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Post-traumatic stress disorder (PTSD) and opioid use disorder (OUD) are comorbid in clinical populations. However, both pre-clinical and clinical studies of these co-occurring disorders have disproportionately represented male subjects, limiting the applicability of these findings. Our previous work has identified chronic escalating heroin administration and withdrawal can produce enhanced fear learning. This behavior is associated with an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and glial fibrillary acidic protein (GFAP) immunoreactivity. Further, we have shown that these increases in IL-1β and TNF-α are mechanistically necessary for the development of enhanced fear learning. Although these are exciting findings, this paradigm has only been studied in males. The current studies aim to examine sex differences in the behavioral and neuroimmune effects of chronic heroin withdrawal and future enhanced fear learning. In turn, we determined that chronic escalating heroin administration can produce withdrawal in female rats comparable to male rats. Subsequently, we examined the consequence of heroin withdrawal on future enhanced fear learning and IL-1β, TNF-α, and GFAP immunoreactivity. Strikingly, we identified sex differences in these neuroimmune measures, as chronic heroin administration and withdrawal does not produce enhanced fear learning or immunoreactivity changes in females. Moreover, we determined whether heroin withdrawal produces short-term and long-term anxiety behaviors in both female and males. Collectively, these novel experiments are the first to test whether heroin withdrawal can sensitize future fear learning, produce neurobiological changes, and cause short-term and long-term anxiety behaviors in female rats.

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, yet there is a lack of preclinical research investigating how prior ethanol (EtOH) dependence influences the development of a PTSD-like phenotype. Furthermore, the neuroimmune system has been implicated in the development of both AUD and PTSD, but the extent of glial involvement in this context remains unclear. A rodent model was developed to address this gap in the literature.We used a 15-day exposure to the 5% w/v EtOH low-fat Lieber-DeCarli liquid diet in combination with the stress-enhanced fear learning (SEFL) paradigm to investigate the effects of chronic EtOH consumption on the development of a PTSD-like phenotype. Next, we used a reverse transcription quantitative real-time polymerase chain reaction to quantify mRNA expression of glial cell markers GFAP (astrocytes) and CD68 (microglia) following severe footshock stress in EtOH-withdrawn rats. Finally, we tested the functional contribution of dorsal hippocampal (DH) astrocytes in the development of SEFL in EtOH-dependent rats using astrocyte-specific GResults demonstrate that chronic EtOH consumption and withdrawal exacerbate future SEFL. Additionally, we found significantly increased GFAP mRNA expression in the dorsal and ventral hippocampus and amygdalar complex following the severe stressor in EtOH-withdrawn animals. Finally, the stimulation of the astroglial GCollectively, results indicate that prior EtOH dependence and withdrawal combined with a severe stressor potentiate future enhanced fear learning. Furthermore, DH astrocytes significantly contribute to this change in behavior. Overall, these studies provide insight into the comorbidity of AUD and PTSD and the potential neurobiological mechanisms behind increased susceptibility to a PTSD-like phenotype in individuals with AUD.

Cerebellar ataxic syndromes, although uncommon, have been reported previously in patients taking metronidazole. However, almost all cases describe instances where patients were taking prolonged or high doses of the drug. We report a 65-year-old man who consumed 400 mg of metronidazole 3 times over 1 day and presented with slurring of speech, imbalance while walking and diplopia. The symptoms developed the day after consumption of metronidazole. Examination showed slurring of speech, gaze-evoked nystagmus, and dysmetria in all limbs. MRI brain revealed symmetric hyperintense lesions in the dentate nucleus and pons on T2-weighted imaging and FLAIR, which have a well-established association with metronidazole-induced central nervous system (CNS) toxicity. On discontinuation of the drug, symptoms improved, and complete recovery was noted at follow-up 2 weeks later. This case indicates that CNS side effects of metronidazole may not necessarily occur only at high doses or after prolonged courses of metronidazole, but may occur as an idiosyncratic reaction to the drug. Reasons for variable susceptibility require further investigation.

Radio mini-halos are clouds of diffuse, low surface brightness synchrotron emission that surround the Brightest Cluster Galaxy (BCG) in massive cool-core galaxy clusters. In this paper, we use third generation calibration (3GC), also called direction-dependent (DD) calibration, and point source subtraction on MeerKAT extragalactic continuum data. We calibrate and image archival MeerKAT L-band observations of a sample of five galaxy clusters (ACO 1413, ACO 1795, ACO 3444, MACS J1115.8+0129, MACS J2140.2-2339). We use the CARACal pipeline for direction-independent (DI) calibration, DDFacet and killMS for 3GC, followed by visibility-plane point source subtraction to image the underlying mini-halo without bias from any embedded sources. Our 3GC process shows a drastic improvement in artefact removal, to the extent that the local noise around severely affected sources was halved and ultimately resulted in a 7\% improvement in global image noise. Thereafter, using these spectrally deconvolved Stokes I continuum images, we directly measure for four mini-halos the flux density, radio power, size and in-band integrated spectra. Further to that, we show the in-band spectral index maps of the mini-halo (with point sources). We present a new mini-halo detection hosted by MACS J2140.2-2339, having flux density $S_{\rm 1.28\,GHz} = 2.61 \pm 0.31$ mJy, average diameter 296 kpc and $\alpha^{\rm 1.5\,GHz}_{\rm 1\,GHz} = 1.21 \pm 0.36$. We also found a $\sim$100 kpc southern extension to the ACO 3444 mini-halo which was not detected in previous VLA L-band observations. Our description of MeerKAT wide-field, wide-band data reduction will be instructive for conducting further mini-halo science., Comment: 16 pages. 10 figures

