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We report the results of long-term reverberation mapping (RM) campaigns of the nearby active galactic nuclei (AGN) NGC 4151, spanning from 1994 to 2022, based on archived observations of the FAST Spectrograph Publicly Archived Programs and our new observations with the 2.3m telescope at the Wyoming Infrared Observatory. We reduce and calibrate all the spectra in a consistent way, and derive light curves of the broad H$\beta$ line and 5100\,{\AA} continuum. Continuum light curves are also constructed using public archival photometric data to increase sampling cadences. We subtract the host galaxy contamination using {\it HST} imaging to correct fluxes of the calibrated light curves. Utilizing the long-term archival photometric data, we complete the absolute flux-calibration of the AGN continuum. We find that the H$\beta$ time delays are correlated with the 5100\,{\AA} luminosities as $\tau_{\rm H\beta}\propto L_{5100}^{0.46\pm0.16}$. This is remarkably consistent with Bentz et al. (2013)'s global size-luminosity relationship of AGNs. Moreover, the data sets for five of the seasons allow us to obtain the velocity-resolved delays of the H$\beta$ line, showing diverse structures (outflows, inflows and disks). Combining our results with previous independent measurements, we find the measured dynamics of the H$\beta$ broad-line region (BLR) are possibly related to the long-term trend of the luminosity. There is also a possible additional $\sim$1.86 years time lag between the variation in BLR radius and luminosity. These results suggest that dynamical changes in the BLR may be driven by the effects of radiation pressure., Comment: Accepted for publication in MNRAS; comments welcome!

Background Primary sclerosing cholangitis (PSC) is a progressive choleostatic disease and up to 80% of patients also have ulcerative colitis (PSC-UC). This presents a clinical challenge owing to difficulty in diagnosis and increased risk for developing cancer. While several multifactorial processes including inflammation and microbial dysbiosis have been associated with PSC-UC pathogenesis, the precise molecular factors that regulate the phenotype of this disease subtype remain unknown. Methods Here, we applied methyl-capture sequencing and mRNA sequencing to colonic mucosal biopsies to identify transcriptomic and epigenetic alterations differentiating UC from PSC-UC. Samples were taken from 3 groups of treatment-naïve children at diagnosis who participated in the DOCHAS study (GEN-193/11) - UC (n=10), PSC-UC (n=10) and healthy controls(n=10). Results Differential gene expression between UC and PSC-UC identified disease-associated genes that were either up- or down-regulated in UC or PSC relative to controls. Furthermore, expression of these genes was intricately regulated by master transcriptional regulators (pro-caspases, IL7RA) and transcription factors (AR, p53, JUND, CEBPA). Importantly, gene expression comparison between UC vs PSC-UC revealed 4 up-regulated genes in PSC-UC (RAB31, TENM3, KLHL17 and COL7A1). Notably, RAB31 and TENM3 are also significantly up-regulated in gastrointestinal (GI) cancers. We also identified 4 down-regulated genes in PSC-UC (H3C15, SLC37A2, SLC14A2 and IL20RA). Differential methylation analysis between healthy control biopsies vs PSC-UC and UC demonstrated >1000 differentially methylated regions (DMRs, 5Kb), with majority of these sites displaying hypermethylation. Interestingly, PSC-UC vs UC analysis identified 53 regions and 59 DMRs that are hyper- and hypomethylated respectively in PSC-UC, with a large proportion of these DMRs located in gene promoters and putative enhancer regions and notably impacted gene expression of differentially expressed genes identified from the mRNAseq analysis. Conclusion Taken together, our study for the first time identifies distinct gene expression and DNA methylation alterations that differentiate UC from PSC-UC at diagnosis in treatment-naïve paediatric patients, some of which are associated with GI cancers. Their potential utility as predictive biomarkers of PSC development in UC or dysplasia risk in PSC-UC warrants further validation through larger patient cohorts.

Aims To describe patients with periocular solitary extramedullary plasmacytoma (SEMP) and multiple myeloma (MM), together with an estimate of the risk of progression from SEMP to MM. Patients and methods A retrospective case-note review for patients seen between 1978 and 2020, examining demographics, presentation, imaging, pathology, management, and outcome. Results Twenty patients (10 male; 50%) presented at a mean age of 60.9 years, with an average symptom duration of 4.5 months. Ten (50%) patients had known systemic myeloma at ophthalmic presentation (the MM group) and, on average, they presented one decade earlier than those with occult MM discovered after orbital biopsy (p = 0.06); the majority (9/15; 60%) of patients with MM were female, whereas there was a male bias (4/5; 80%) with SEMP (p = 0.30). Most tumors (15/20; 75%) were within the anterior part of the orbit, especially superolaterally (16 patients; 80%), and the soft-tissue mass often appeared to "explode" from the frontal bone or greater wing of the sphenoid (16/20; 80%). Full treatment details were known for 19 patients: 6 (32%) had solely orbital radiotherapy, 4 (21%) chemotherapy, 6 (32%) combined chemoradiation, and 3 (16%) had combined chemoradiation with stem-cell transplant (Table 3). After an average follow up of 58 months, 1/5 (20%) patients with SEMP and 11/15 (73%) with MM had tumor-related death. The overall survival probability for all 20 patients with periocular plasmacytoma was 34% at 5 and 10 years, with MM patients having a worse outlook (27% 5-year, and 18% 10-year survival) compared with SEMP (53% survival at 5 and 10 years) (p = 0.18). None of the 5 patients with SEMP progressed to systemic MM over an average follow up of 9.1 years. Conclusions Although 50% patients with periocular plasmacytoma appear to have a SEMP at ophthalmic presentation, a half of these patients were found to have occult MM within 6 months of biopsy. Of those without systemic disease around the time of biopsy, none developed MM over an average follow up of more than 9 years.

