associated with increased oligodendrogenesis which was positively correlated with platelet/endothelial cell adhesion molecule (PECAM-1) expression in the medial prefrontal cortex (mPFC). The current study investigated whether newly born oligodendrocytes form close physical associations with endothelial cells expressing PECAM-1 and whether these changes were accompanied by altered blood–brain barrier (BBB) integrity. Colableling and confocal analysis demonstrate that newly born oligodendroglia were always located in close physical proximity to PECAM-1 in the mPFC of rats that were ethanol dependent and demonstrated high propensity for relapse. Notably, the endothelial proximity of new oligodendrocytes was associated with reduced expression of endothelial barrier antigen (SMI-71), a marker for BBB integrity. Furthermore, voluntary wheel running during abstinence enhanced SMI-71 expression in endothelial cells, indicating protection against abstinence-induced reduction in BBB integrity. Taken together, these results suggest that ethanol experience and abstinence disrupts homeostasis in the oligo-vascular niche in the mPFC. Reversing these mechanisms may hold the key to reducing propensity for relapse in individuals with moderate to severe alcohol use disorder.

The author reports that data for electrophysiology findings reported in Figs. 4 and 5 for control group and Meth Rst group have been published previously (Galinato MH et al., J Neurosci. 2018 Feb 21; 38(8):2029-2042.

Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05 mg/kg, 6h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for three weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self-administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase (TH) immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings also suggest that wheel running may be preventing certain allostatic changes in the brain reward and stress systems contributing to the negative reinforcement and perpetuation of the addiction cycle.

The hippocampal formation undergoes significant morphological and functional changes after prolonged caloric and dietary restriction (DR). In this study we tested whether prolonged DR results in deleterious alterations in hippocampal neurogenesis, density of granule cell neurons and mossy fibers, all of which support plasticity in the dentate gyrus. Young adult animals either experienced free access to food (control condition), or every-other-day feeding regimen (DR condition) for 3 months. The number of Ki-67 cells and 28-day old 5-bromo-2’-deoxyuridine (BrdU) cells were quantified in the dorsal and ventral dentate gyrus to determine the effect of DR on cellular proliferation and survival of neural progenitor cells in the anatomically defined regions of the dentate gyrus. The density of granule cell neurons and synaptoporin were also quantified to determine the effect of DR on granule cell neurons and mossy fiber projections in the dentate gyrus. Our results show that DR increases cellular proliferation and concurrently reduces survival of newly born neurons in the ventral dentate gyrus without effecting the number of cells in the dorsal dentate gyrus. DR reduced density of granule cell neurons in the dorsal dentate gyrus. These alterations in the number of granule cell neurons did not affect mossy fiber density in DR animals, which was visualized as no differences in synaptoporin expression. Our findings demonstrate that granule cell neurons in the dentate gyrus are vulnerable to chronic DR and that the reorganization of granule cells in the dentate gyrus subregions is not producing concomitant alterations in dentate gyrus neuronal circuitry with this type of dietary restriction.

A Free Electron Laser (FEL) test facility, CLARA (Compact Linear Advanced ResearchAccelerator), is proposed to be constructed at Daresbury Laboratory in the UK. The aim ofCLARA is to develop a normal conducting test accelerator able to generate longitudinallyand transversely bright electron bunches and to use these bunches in the experimentalproduction of stable, synchronised, ultra short photon pulses of coherent light from asingle pass FEL with techniques directly applicable to the future generation of lightsource facilities. In addition the facility will be an ideal test bed for demonstratinginnovative technologies such as high repetition rate normal conducting RF linacs andadvanced undulator designs. This paper will describe the design of CLARA, pointing out theflexible features that will be incorporated to allow multiple novel FEL schemes to beproven. Copyright © 2012 by IEEE.