In this paper we present results from a radio-optical study of the galaxy populations of the galaxy clusters Abell 1300 and MACS J1931.8$-$2634, a merger and a relaxed system respectively both located at $z \sim 0.3$, aimed at finding evidence of merger-induced radio emission. Radio observations are taken at 1.28 GHz with the MeerKAT interferometer during its early-stage commissioning phase, and combined with archive optical data. We generated catalogues containing 107 and 162 radio sources in the A$~$1300 and MACS J1931.8--2634 cluster fields respectively, above a 0.2 mJy threshold and within a 30~arcmin radius from the cluster centre (corresponding to 8.1 and 8.8 Mpc respectively). By cross-correlating the radio and optical catalogues, and including spectroscopic information, 9 and 6 sources were found to be cluster members and used to construct the radio luminosity functions respectively for both clusters. The comparison of the radio source catalogues between the two cluster fields leads to a marginal difference, with a $2��$ statistical significance. We derived the radio luminosity function at 1.28 GHz in both clusters, in the power range $22.81 < \rm {log~P_{1.28~GHz}~(W/Hz)} < 25.95$, and obtained that in A 1300 the radio luminosity function averaged over the full radio power interval is only $3.3 \pm 1.9$ times higher than the MACS J1931.8--2634 one, suggesting no statistical difference in their probability to host nuclear radio emission. We conclude that, at least for the two clusters studied here, the role of cluster mergers in affecting the statistical properties of the radio galaxy population is negligible., 18 pages, 8 figures, MNRAS accepted

RXCJ0232.2–4420, at z = 0.28, is a peculiar system hosting a radio halo source around the cool-core of the cluster. To investigate its formation and nature, we used archival Chandra and XMM–Newton X-ray data to study the dynamical state of the cluster and detect possible substructures in the hot gas. Its X-ray surface brightness distribution shows no clear disruption except an elongation in the north-east to south-west direction. We perform the unsharp masking technique and compute morphology parameters (Gini, M20, and concentration) to characterize the degree of disturbance in the projected X-ray emission. Both of these methods revealed a substructure, which is located at ∼1 arcmin from the cluster core in the south-west direction. Previous spectral analysis conducted for RXCJ0232.2–04420 concluded that there are a short cooling time and low entropy at the cluster centre, indicating that the cluster has a cool core. Thus, we suggest that RXCJ0232.2–4420 may be a system where the core of the cluster is not showing any sign of disturbance, but the south-west substructure could be pumping energy to the detected radio halo via turbulence.

There is significant comorbidity of opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) in clinical populations. However, the neurobiological mechanisms underlying the relationship between chronic opioid use and withdrawal and development of PTSD are poorly understood. Our previous work identified that chronic escalating heroin administration and withdrawal can produce enhanced fear learning, an animal model of hyperarousal, and is associated with an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β). However, other cytokines, such as TNF-α, work synergistically with IL-1β and may have a role in the development of enhanced fear learning. Based on both translational rodent and clinical studies, TNF-α has been implicated in hyperarousal states of PTSD, and has an established role in hippocampal-dependent learning and memory. The first set of experiments tested the hypothesis that chronic heroin administration followed by withdrawal is capable of inducing alterations in DH TNF-α expression. The second set of experiments examined whether DH TNF-α expression is functionally relevant to the development of enhanced fear learning. We identified an increase of TNF-α immunoreactivity and positive cells at 0, 24, and 48 h into withdrawal in the dentate gyrus DH subregion. Interestingly, intra-DH infusions of etanercept (TNF-α inhibitor) 0, 24, and 48 h into heroin withdrawal prevented the development of enhanced fear learning and mitigated withdrawal-induced weight loss. Overall, these findings provide insight into the role of TNF-α in opioid withdrawal and the development of anxiety disorders such as PTSD.

We aim to carry out a radio study of the SoUthern Cluster sCale Extended Source Survey (SUCCESS) sample consisting of twenty massive (M$_{500} > 5\times10^{14}$ M$_{\odot}$), nearby (redshift $, 20 pages, 17 figures, accepted for publication in MNRAS

Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple mutations in SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover or spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 spike protein, defining and structurally illustrating seven receptor binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles. Pseudovirion-based neutralization assays reveal spike mutations, individually and clustered together in variants, that affect antibody function among the communities. Key classes of RBD-targeted antibodies maintain neutralization activity against these emerging SARS-CoV-2 variants. These results provide a framework for selecting antibody treatment cocktails and understanding how viral variants might affect antibody therapeutic efficacy.