Background The DUBLIN (Degree of Ulcerative colitis Burden of Luminal Inflammation) is a novel simple clinical score of inflammation in patients with Ulcerative Colitis (UC) which can be used easily in outpatients and at the bedside. Methods We sought to validate the clinical utility of scoring UC inflammatory burden at diagnosis in predicting disease outcomes using the DUBLIN score (DS). We performed a multicentre retrospective study of patients recruited to the Genuity medicine IBD research project at three centres. DS at diagnosis was calculated based on disease extent and endoscopic severity. Study outcomes were need for immunomodulators and/or biologic therapy and need for surgery. We also examined the association between DS and FCP, albumin and C-reactive protein. Results 679 patients with confirmed UC were identified. 291 had data allowing calculation of DS at diagnosis (median age 38.9 years, 53% male). Median DS was 4 [1–9]. 122 patients were treated with biologic therapy during follow-up. Median DS at diagnosis was significantly higher in patients requiring biologic therapy compared to those not requiring biologic therapy [4 versus 3, p = < 0.001]. Of patients requiring biologic therapy patients with a DS > 3 had a significantly shorter time on 1st biologic therapy [2.1 versus 3.9 years, p = 0.005]. There was no difference in median DS dependent on immunomodulator use. Similarly median DS at diagnosis was significantly higher in patients requiring colectomy compared to those not requiring colectomy [6 versus 4, p = 0.001]. There was a weak positive correlation between both DS and faecal calprotectin [correlation coefficient 0.27, p = 0.001] and C-reactive protein [correlation coefficient 0.7, p = 0.01] and a weak negative correlation between DS and albumin level [correlation coefficient -0.22, p = 0.04]. Conclusion Our study validates the clinical utility DS is an accurate clinical tool at diagnosis and during a patients’ disease course for identifying disease burden. A higher DS correlates with an increased need for biologic therapy, need for colectomy and increased biomarkers of disease activity. This is a useful tool for day to day use in clinical practise providing personalised management of patients with UC.

Background Patients with inflammatory bowel disease (IBD) have attenuated responses to current vaccinations. There is a limited body of evidence suggesting patients with IBD receiving TNF antagonists have an attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and various medications for the treatment of IBD on antibody responses to vaccination against COVID-19. Methods Patients with IBD (n=270) and healthy controls (HC, n=116) were recruited prospectively and quantitative antibody responses were assessed following 1st and 2nd doses of COVID-19 vaccination. The impact of IBD and medications for treatment of IBD on vaccine response rates was investigated. Results All HC seroconverted post complete vaccination [100%]. A small proportion of patients with IBD failed to seroconvert [2%]. Median IgG spike protein (SP) antibody levels post-complete vaccination in our IBD cohort was significantly lower than HC [2,613 AU/mL versus 6,871 AU/mL, p= Conclusion Patients with IBD who do not seroconvert post-vaccination against COVID-19 are a vulnerable cohort. Patient with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy further impacts IgG SP antibody levels. Impaired response to vaccination in our study highlights the importance of booster vaccination programmes for patients with IBD.

Background Anti-TNF agents are effective therapies for Inflammatory Bowel Disease (IBD), however, a significant proportion of patients lose response over time. Real world data on prescribing practices and outcome of anti-TNF therapy are of utility to practicing clinicians Methods To evaluate Anti-TNF prescribing practice and durability of Anti-TNF response in a large multicentre IBD cohort. IBD patients commencing an anti-TNF agent, as first biologic therapy, at participating academic centres were identified from institutional databases. Baseline demographic data, concomitant medication and biologic therapy history were collected. Adalimumab(ADA) and Golimumab(GOL) were consider subcutaneous(SC) anti-TNF agents. Date of commencement and discontinuation of first and second line anti-TNF therapy was documented. Kaplan-Meier survival curves were constructed for time based analyses. P values less than 0.05 were considered significant in all analyses. Results N=991 patients with IBD were included in the study. 29%, 69% and 2% had UC, CD and IBD-U respectively; median [IQR] age 27 [19–37] years; 50% female. 31%, 63% and 4% received infliximab(IFX), ADA and GOL respectively as first-line anti-TNF therapy. 35% of patients received an immunomodulator in combination with first-line anti-TNF agent. Median [95% CI] survival free of therapy discontinuation for first and second-line anti-TNF agents was 4.6 [3.7 – 5.3] years and 3.0 [2.1 – 3.9] years respectively. Survival free of anti-TNF discontinuation was significantly shorter for IFX monotherapy group compared with IFX combination therapy, SC anti-TNF monotherapy and SC anti-TNF combination therapy groups, p=0.005. Conclusion While anti-TNF therapies are effective a significant proportion of patients discontinue therapy over time. Second line anti-TNF therapy results in a less durable response with a shorter time to drug discontinuation compared with first line anti-TNF therapy. The use of a combination immunomodulator is particularly important with infliximab therapy, however, does not influence durability of response for subcutaneous anti-TNF agents.