Chronic stress is a vulnerability factor for a number of psychiatric disorders, including anxiety and affective disorders. Social defeat in rats has proven to be a useful paradigm to investigate the neural mechanisms underlying physiologic and behavioral adaptation to acute and chronic stress. Previous studies suggest that serotonergic systems may contribute to the physiologic and behavioral adaptation to chronic stress, including social defeat in rodent models. In order to test the hypothesis that repeated social defeat alters the emotional behavior and the excitability of brainstem serotonergic systems implicated in control of emotional behavior, we exposed adult male rats either to home cage control conditions, acute social defeat, or social defeat followed 24 h later by a second social defeat encounter. We then assessed behavioral responses during social defeat as well as the excitability of serotonergic neurons within the dorsal raphe nucleus using immunohistochemical staining of tryptophan hydroxylase, a marker of serotonergic neurons, and the protein product of the immediate-early gene, c-fos. Repeated social defeat resulted in a shift away from proactive emotional coping behaviors, such as rearing (explorative escape behavior), and toward reactive emotional coping behaviors such as freezing. Both acute and repeated defeat led to widespread increases in c-Fos expression in serotonergic neurons in the dorsal raphe nucleus. Changes in behavior following a second exposure to social defeat, relative to acute defeat, were associated with decreased c-Fos expression in serotonergic neurons within the dorsal and ventral parts of the mid-rostrocaudal dorsal raphe nucleus, regions that have been implicated in 1) serotonergic modulation of fear- and anxiety-related behavior and 2) defensive behavior in conspecific aggressive encounters, respectively. These data support the hypothesis that serotonergic systems play a role in physiologic and behavioral responses to both acute and repeated social defeat.

A myriad of downstream communities and industries rely on streams fed by both groundwater discharge and glacier meltwater draining the Cordillera Blanca, Northern Peruvian Andes, which contains the highest density of glaciers in the tropics. During the dry season, approximately half the discharge in the region's proglacial streams comes from groundwater. However, because of the remote and difficult access to the region, there are few field methods that are effective at the reach scale to identify the spatial distribution of groundwater discharge. An energy balance model, Rhodamine WT dye tracing, and high-definition kite-borne imagery were used to determine gross and net groundwater inputs to a 4-km reach of the Quilcay River in Huascaran National Park, Peru. The HFLUX computer programme () was used to simulate the Quilcay River's energy balance using stream temperature observations, meteorological measurements, and kite-borne areal photography. Inference from the model indicates 29% of stream discharge at the reach outlet was contributed by groundwater discharge over the study section. Rhodamine WT dye tracing results, coupled with the energy balance, show that approximately 49% of stream water is exchanged (no net gain) with the subsurface as gross gains and losses. The results suggest that gross gains from groundwater are largest in a moraine subreach but because of large gross losses, net gains are larger in the meadow subreaches. These insights into pathways of groundwater-surface water interaction can be applied to improve hydrological modelling in proglacial catchments throughout South America.

Sustainable first year experience (FYE) strategies require systematic approaches that engage academic and professional staff across the institution in improving the student experience. This paper describes a distributed leadership approach to implementing a FYE strategy aimed at improving student success and retention. The approach involves coordination at central and faculty levels, along with university-wide and faculty learning communities for academic and professional staff, first year grants and resource development. The paper outlines the range of activities and analyses them in terms of criteria for distributed leadership, including involvement of people, supportive processes, professional development and availability of resources, combined with the values of trust, a culture of respect, recognising a variety of change inputs and collaborative relationships (Jones et al., 2012). Evidence from coordinator reflections based on these criteria and values is used to illustrate the aspects of the strategy that are working well, and those that need attention.

This paper describes a systematic, whole-of-institution strategy that uses distributed leadership to engage academics and professional staff in supporting transition, success and retention for first year students at an Australian university. A set of interrelated activities has achieved outcomes that include cross-institutional engagement and collaboration, student success and institutional recognition.

Alcoholism is a chronic relapsing disorder with few therapeutic strategies that address the core pathophysiology. Brain tissue loss and oxidative damage are key components of alcoholism, such that reversal of these phenomena may help break the addictive cycle in alcohol use disorder (AUD). The current review focuses on platelet endothelial cell adhesion molecule 1 (PECAM-1), a key modulator of the cerebral endothelial integrity and neuroinflammation, and a targetable transmembrane protein whose interaction within AUD has not been well explored. The current review will elaborate on the function of PECAM-1 in physiology and pathology and infer its contribution in AUD neuropathology. Recent research reveals that oligodendrocytes, whose primary function is myelination of neurons in the brain, are a key component in new learning and adaptation to environmental challenges. The current review briefly introduces the role of oligodendrocytes in healthy physiology and neuropathology. Importantly, we will highlight the recent evidence of dysregulation of oligodendrocytes in the context of AUD and then discuss their potential interaction with PECAM-1 on the cerebral endothelium.