A polarized collecting duct (CD), formed from the branching ureteric bud (UB), is a prerequisite for an intact kidney. The small Rho GTPase Rac1 is critical for actin cytoskeletal regulation. We investigated the role of Rac1 in the kidney collecting system by selectively deleting it in mice at the initiation of UB development. The mice exhibited only a mild developmental phenotype; however, with aging, the CD developed a disruption of epithelial integrity and function. Despite intact integrin signaling, Rac1-null CD cells had profound adhesion and polarity abnormalities that were independent of the major downstream Rac1 effector, Pak1. These cells did however have a defect in the WAVE2–Arp2/3 actin nucleation and polymerization apparatus, resulting in actomyosin hyperactivity. The epithelial defects were reversible with direct myosin II inhibition. Furthermore, Rac1 controlled lateral membrane height and overall epithelial morphology by maintaining lateral F-actin and restricting actomyosin. Thus, Rac1 promotes CD epithelial integrity and morphology by restricting actomyosin via Arp2/3-dependent cytoskeletal branching.

Introduction A thoroughly completed Burns Proforma can provide vital information for the effective management of a burn and enables the sharing of information with other members of the multidisciplinary team. Aim We aimed to assess the quality of record-keeping of the new Burns Proforma, compared it with the previous cycle, and identified areas of improvement. Method Data on 76 fields on version 4.0 of the Mersey Burns Proforma was collected for 92 patients between January and February 2020. The data was compared to cycle 1of the audit collected in July 2019. Results Assessing the 61 comparable fields between audit cycles, 58 fields (95%) improved while 3 (5%) deteriorated. 21 fields achieved a completion rate greater than 80%. Vital information such as history, comorbidities, and drug history achieved 100% completion, up from 94%, 94%, and 95%, respectively. Total body surface area (TBSA) increased to 93% from 83%, the use of the Lund & Browder chart remained the same, treatment plan documentation increased to 95% from 91%, documentation of admission increased from 24% to 51%, consultant confirmation of TBSA increased to 10% from 5%, but this requires further improvement. Comments stated the proforma was clearer and provided a flowchart layout which made documentation easier. Conclusions The Burns Admission Proforma has made significant improvements. Working with the nursing staff and consultant body, we aim to improve our completion rates of vital information further. It sets a high standard for data collection and presents itself as a useful tool for other Burns Units across the United Kingdom.

Aim We aimed to assess the quality of record-keeping of the departments hand trauma proforma, identify areas of improvement, and to implement and assess the quality of an updated proforma. Method Data from 101 parameters was collected for 20 patients undergoing surgery for an upper limb injury in November 2019. An updated proforma was implemented and a further 20 patients were analysed in February 2020. All fields were compared between two audit cycles and comments were collected. Results The overall completion rate increased. Documentation of the responsible consultant increased to 100%, along with an increase in documenting of hobbies and injury mechanism. X-ray findings (55% to 85%) and antibiotic plan (35% to 80%) increased. Implementation of a free text box resulted in written descriptions of injury to compliment sketches. In the operation note, documentation of anaesthetic type used increased, along with tourniquet use and time. There was clearer documentation of the injury, findings, and procedure, with greater use of diagrams to illustrate the repair. There was a drop in the recording of post-op plans (100% to 85%), post-op antibiotics (90% to 75%), and follow-up plan (95% to 60%). Clinicians commented to increase the size of the free-text box and hand diagram on the operative page to facilitate easier drawings. Conclusions The Hand Trauma Proforma has made good progress from its original version but requires further adjustments to ensure complete data input. It sets a high standard for data collection and presents itself as a useful tool for units across the United Kingdom.

Patients with underlying psychiatric conditions are vulnerable to the experience of sexual violence. Barriers and facilitators to disclosure exist, at the level of the individual, healthcare system, legal system and society in general. Management requires a trauma-informed approach with a focus on avoidance of stigma, optimisation of pre-existing psychiatric conditions and appropriate treatment of psychological sequalae. Preventive strategies by the patient, practitioner and healthcare system, may assist to reduce the risk of future sexual violence.

Purpose:Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.Patients and Methods:Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.Results:The study included 187 patients. The most common treatment-related adverse events were hyperphosphatemia (64%), dry mouth (42%), and asthenia (28%), generally grade 1/2 severity. All cases of hyperphosphatemia were grade 1/2 except for 1 grade 3 event. Skin, nail, and eye changes were observed in 43%, 33%, and 28% of patients, respectively (mostly grade 1/2 and reversible after temporary dosing interruption). Urothelial carcinoma and cholangiocarcinoma were most responsive to erdafitinib, with objective response rates (ORR) of 46.2% (12/26) and 27.3% (3/11), respectively, in response-evaluable patients with FGFR mutations or fusions. All patients with urothelial carcinoma and cholangiocarcinoma who responded to erdafitinib carried FGFR mutations or fusions. Median response duration was 5.6 months for urothelial carcinoma and 11.4 months for cholangiocarcinoma. ORRs in other tumor types were Conclusions:Erdafitinib shows tolerability and preliminary clinical activity in advanced solid tumors with genomic changes in the FGFR pathway, at two different dosing schedules and with particularly encouraging responses in urothelial carcinoma and cholangiocarcinoma.