Background Ulcerative colitis (UC) is a chronic inflammatory condition characterized by significant morbidity and escalating economic costs. Effective patient management is severely hampered by a lack of unambiguous molecular biomarkers that can predict response to anti-TNFα treatment such and/or disease progression. While, both genetic and epigenetic factors have been reported to impact UC pathogenesis, their role in regulating disease progression and treatment response remains unclear. Methods Here, we applied methyl-capture sequencing and RNAsequencing to mucosal biopsies derived from clinical cohorts of patients with mild-to-moderate and severe UC with the aim of identifying various regulatory factors that orchestrate treatment response and disease severity in these patients. Results First, differential gene expression analysis between responders and non-responders to infliximab and vedolizumab (anti-TNFα) enabled identification of disease-associated genes that were either up- or down-regulated in responders to both these anti-TNFα agents. Next, upstream analysis of these differentially expressed genes revealed that both up- and downregulated genes in responders are intricately regulated by “master regulators” (MRs) including chemokine ligands and receptors such as FGFR2 and IL8 respectively. Moreover, we show that these MRs play a pivotal role in regulating gene expression through a complex signalling network mediated by transcription factors (TFs) such as FYN and ICAM1. These results for the first time provide evidence of impact of MRs and TFs on genes involved in differential response to anti-TNFα agents in patients with UC. In parallel, targeted DNA methylation profiling of mucosal biopsies derived from mild-to-moderate (n=85) and severe UC (n=33) patients enabled identification of a wide-spread DNA methylation alterations at regulatory regions such as promoters and enhancers. Moreover, we identified distinct significant methylation differences between UC patients who progress in their disease course leading to treatment with anti-TNFα/immunodulators agents vs. patients who are on 5’Asa maintenance treatment. Indeed, similar differences was also observed between responders and non-responders of anti-TNFαagents. Conclusion Taken together, our preliminary results for the first time highlight the regulatory role of master regulator-mediated signalling networks involving transcription factors that regulate gene expression underpinning response to anti-TNFa in UC patients. In parallel, these results identify specific DNA methylation alterations that impact treatment response and disease severity and therefore could ultimately enact as predictive biomarkers in UC.

Background Novel medications including the introduction of biologic therapies in the last decade have expanded treatment options for patients with ulcerative colitis (UC). Large studies in the USA and Europe have shown colectomy rates in UC patients are reducing over the past two decades. Methods We performed a single-centre retrospective study of our prospectively maintained IBD database. Our aim was to look at changes in colectomy rates in patients with UC over the past three decades and need for biologic therapy. Basic demographics, need for biologic therapy and colectomy rates were collected. Need for colectomy and biologic therapy within, 10 years of diagnosis was determined across three groups dependent on decade of diagnosis. Results 2229 patients with confirmed UC were included in our study. Median age at diagnosis was, 37 years [range, 4.9 -92.6]., 1210 [54.28%] were male., 595 patients were diagnosed between, 1990–2000, 795 between, 2000–2010 and, 790 between, 2010–2020. A total of, 366 (16.4%) patients had a colectomy during follow-up and, 363 (16.3%) were treated with biologic therapies. We found rates of colectomy within, 10 years of diagnosis have significant dropped over the past three decades. From, 1990 -2000, 595 patients were diagnosed with UC and, 131 [22%] patients had colectomies, in, 2000-2010, 794 patients were diagnosed with UC and, 135 [17%] had a colectomy and between, 2010-2020, 784 patients were diagnosed with UC and, 55 [7%] had a colectomy [p = Conclusion Management of UC has changed over the past three decades including the introduction of multiple biologic therapies and the use of therapeutic drug monitoring has allowed a more personalised approach to management of UC. We can see from this study changes in the management of UC over the past decade have resulted in significant reduction in need for colectomy and an increase in the use of biologics.

Background Anti-TNF agents are effective treatments for Inflammatory Bowel Disease (IBD), however, a significant proportion of patients require second-line biologic therapy. Real-world data on the outcome of second line biologic therapy can inform clinical decision-making. Methods To evaluate prescribing practice and second-line biologic therapy persistence in IBD patients. IBD patients, who had received one prior anti-TNF agent and commenced a second-line biologic, at participating centres, were identified. Baseline demographic data, concomitant medication and biologic therapy history were characterised by retrospective review of patients records. Adalimumab(ADA) and golimumab(GOL) were considered subcutaneous(SC) anti-TNF agents. Date of commencement and discontinuation of therapies were documented. Kaplan-Meier survival curves were constructed for time based analyses. P values < 0.05 were considered significant in analyses. Results N=395 IBD patients were included; 30%, 68% and 2% had UC, CD and IBD-U respectively; age (median[IQR]) 26[18–35] years; 56% female; 35% receiving a concomitant immunomodulator (IMM); follow-up time (median [IQR]) 1.5[0.7–3.3] years. Second-line biologic therapy with SC anti-TNF, infliximab(IFX), vedolizumab(VDZ), and ustekinumab(USTK) was used in 36%(n=143), 38%(n=151), 10%(n=38), and 16%(n=63) of patients respectively. Follow-up time (median[IQR]) was significantly longer for SC anti-TNF and IFX compared with VDZ and USTK groups: 1.7 [0.7–3.6], 1.7 [0.7–3.5], 1.1[0.3–2.5], 1.3[0.5–2.3] years respectively, p=0.03. A greater proportion of patients receiving anti-TNF therapy versus alternate class biologic therapy received a concomitant IMM: 42%, 34%, 18% and 29% of SC anti-TNF, IFX, VDZ and USTK treated patients respectively, p=0.03. In a univariate survival analysis there was no significant difference in survival-free of drug discontinuation comparing second-line biologic agents, p=0.8. In a multivariate analysis, including second-line biologic agent type, concomitant IMM use, gender and IBD phenotype the only factor significantly associated with time to drug discontinuation was UC phenotype, Hazard ratio (95%CI): 1.5 (1.1 – 2.1), p=0.007. Conclusion While follow-up time was shorter for VDZ and USTK treated patients, the durability of response to second-line biologic therapy, assessed by drug persistence, appeared similar between agents. UC phenotype was associated with a shorter time to therapy discontinuation.

Achieving long duration capabilities has long been an important goal of research in autonomous systems. Persistence can enable such systems to be on station to respond to events and situations that were unknown at the start of a mission. It can enable data collection in spatially and temporally variable environments over time scales appropriate for understanding a wide range of phenomena. Long duration systems have improved ability to cover large distances, travel in ways that minimize energy consumption, and go places that may not be practical for manned or shorter duration systems. Long duration is also an important part of the design trade space for minimizing the costs involved in achieving certain kinds of mission capabilities. This is particularly true when thinking of long duration in terms of entire systems and not just individual platforms. For example, a system with an infrastructure that supports autonomously keeping sufficient numbers of individual platforms on station continuously would fall within this category even if each platform or sensor had only limited persistence individually. Additionally, what constitutes long duration with regards to these challenges may vary significantly from system to system. Much work in the past has focused on extending system limitations through methods such as efficient management of resources, energy harvesting, detection, identification, and

Despite independent evidence that reminiscing about positive events has positive emotional benefits, and that laughter plays a role in seemingly successful relationships, there is a lack of empirical research examining how reminiscing about laughter might influence relationship well being. Specifically, the current study assessed whether reminiscing about shared laughter would increase relationship satisfaction among romantic couples. Fifty-two couples were randomly assigned to one of four reminiscing conditions and completed pre- and post-manipulation assessments of relationship satisfaction. As predicted, couples who reminisced about events involving shared laugher reported higher relationship satisfaction at the post-manipulation satisfaction assessment as compared to couples in the three control conditions. The effect was not attributed to positive mood induction as mood scores across groups were similar. Results show preliminary support for the notion that reminiscing about laughter may have a more potent influence on relationship well being than reminiscing about other positive events.

To examine patient survival, visual function and complications in all patients with choroidal melanoma treated with I125 brachytherapy between 1995 and 2003 at the authors' institution. To compare the results from their institution with those from international series.Data were collected on 92 consecutive patients. Dosimetry was calculated for the lens, fovea, optic nerve and tumour apex. Follow-up status of each patient domiciled outside the treatment centre was analysed from a postal questionnaire.Average pretreatment tumour dimensions were 3.9 mm (thickness) and 15.2 mm (diameter). Complete follow-up data were available on 92% of patients. Regression of tumour occurred in 88% of cases. Five enucleations were performed. There were five melanoma-related deaths. Visual acuity remained6/12 in 35% of patients and6/60 in 51% of patients. The most frequently observed complication was radiation retinopathy (maculopathy 23%, peripheral retinopathy 17%). Radiation cataract was seen in 11% and optic neuropathy in 10%. Dose of more than 90 Gy to the macula gave a 63% chance of developing maculopathy (P0.01). A tumour larger than 4 mm significantly increased the risk of developing radiation maculopathy (P = 0.003). Development of radiation cataract was dose-related;25 Gy to the lens gave a 44% risk of cataract development (P0.001). For tumours less than 4 mm from the disc margin there was a 50% risk of optic neuropathy (P0.001).Patient outcomes following brachytherapy were excellent with a high percentage of patients retaining mobility vision. Development of complications was related to the tumour location and dose to non-tumour structures.