Background We performed a randomized phase 3 study of trabectedin versus dacarbazine in previously‐treated patients with liposarcoma/leiomyosarcoma (LPS/LMS). Methods Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every 3 weeks. The primary objective was overall survival (OS). Secondary objectives were progression‐free survival, objective response rate, safety, and patient‐reported outcomes, all previously reported and demonstrating superior disease control with trabectedin. Results of the final OS analysis in preplanned subgroups of patients with LPS/LMS are presented. Results At the time of the final OS analysis, 577 patients had been assigned randomly, including 423 (73%) with LMS and 154 (27%) with LPS. The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (≥6 cycles: 42% vs 22%). This pattern was consistent across histological subgroups: the median number of treatment cycles (4 vs 2 for both subgroups) and proportion of patients with ≥6 treatment cycles (LMS, 43% vs 24%; LPS, 40% vs 16%). Despite improved disease control by trabectedin, no improvement in OS was observed; the final median OS for trabectedin versus dacarbazine was 13.7 versus 13.1 months (P = .49). Sensitivity analyses of OS suggest confounding by post‐study anticancer therapies, which were utilized in most patients in both treatment arms (71% vs 69%, respectively). Conclusion The final OS results demonstrated comparable survival between LPS/LMS patients receiving trabectedin or dacarbazine, which is consistent with the interim analysis results. Both LPS and LMS demonstrated improved disease control with trabectedin., A final analysis of overall survival demonstrates comparable results between patients with liposarcoma/leiomyosarcoma receiving trabectedin or dacarbazine, which is consistent with interim analysis results. Both liposarcoma and leiomyosarcoma show improved disease control with trabectedin.

We present the discovery of a single radio relic located at the edge of the galaxy cluster A2384, using the MeerKAT radio telescope. A2384 is a nearby ($z$ = 0.092), low mass, complex bimodal, merging galaxy cluster that displays a dense X-ray filament ($\sim$ 700 kpc in length) between A2384(N) (Northern cluster) and A2384(S) (Southern cluster). The origin of the radio relic is puzzling. By using the MeerKAT observation of A2384, we estimate that the physical size of the radio relic is 824 $\times$ 264 kpc$^{2}$ and that it is a steep spectrum source. The radio power of the relic is $P_{1.4\mathrm{GHz}}$ $\sim$ (3.87 $\pm$ 0.40) $\times$ 10$^{23}$ W Hz$^{-1}$. This radio relic could be the result of shock wave propagation during the passage of the low-mass A2384(S) cluster through the massive A2384(N) cluster, creating a trail appearing as a hot X-ray filament. In the previous GMRT 325 MHz observation we detected a peculiar FR I radio galaxy interacting with the hot X-ray filament of A2384, but the extended radio relic was not detected; it was confused with the southern lobe of the FR I galaxy. This newly detected radio relic is elongated and perpendicular to the merger axis, as seen in other relic clusters. In addition to the relic, we notice a candidate radio ridge in the hot X-ray filament. The physical size of the radio ridge source is $\sim$ 182 $\times$ 129 kpc$^{2}$. Detection of the diffuse radio sources in the X-ray filament is a rare phenomenon, and could be a new class of radio source found between the two merging clusters of A2384(N) and A2384(S)., 12 pages, 6 figures, accepted in MNRAS

Converging evidence suggests opioid abuse can increase the incidence and severity of post-traumatic stress disorder (PTSD) in clinical populations. Interestingly, opioid withdrawal alone can produce symptoms similar to those of PTSD. Despite this association, the neural mechanisms underlying the relationship of opioid abuse, withdrawal, and PTSD is poorly understood. Our laboratory has investigated the neurobiological underpinnings of stress enhanced fear learning (SEFL), an animal model of PTSD-like symptoms. We have previously shown that, in SEFL, a severe footshock induces an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β) and subsequent fear learning is blocked by DH IL-1 receptor antagonism (IL-1RA). Given that opioids and stress engage similar neuroimmune mechanisms, the present experiments investigate whether the same mechanisms drive heroin withdrawal to induce a PTSD-like phenotype. First, we tested the effect of a chronic escalating heroin dose and withdrawal regimen on fear learning and found it produces enhanced future fear learning. Heroin withdrawal also induces a time-dependent, region-specific increase in IL-1β and glial fibrillary acidic protein (GFAP) immunoreactivity within the dentate gyrus of the DH. IL-1β was significantly colocalized with GFAP, indicating astrocytes may be involved in increased IL-1β. Moreover, intra-DH infusions of IL-1RA 0, 24, and 48 hours into heroin withdrawal prevents the development of enhanced fear learning but does not alter withdrawal-induced weight loss. Collectively, our data suggests heroin withdrawal is sufficient to produce enhanced fear learning, astrocytes may play a role in heroin withdrawal-induced IL-1β, and DH IL-1 signaling during withdrawal mediates the development of heroin withdrawal-enhanced fear learning.