Traumatic globe rupture following penetrating keratoplasty is a life-long postoperative concern. We look at a series of penetrating keratoplasties in one institution and determine the rates of traumatic rupture and the outcomes following rupture. The reasons for persisting wound weakness are reviewed, and recommendations for eye protection based on wound strength are given.A case-control study compared the postsurgical rupture rates for all cases of penetrating keratoplasty to those cases of globe rupture after extracapsular cataract surgery and phacoemulsification. A literature review of corneal wound healing was completed.Over 10 years 139 penetrating keratoplasties were performed. The incidence of traumatic rupture following keratoplasty was 5.8%. Fifty percent of those with ruptured globes had a visual outcome of hand movement vision or worse. Of the traumatic ruptures, 37.5% occurred in the first postoperative month. The indication for initial keratoplasty did not influence the rupture rate. In comparison, the general rate of penetrating eye injuries in the population was 2.2/100,000 per annum. The rupture rate for extracapsular cataract surgery was 1/221 (0.45%) and 0/6450 for phacoemulsification. Both of these rates were significantly less than after penetrating keratoplasty (P=0.005, P0.0001).Penetrating keratoplasty cases have a higher rate of globe rupture than other ocular procedures. There are 5 important time periods of wound integrity after penetrating keratoplasty. The highest risk period is the month following surgery, when wound strength is derived almost entirely from sutures. The 18 months following surgery are moderately high risk. The month following removal of sutures is a second high-risk period. In the 6 months following this, the wound has a similar strength to the first postoperative year. Following penetrating keratoplasty the cornea never regains its preoperative strength and remains at risk for traumatic rupture for the remainder of the patient's life.

Background Unilateral medial rectus recession is suitable for some cases of small-angle deviation in esotropia. This approach limits surgery to one eye, leaves other muscles untouched, and should be quicker than bilateral muscle surgery. This study compared the results of a range of medial rectus recessions, both unilateral and bilateral, performed by one surgeon. Methods Data were collected on all pediatric patients who had undergone medial rectus recession, unilateral and bilateral, performed by one surgeon between August 1, 1995, and March 31, 2002. Postoperative deviations were calculated from the short- (2 to 8 weeks) and long-term (6 to 48 months) follow-up visits. Results Medial rectus recessions were performed on 107 patients, 56 unilateral and 51 bilateral. After exclusions were made, 45 (80%) of the unilateral procedures and 41 (80%) of the bilateral cases were studied. At long-term follow-up, the mean prism diopter (PD) change in deviation per millimeter recessed (at distance) for unilateral recessions of 5 mm, 6 mm, 7 mm, and 8 mm were 2.3, 2.2, 2.3, and 2.5, respectively. For equivalent bilateral recessions the mean changes in deviation were 4.2, 4.0, 4.3, and 5.0 PD/mm. Conclusion Unilateral medial rectus recession is a predictable method for surgical correction of small-angle pediatric esotropia. The change in deviation per millimeter of recession after unilateral recession is significantly less than that obtained from equivalent amounts of bilateral recession (P

Objectives Anti-citrullinated protein antibodies (ACPA) have been shown to cause platelet activation in vitro, through the low-affinity immunoglobulin G (IgG) receptor (FcγRIIa) on platelets. Platelet activation via engagement of FcγRIIa results in proteolytic cleavage and shedding of platelet specific glycoprotein VI (GPVI) which can be detected in the plasma as soluble GPVI (sGPVI). We hypothesized that plasma levels of sGPVI would be increased among patients with seropositive RA as a consequence of antibody-induced platelet activation and GPVI shedding. Methods Samples from 84 patients with RA (65 seropositive and 19 seronegative) and 67 healthy controls were collected prospectively and analysed for sGPVI using a standardised ELISA. Results Patients with seropositive RA had significantly higher levels of sGPVI compared to seronegative RA and controls. Median (IQR) sGPVI levels were 4.2 ng/ml (3.2, 8.0) in seropositve RA, 2.2 ng/ml (1.5, 3.5) in seronegative RA and 2.2 ng/ml (1.6, 3.4) in controls (p