The physiological and motivational effects of heroin and other abused drugs become associated with environmental (contextual) stimuli during repeated drug use. As a result, these contextual stimuli gain the ability to elicit drug-like conditioned effects. For example, after context-heroin pairings, exposure to the heroin-paired context alone produces similar effects on peripheral immune function as heroin itself. Conditioned immune effects can significantly exacerbate the adverse health consequences of heroin use. Our laboratory has shown that exposure to a heroin-paired context suppresses lipopolysaccharide (LPS)-induced splenic nitric oxide (NO) production in male rats, and this effect is mediated in part by the dorsal hippocampus (dHpc). However, specific dHpc output regions, whose efferents might mediate conditioned immune effects, have not been identified, nor has the contribution of ventral hippocampus (vHpc) been investigated. Here, we evaluated the role of CaMKIIα-expressing neurons in the dHpc and vHpc main output regions by expressing G(i)-coupled designer receptors exclusively activated by designer drugs (DREADDs) under a CaMKIIα promoter in the dorsal subiculum and CA1 (dSub, dCA1) or ventral subiculum and CA1 (vSub, vCA1). After context-heroin conditioning, clozapine-N-oxide (CNO, DREADD agonist) or vehicle was administered systemically prior to heroin-paired context (or home-cage control) exposure and LPS immune challenge. Chemogenetic inhibition of CaMKIIα-expressing neurons in dHpc, but not vHpc, output regions attenuated the expression of conditioned splenic NO suppression. These results establish that the main dHpc output regions, the dSub and dCA1, are critical for this context-heroin conditioned immune effect.

Objective The study aimed to highlight the relationship between forensic science and endodontics by illustrating CBCT records can be used as legal evidence for forensic analysis and evaluate the effect of elevated temperature on the endodontically treated teeth. Methods The present study was conducted on 40 extracted permanent mandibular premolars, which were divided into two groups based on predetermined incineration temperature: Group I - 400°C & Group II - 800°C subjected for 15 minutes holding time in a digital burnout furnace. The root canal treatment was performed for both the groups and a Pre-incineration CBCT scan was taken for both the groups as an ante-mortem data. Following heating analysis, root canal treated teeth were examined using a stereomicroscope at 20x resolution to evaluate the morphological changes. The post-incineration CBCT scan was taken as the post-mortem record for each group. Both ante-mortem records and post-mortem records were compared for the forensic analysis. Results The endodontically treated teeth display a series of macroscopic and stereo-microscopic changes for each temperature scale. The CBCT records identify the thermal stress-induced 3D alterations in the gutta-percha filled teeth. Conclusion Knowledge of changes in human dentition and traces of the endodontically treated teeth can help forensic experts for the identification of the fire victims.

MeerKAT's large number of antennas, spanning 8 km with a densely packed 1 km core, create a powerful instrument for wide-area surveys, with high sensitivity over a wide range of angular scales. The MeerKAT Galaxy Cluster Legacy Survey (MGCLS) is a programme of long-track MeerKAT L-band (900-1670 MHz) observations of 115 galaxy clusters, observed for $\sim$6-10 hours each in full polarisation. The first legacy product data release (DR1), made available with this paper, includes the MeerKAT visibilities, basic image cubes at $\sim$8" resolution, and enhanced spectral and polarisation image cubes at $\sim$8" and 15" resolutions. Typical sensitivities for the full-resolution MGCLS image products are $\sim$3-5 {\mu}Jy/beam. The basic cubes are full-field and span 4 deg^2. The enhanced products consist of the inner 1.44 deg^2 field of view, corrected for the primary beam. The survey is fully sensitive to structures up to $\sim$10' scales and the wide bandwidth allows spectral and Faraday rotation mapping. HI mapping at 209 kHz resolution can be done at $0, Comment: 43 pages, 33 figures, 6 tables. Accepted for publication in Astronomy and Astrophysics

Repeated pairings of heroin and a context results in Pavlovian associations which manifest as heroin-conditioned appetitive responses and peripheral immunomodulation upon re-exposure to heroin-paired conditioned stimuli (CS). The dorsal hippocampus (DH) plays a key role in the neurocircuitry governing these context-heroin associations. Within the DH, expression of the pro-inflammatory cytokine interleukin-1β (IL-1β) is required for heroin-conditioned peripheral immunomodulation to occur. However, the role of signaling via IL-1 receptor type 1 (IL-1R1) has not been examined. Furthermore, it has not been evaluated whether the involvement of IL-1 in associative learning extends to classically conditioned appetitive behaviors, such as conditioned place preference (CPP). The first set of experiments investigated whether DH IL-1R1 signaling during CS re-exposure modulates heroin-conditioned immunomodulation and heroin-CPP. The second set of experiments employed chemogenetic techniques to examine whether DH astroglial signaling during CS re-exposure alters the same Pavlovian responses. This line of investigation is based on previous research indicating that astrocytes support hippocampal-dependent learning and memory through the expression of IL-1β protein and IL-1R1. Interestingly, IL-1R1 antagonism disrupted heroin-conditioned suppression of peripheral immune parameters but failed to alter heroin-CPP. Similarly, chemogenetic stimulation of Gi-signaling in DH astrocytes attenuated heroin-conditioned peripheral immunomodulation but failed to alter heroin-CPP. Collectively our data show that both IL-1R1 stimulation and astrocyte signaling in the DH are critically involved in the expression of heroin-conditioned immunomodulation but not heroin-CPP. As such these findings strongly suggest hippocampal neuroimmune signaling differentially regulates Pavlovian immunomodulatory and appetitive behaviors.

Ebola virus infection causes severe disease in humans and represents a global health threat. Candidates for immunotherapeutics and vaccines have shown promise in clinical trials, although they are ineffective against other members of the Ebolavirus genus that also cause periodic, lethal outbreaks. In this study, we present a crystal structure of a pan-ebolavirus antibody, 6D6, as well as single-particle electron microscopy reconstructions of 6D6 in complex with Ebola and Bundibugyo virus glycoproteins. 6D6 binds to the conserved glycoprotein fusion peptide, implicating it as a site of immune vulnerability that could be exploited to reliably elicit a pan-ebolavirus neutralizing antibody response.

BACKGROUND: Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. PATIENTS AND METHODS: Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. RESULTS: Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population. CONCLUSIONS: This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01343277.

Objective Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). Methods Of 577 patients randomized 2:1 to receive trabectedin 1.5mg/m 2 by 24-hour IV infusion or dacarbazine 1g/m 2 by 20–120-minute IV infusion once every three weeks, 232 had uLMS (trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. Results PFS for trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41–0.81; P =0.0012). OS was similar (trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65–1.24; P =0.51) between groups. ORR was 11% with trabectedin vs. 9% with dacarbazine ( P =0.82). CBR for trabectedin was 31% vs. 18% with dacarbazine ( P =0.05); median DOR was 6.5months for trabectedin vs. 4.1months for dacarbazine ( P =0.32). Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients in the trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. Conclusions In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS.

Diffuse radio sources associated with the intra-cluster medium are direct probes of the cosmic ray electrons and magnetic fields. We report the discovery of a diffuse radio source in the galaxy cluster RXCJ0232.2-4420 (SPT-CL J0232-4421, $z=0.2836$) using 606 MHz observations with the Giant Metrewave Radio Telescope. The diffuse radio source surrounds the Brightest Cluster Galaxy in the cluster like typical radio mini-halos. However the total extent of it is $550\times800$ kpc$^{2}$, which is larger than mini-halos and similar to that of radio halos. The BCG itself is also a radio source with a marginally resolved core at $7''$ (30 kpc) resolution. We measure the 606 MHz flux density of the RH to be $52\pm5$ mJy. Assuming a spectral index of 1.3, the 1.4 GHz radio power is $4.5 \times 10^{24}$ W Hz$^{-1}$. The dynamical state of the cluster has been inferred to be "relaxed" and also as "complex" depending on the classification methods based on the morphology of the X-ray surface brightness. This system thus seems to be in the transition phase from a mini-halo to a radio halo., Accepted for publication in MNRAS Letters

Clusters of varying mass ratios can merge and the process significantly disturbs the cluster environments and alters their global properties. Active radio galaxies are another phenomenon that can also affect cluster environments. Radio jets can interact with the intra-cluster medium (ICM) and locally affect its properties. Abell~2384 (hereafter A2384) is a unique system that has a dense, hot X-ray filament or bridge connecting the two unequal mass clusters A2384(N) and A2384(S). The analysis of its morphology suggests that A2384 is a post-merger system where A2384(S) has already interacted with the A2384(N), and as a result hot gas has been stripped over a ~ 1 Mpc region between the two bodies. We have obtained its 325 MHz GMRT data, and we detected a peculiar FR I type radio galaxy which is a part of the A2384(S). One of its radio lobes interacts with the hot X-ray bridge and pushes the hot gas in the opposite direction. This results in displacement in the bridge close to A2384(S). Based on Chandra and XMM-Newton X-ray observations, we notice a temperature and entropy enhancement at the radio lobe-X-ray plasma interaction site, which further suggests that the radio lobe is changing thermal plasma properties. We have also studied the radio properties of the FR I radio galaxy, and found that the size and radio luminosity of the interacting north lobe of the FR I galaxy are lower than those of the accompanying south lobe., Comment: 12 pages

BACKGROUND Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m2 intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050–6. © 2016 American Cancer Society.