Background: Golimumab (GLB) is a subcutaneous anti-tumour necrosis factor alpha (anti-TNF) therapy. Randomised controlled trials have demonstrated GLB efficacy in the induction and maintenance of remission in ulcerative colitis (UC). Data are few on the outcome of GLB therapy for UC in routine clinical practice. Aims: To describe the outcome of GLB therapy for UC in routine clinical practice in Ireland. Methods: Patients receiving GLB as therapy for UC were identified (n=77) from six Irish Medical centers. Only ambulatory outpatients, with 6 months of follow up post GLB initiation were included (n=69). Baseline clinical, demographic and laboratory data were collected. The primary endpoints were factors associated with durability of GLB response measured by time to drug discontinuation; 3-month clinical response; and 6-month corticosteroid free remission rates. Clinical response was defined as a decrease from baseline in partial Mayo score of at least 3 points and ongoing receipt of GLB. Clinical remission was defined as a partial Mayo score of less than or equal to 2 and continuing receipt of GLB. Secondary endpoints included rates of dose optimisation, dose intervention strategy and adverse events. Raw p values are reported with p values

The concept of operations (CONOPS) for unmanned maritime systems (UMS) continues to envision systems that are multi-mission, re-configurable and capable of acceptable performance over a wide range of environmental and contextual variability. Key enablers for these concepts of operation are an autonomy module which can execute different mission directives and a mission payload consisting of re-configurable sensor or effector suites. This level of modularity in mission payloads enables affordability, flexibility (i.e., more capability with future platforms) and scalability (i.e., force multiplication). The modularity in autonomy facilitates rapid technology integration, prototyping, testing and leveraging of state-of-the-art advances in autonomy research. Capability drivers imply a requirement to maintain an open architecture design for both research and acquisition programs. As the maritime platforms become more stable in their design (e.g. unmanned surface vehicles, unmanned underwater vehicles) future developments are able to focus on more capable sensors and more robust autonomy algorithms. To respond to Fleet needs, given an evolving threat, programs will want to interchange the latest sensor or a new and improved algorithm in a cost effective and efficient manner. In order to make this possible, the programs need a reference architecture that will define for technology providers where their piece fits and how to successfully integrate. With these concerns in mind, the US Navy established the Unmanned Maritime Systems Reference Architecture (UMS-RA) Working Group in August 2011. This group consists of Department of Defense and industry participants working the problem of defining reference architecture for autonomous operations of maritime systems. This paper summarizes its efforts to date.

A case of bilateral upper eyelid ptosis in an HIV-infected patient with severe antiretroviral-associated facial lipodystrophy is presented. The features, treatment, and outcome are discussed. Dehiscence of the levator aponeurosis may be directly associated with highly active antiretroviral therapy-induced lipodystrophy.

Triethylene glycol monomethyl ether (TGME) was administered orally via gavage stomach tube to mated Caesarean delivered (CD) rats and artificially inseminated New Zealand white rabbits on days 6–15 and 6–18 of gestation, respectively, at dose levels of 0, 625, 1,250, 2,500, or 5,000 mg/kg/day (rats) and 0, 250, 500, 1,000, or 1,500 mg/kg/day (rabbits). Clinical signs, maternal body weights, and feed consumption were monitored throughout the treatment period. The surviving rats and rabbits underwent Caesarean section on day 20 and day 29 of gestation, respectively. Fetuses were weighed, sexed, and examined externally and for soft tissue and skeletal alterations. In rats, the high dose significantly reduced maternal body weights, feed consumption, and gravid uterine weights. One dam in this group died on day 13 of gestation. Treatment-related clinical signs were seen only at the highest dose tested. Maternal feed consumption was significantly reduced at 5,000 and 2,500 mg/kg and slightly, but not significantly, reduced at 1,250 mg/kg. Doses as high as 5,000 mg/kg/day did not affect pregnancy rate, implantations, corpora lutea, live fetuses, or fetal sex ratios. Resorptions were significantly increased at 5,000 mg/kg, and fetal body weights were slightly reduced at 1,250 mg/kg and significantly reduced at 2,500 and 5,000 mg/kg. The incidences of malformations and external or internal soft tissue variations were not increased at doses as high as 5,000 mg/kg. Incidences of skeletal variations were increased at doses of 1,250 mg/kg and higher. The no-observable-effect level (NOEL) in rats, for both maternal and developmental toxicity, was 625 mg/kg, while 1,250 mg/kg was a no-observable-adverse-effect level (NOAEL) for maternal toxicity and may be very near the NOAEL for developmental toxicity. In rabbits, 1,500 mg/kg/day reduced maternal body weights and feed consumption and caused death, abortions, treatment-related clinical signs of toxicity, and reduced gravid uterine weights. One doe in the 1,000 mg/kg group died on day 18 of gestation, but no treatment-related signs were seen in the other animals in this group. Doses as high as 1,500 mg/kg did not significantly affect pregnancy rate, implantations, corpora lutea, resorptions, live fetuses, fetal body weights, or sex ratio. Incidences of malformations or external and internal variations were not increased at any of the dose levels. The only developmental toxicity seen in the rabbit was an increase in the incidence of two common skeletal variations, angulated hyoid alae and delayed ossification of the xiphoid process, at the highest dose tested. For maternal toxicity, the NOEL and NOAEL were 250 mg/kg and 500 mg/kg, respectively, and for developmental toxicity the NOEL and NOAEL were 1,000 mg/kg and 1,500 mg/kg, respectively. These studies indicate that TGME was not selectively toxic to developing rat or rabbit conceptuses.