Aim: The purpose of this study was to investigate temperature-dependent rheological properties of three endodontic sealers MTA Fillapex (Angelus, Brazil), AH Plus (Dentsply, Germany), and EndoREZ (Ultradent, USA). Materials and Methods: Five samples of each group of endodontic sealers (n = 30) were freshly mixed and placed on the plate of a rheometer (MCR 301, AntonPaar, Physica) and examined at 25° C and 37° C temperature, respectively. Rheological properties of the sealers were calculated according to the loss modulus (G), storage modulus (G'), loss factor (Tan δ), and complex viscosity (c*) using dynamic oscillatory shear tests. Results: Statistical analysis (Wilcoxon signed-rank test) demonstrated that MTA Fillapex exhibited higher loss modulus (G > G') and a crossover region. AH Plus and EndoREZ had a higher storage modulus (G' > G) at both temperatures. Loss factor (Tan δ) of MTA Fillapex was the highest compared to AH Plus, followed by EndoREZ. With a temperature change from 25°C to 37°C, MTA Fillapex exhibited a decrease while AH Plus exhibited an increase and, EndoREZ exhibited the least change, in complex viscosity (c* ). Conclusions: EndoREZ exhibited better rheological properties compared to the other two test sealers.

Background: Age-related macular degeneration (ARMD) is the leading cause of irreversible blindness in individuals over 50 years in developed countries. The objective was to study the effect of intravitreal bevacizumab in patients of choroidal neovascular membrane of eye by visual acuity and fluorescence angiography photograph. Methods: Non-randomized, open label, prospective analysis of 30 eyes in 30 patients with choroidal neovascualr diagnosed by direct ophthalmoscope and slit lamp 90D biomicroscopy. Visual acuity of the clinically diagnosed patient was taken by ETDRS (early treatment diabetic retinopathy system) visual acuity chart. Fundus fluorescence angiography was done by topcon retinal camera. Now all patients regardless of type were given 3 injections of 0.05 ml of injection bevacizumab intravitreally at infratemporal site 3.5 mm and 4 mm away from the limbus in pseudophakic and phakic eye repectively at interval of 1 month. After 1 month of last dose, patient was assessed with ETDRS chart for visual acuity, FFA for anatomical changes. FFA was done before and after giving 3 injection of bevacizumab at monthly interval. Patients were asked for regular follow-up and patients were examined after 6 hours, 48 hours and 7 days for any early and late complications. Results: There was significant improvement of visual acuity after intravitreal bevacizumab treatment (before 1.196 log MAR and after 0.95067 log MAR with p value is 0.0001, paired t-test with t=6.333 with 29 degree of freedom) in cases of choroidal neovascular membrane. Gain in visual acuity was accompanied by a significant decrease in leakage in fluorescein angiography (FFA) Conclusions: We present evidence that intravitreal bevacizumab is an effective treatment for choroidal neovascular membrane.

Background: Increased use of computers led to an increase in the number of patients complaining about ocular and non-ocular symptoms related to computer use. One of such computer associated ill-effect is, “Computer Vision Syndrome” manifesting as dry eye. This study was done to find out prevalence of dry eye. Methods: Computer users were grouped in Group A > 2hours to ≤ 4 hours, Group B >4 hours to ≤ 6 hours, Group C > 6 hours to ≤ 8 hours according to their exposure to computer per day. Dry eye evaluation was done with ocular surface disease index questionnaire, tear meniscus height, and tear film brake up time, schirmer test. One way analysis of variance test was used to compare mean values, find p values and ensuring statistical significance. Results: In our study prevalence among the males and females was found to be of 25%. The prevalence of dry eye among 20 to 30 and 31 to 40 years of age is 13.04% and 51.64 % suggesting that the prevalence of dry eye increases as the years of computer exposure increases. The overall prevalence of dry eye in computer users was found to be 25% with prevalence of 9.3%, 18.18% and 45.71% in groups A, B and C respectively. Conclusions: It seems prevalence of dry eye is increasing with increase in duration of computer use per day. OSDI together with TBUT, schirmer-1 test cab be performed easily and used to support diagnosis of dry eye.

Marburg virus (MARV) and Ebola virus (EBOV) belong to the family Filoviridae. MARV causes severe disease in humans with high fatality. We previously isolated a large panel of monoclonal antibodies (mAbs) from B cells of a human survivor with previous naturally acquired MARV infection. Here, we characterized functional properties of these mAbs and identified non-neutralizing mAbs targeting the glycoprotein (GP) 2 portion of the mucin-like domain (MLD) of MARV GP, termed the wing region. One mAb targeting the GP2 wing, MR228, showed therapeutic protection in mice and guinea pigs infected with MARV. The protection was mediated by the Fc fragment functions of MR228. Binding of another GP2 wing-specific non-neutralizing mAb, MR235, to MARV GP increased accessibility of epitopes in the receptor-binding site (RBS) for neutralizing mAbs, resulting in enhanced virus neutralization by these mAbs. These findings highlight an important role for non-neutralizing mAbs during natural human MARV infection.