Interactions between CD4+ T cells and B cells are mediated by both soluble factors and cell surface molecules. The Ag-independent interaction between the CD40 ligand, expressed on activated T cells, and its CD40 receptor, expressed on B cells, enhances B cell proliferation in response to IL-4 stimulation. The expression of the CD40 ligand is induced on CD4+ T cells by stimulation with Ag-pulsed APC or mitogens. Here, we show that at least some IL-4-producing murine CD8+ T cell clones can be induced to express the CD40 ligand when stimulated with anti-CD3 mAb. Additionally, such activated CD8+ IL-4-producing clones potentiate the proliferative response of small resting B cells to IL-4 and induce Ig secretion by small resting B cells to IL-4 and IL-5. Proliferation of small resting B cells cultured with IL-4 in the presence of activated IL-4-producing CD8+ murine T cell clones appeared to be mediated by the expression of the CD40 ligand on the T cell because an anti-CD40 ligand mAb inhibited this proliferative response. A conventional murine CD8+ CTL clone, which did not produce IL-4 or express CD40 ligand upon activation, did not potentiate proliferation of small resting B cells exposed to IL-4. Thus, under some circumstances, CD8+ T cells that are able to express CD40 ligand may be able to provide B cell help.

Open architecture (OA) within military systems enables delivery of increased warfighter capabilities in a shorter time at a reduced cost.i In fact in today's standards-aware environment, solutions are often proposed to the government that include OA as one of its basics design tenets. Yet the ability to measure and assess OA in an objective manner, particularly at the subsystem/component level within a system, remains an elusive proposition. Furthermore, it is increasingly apparent that the establishment of an innovation ecosystem of an open business model that leverages thirdparty development requires more than just technical modifications that promote openness. This paper proposes a framework to migrate not only towards technical openness, but also towards enabling and facilitating an open business model, driven by third party development, for military systems. This framework was developed originally for the U.S. Navy Littoral and Mine Warfare community; however, the principles and approach may be applied elsewhere within the Navy and Department of Defense.© (2012) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

Mature CD4+ helper T lymphocytes have been categorized into two major functional phenotypes, TH1 and TH2, which produce distinct arrays of lymphokines and which are thought to arise from a pluripotential precursor cell termed TH0. Clonal anergy can be induced in TH1 clones by stimulating via the T cell receptor (TCR) complex in the absence of a costimulator molecule; however, anergy has been difficult to demonstrate in TH2 clones. We show here that treatment of cloned TH0 lines with anergizing stimuli results in the selective loss of TH1 characteristics and retention of a TH2 phenotype. Treated cells exhibit a substantial reduction in interleukin 2 (IL-2) production and antigen-specific cytolytic activity, but retain comparable IL-4 and IL-5 production in response to restimulation via the TCR complex. TH0 clones exposed to anergizing stimuli also increase in size, thus morphologically resembling TH2 cells. The signaling characteristics of these cells also are altered, in that they exhibit an elevated basal level of intracellular free calcium which fails to increase significantly with subsequent restimulation, reminiscent of the signaling characteristics of TH2 cells. "Anergized" TH0 clones thus share several functional, morphologic, and physiologic properties with cells of the TH2 phenotype, suggesting that TH2 cells may arise when TH0 cells are stimulated via the TCR complex in the absence of a putative costimulator molecule.

The purpose of this paper is to define the vision and future strategy for advancing the use of automation in underwater mine recognition. The technical portion of this strategy is founded on the principle of adapting the automation in situ based on a highly variable environment / context and the occasional availability of the human operator. To frame this strategy, a survey of past and current algorithm development for underwater mine recognition is presented and includes a detailed description on adaptive algorithms. This discussion is motivated by illustrating the extreme variability in the underwater environment and that performance estimation techniques are now emerging that are capable of quantifying these variations in situ. It is the in situ linkage of performance estimation with adaptive recognition that forms one of the key technological enablers of this future strategy. The non-technical portion of this strategy is centered on enabling an effective human-machine team. Enabling this teaming relationship involves both gaining trust and establishing an overall support system that is amenable to such human-machine interactions. Aspects of trust include both individual trust and institutional trust, and a path for gaining both is discussed. Overall aspects of the support system are highlighted and include standards for data and interoperability, network-centric software architectures, and issues in proliferating knowledge that is learned in situ by multiple distributed algorithms. This paper concludes with an articulation of several important and timely research questions concerning automation for underwater mine recognition.