5562 Background: PC is characterized by a relatively low prevalence of recurrent somatic point mutations. ctDNA is shed from PC and can be analyzed to profile somatic point mutations and copy number changes. We evaluated a computational approach to detect ctDNA (ie. ctDNA+) in PC based on allele frequencies of polymorphisms and mutations. We then sought to confirm the association of this biomarker with disease burden and clinical outcome. Methods: Customized, hybrid capture, high-depth next-generation sequencing was performed on pre-treatment (PT) plasma samples from a phase 2 line 3+ metastatic castration-resistant PC (mCRPC) study (NCT02854436, GALAHAD) and PT and end of treatment (EOT) samples from randomized Phase 3 study in non-metastatic (nm) CRPC (NCT01946204, SPARTAN) and from metastatic castration-sensitive PC (mCSPC) (NCT02489318, TITAN). Associations of ctDNA+ with bone lesions (number), visceral metastases (+/-), circulating tumor cells count (CTCc), and serum prostate specific antigen (PSA), alkaline phosphatase (AP) and lactate dehydrogenase (LD) were tested. Also, associations of ctDNA+ with overall survival (OS) and second progression free survival (PFS2) were evaluated in randomized studies using Cox regression. Results: ctDNA+ at PT was 7.5% in nmCRPC, 23.7% in mCSPC and 66% in heavily pre-treated mCRPC. ctDNA+ increased from PT to EOT in nmCRPC (7.5% to 27%) and mCSPC (23.7% to 63.6%). Disease burden metrics were evaluated in ctDNA+ vs ctDNA- patients. ctDNA+ was associated with higher disease burden in mCRPC (Table), nmCRPC and mCSPC. At EOT, ctDNA+ patients had shorter OS and PFS2 in nmCRPC (HR [95% CI] OS: 2.73 [1.83, 4.08], p < 0.0001; PFS2: 2.00 [1.38, 2.90], p = 0.0002) and mCSPC (HR [95% CI] OS: 7.59 [3.22, 17.91], p < 0.0001; PFS2: 4.84 [2.47, 9.47], p < 0.0001). Conclusions: ctDNA+ assessed using our novel, composite biomarker increases with advanced disease state and disease progression, is significantly associated with disease burden and poor clinical outcome in PC and could be a clinically relevant metric for monitoring response to therapy. Clinical trial information: NCT02854436 . [Table: see text]

Coronary angiography and angioplasty procedures were commonly performed via transfemoral or transradial approaches. Recently, anatomical snuffbox arterial access has been explored with low access site bleeding-related complications comparable to the transradial access. In this study, our initial

Objective: To evaluate the interference of active cellphones during electronic working length (EWL) determination of a root canal. Materials and Methods: Thirty patients requiring root canal treatment in the anterior teeth or premolars having single canal and mature apices were selected for this study. Working length determination was done using no. 15 K-file. Electronic apex locators ProPex Pixi and Root ZX mini were used for working length determination. Cellphones iPhone 6s and Xolo Q3000 were evaluated for their interference. The experiment was conducted in a closed room (9 feet × 9 feet). Working length was measured with no cellphone in the room, iPhone 6s in a calling mode, Xolo Q3000 in a calling mode, and Xolo Q3000 and iPhone 6s simultaneously in a calling mode. Stability of the readings was also determined for every condition. Statistical Analysis: The data were statistically analyzed using one-way ANOVA and paired t-test at 0.05 level of significance. Results: Results were not statistically significant. Conclusion: Within the limitations of the present study, cellphones do not interfere with the EWL determination.

Multiple sclerosis (MS) is a chronic inflammatory disease that causes demyelination of neurons in the central nervous system. Traditional therapies for MS have involved anti-inflammatory and immunosuppressive drugs with significant side effects that often only provide short-term relief. A more desirable outcome of immunotherapy would be to protect against disease before its clinical manifestation or to halt disease after its initiation. One attractive approach to accomplish this goal would be to restore tolerance by targeting immunoregulatory cell networks. Although much of the work in this area has focused on CD4(+) Foxp3(+) regulatory T cells, other studies have investigated natural killer T (NKT) cells, a subset of T cells that recognizes glycolipid antigens in the context of the CD1d glycoprotein. Studies with human MS patients have revealed alterations in the numbers and functions of NKT cells, which have been partially supported by studies with the experimental autoimmune encephalomyelitis model of MS. Additional studies have shown that activation of NKT cells with synthetic lipid antigens can, at least under certain experimental conditions, protect mice against the development of MS-like disease. Although mechanisms of this protection remain to be fully investigated, current evidence suggests that it involves interactions with other immunoregulatory cell types such as regulatory T cells and immunosuppressive myeloid cells. These studies have provided a strong foundation for the rational design of NKT-cell-based immunotherapies for MS that induce tolerance while sparing overall immune function. Nevertheless, additional pre-clinical and clinical studies will be required to bring this goal to fruition.