MDM2 overexpression has been detected in women with benign or cancerous lesions of the breast. Immunohistochemical methods were used to identify overexpression in 11 of 27 benign cases (41%) and 15 of 22 (68%) cancer cases. MDM2 overexpression correlated well with immunohistochemically detected estrogen receptor (ER), suggesting that expression of these proteins was coordinately regulated. To test this, the MCF-10A human breast cell line, negative for both ER and MDM2 expression, was transfected with a wild-type ER. Following transfection, both ER and MDM2 were strongly expressed in two independent clones. Expression of both was reduced in the presence of increasing concentrations of estradiol (10(-10)-10(-8) M) thus, estrogen may be involved in regulation of MDM2 expression in proliferative breast lesions.

Groups of Sprague-Dawley rats were treated dermally with the vehicle, distilled water or with diethylene glycol butyl ether (DGBE) at 10 or 30% v/v aq. solutions or undiluted (0.2, 0.6, or 2.0 g/kg body weight) for 13 weeks under occlusion 6 hr/day, 5 days/week, at the maximum attainable volume of 2 mL/kg. Male and female rats were examined using a functional observational battery (FOB) prestudy, at 1, 6, and 24 hr after the initiation of the first exposure, and prior to treatment on days 7, 14, 35, 63, and 91. Motor activity was determined prestudy and on nontreated days 34, 62, and 90. At the completion of treatment, six control and top dose group animals were perfused for neuropathology. There was no mortality, and the body weights and food consumption were unaffected. Five females in the top dose group had scab formation at the treatment site during the study. There were no other treatment-related clinical findings. The FOB and motor activity tests revealed no findings indicative of a neurotoxic effect, and there were no gross or neuropathological changes that were attributed to treatment. No neurotoxicity or other systemic toxicity was seen at the highest dose tested—2 g/kg/day.

DGBE was evaluated in a forward gene mutation assay at the HGPRT locus of CHO cells in culture and in an in vivo mouse bone marrow micronucleus test for cytogenetic damage. DGBE did not elicit a positive response in the CHO/HGPRT assay when tested up to a maximum concentration of 5000 μg/ml with and without an external metabolic activation system (S-9). In the micronucleus test employing three post-treatment bone marrow sampling times (24, 48, and 72 hr), DGBE was ineffective in increasing the incidence of micronucleated polychromatic erythrocytes (MN-PCE) when tested in both sexes up to a maximum tolerated dose of 3300 mg/kg body weight. Thus, these data and those of others indicate a general lack of genotoxic potential for DGBE in short-term tests.

Human dermal exposure to diethylene glycol butyl ether (DGBE) and its acetate derivative (DGBA) may occur through contact with a variety of commercial products. Absorption and elimination of dermally applied doses of 14C-DGBE and 14C-DGBA were determined in Sprague-Dawley rats. The materials were applied under occlusion for 24 hr at dose levels of 0.2 and 2.0 g/kg (undiluted) and as a 10% aqueous solution (0.2 g/kg DGBE). Preliminary washing efficiency studies with soap and water indicated that greater than 89% of each chemical could be removed from rat skin following 5-min exposures. Female rats excreted a larger proportion of the applied dose of DGBE than did male rats. Similar results were obtained with the low dose of DGBE applied neat or as a 10% aqueous solution, suggesting that the low dose represents a saturating dose. The total recovered 14C for all studies with 14C-DGBE ranged from 83% to 89%, with 14C-DGBA, from 80% to 88%. Urinary excretion accounted for the majority of recovered 14C in all studies. The acid, 2-(2-butoxyethoxy)acetate acid was the major urinary metabolite identified. The glucuronide of DGBE was present at levels of from 5.2 to 8.2% of the urinary 14C. The dermal absorption rates were estimated to be 1.58 (DGBA, male), 1.28 (DGBA, female), 0.73 (DGBE, male), and 1.46 (DGBE, female), expressed as mg/cm2/hr.

The subchronic and reproductive toxicity of diethylene glycol butyl ether (DGBE) by the dermal route was evaluated in Sprague-Dawley rats using a novel combined protocol. DGBE was administered dermally at 10 or 30% v/v in aqueous solutions or undiluted (100%) for 13 weeks under occlusion, 6 hr/day, 5 days/week at a maximum attainable volume of 2 mL/kg. Satellite groups of male and female rats were treated with the top dose of DGBE for 13 weeks, mated, and the females were treated through day 20 of gestation and allowed to deliver and nurse their offspring through day 21 of lactation (weaning). DGBE produced dermal irritation, which was dependent on concentration in incidence, severity, and time of onset and was more severe in females than in males. No corresponding histopathology was evident. The only suggestion of a systemic effect was a slightly increased incidence of urinary occult blood at study termination in the females receiving the 30% or 100% DGBE dose. There was no evidence of histopathologic changes in the testes, and vaginal cytology indicated no adverse effect on estrous cycling. There were no effects on reproductive performance of the DGBE-treated males and females. Litters delivered by treated females contained the same number of live pups as control litters and the growth and survival of pups within the treated litters was comparable to control. No reproductive or systemic toxicity was observed at the highest dose tested—2 g/kg/day.