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This paper investigates the in-plant logistics processes in automotive manufacturing and specifically, the material flows between the storage facility, the production lines, and the internal returns area. The aim is to improve the efficiency of the plant by looking at the current material flows of the case study company. Qualitative and quantitative data was collected through interviews and personal observations and was analysed. Using discrete event-based simulation, the current material flows were investigated. Our analysis showed that in plant’s internal returns area efficiency gains are possible by reducing traffic congestion. A solution with minor changes in the layout was proposed and tested which showed an increase in the capacity of the system and a reduction in delays.

The slow-worm lizards (Anguis) comprise five species occurring throughout most of the Western Palearctic. Although these species are relatively uniform morphologically – with the exception of A. cephallonica, which exhibits a quite unique morphology – they are genetically deeply divergent. Here, we provide detailed distribution maps for each species and discuss their biogeography and conservation based on updated genetic data and a robust distribution database. We pay particular attention to the so called ‘grey zone’, which typically represents secondary contact zones and in some cases confirmed or presumed hybrid zones. Four of the five species live in parapatry, while only two species, A. cephallonica and A. graeca from the southern Balkans occur in partial sympatry. Further research should focus on the eco-evolutionary interactions between species in contact, including their hybridization rates, to reveal deeper details of the slow-worm evolutionary and natural history.

Background Chest computed tomography (CT) is a useful tool for the diagnosis of coronavirus disease-2019 (COVID-19), although its exact value for predicting critical illness remains unclear. This study evaluated the efficacy of chest CT to predict disease progression, pulmonary complications, and viral positivity duration. Methods A single-center cohort study was conducted by consecutively including hospitalized patients with confirmed COVID-19. The chest CT patterns were described and a total severity score was calculated. The predictive accuracy of the severity score was evaluated using the receiver operating characteristic analysis, while a Cox proportional hazards regression model was implemented to identify the radiological features that are linked to prolonged duration of viral positivity. Results Overall, 42 patients were included with 10 of them requiring intensive care unit admission. The most common lesions were ground glass opacities (92.9%), consolidation (66.7%), and crazy-paving patterns (61.9%). The total severity score significantly correlated with inflammatory and respiratory distress markers, as well as with admission CURB-65 and PSI/PORT scores. It was estimated to predict critical illness with a sensitivity and specificity of 75% and 70%, respectively. Time-to-event analysis indicated that patients without ground-glass opacities presented significantly shorter median viral positivity (16 vs. 27 days). Conclusions Chest CT severity score positively correlates with markers of COVID-19 severity and presents promising efficacy in predicting critical illness. It is suggested that ground-glass opacities are linked to prolonged viral positivity. Further studies should confirm the efficacy of the severity score and elucidate the long-term pulmonary effects of COVID-19.

Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE.

Purpose of Review To summarize current knowledge of the impact of coronavirus disease 19 (COVID-19) on patients with systemic lupus erythematosus (SLE). Recent Findings Several observational studies, including case series, patient surveys, and patient registries, have examined the incidence and severity of COVID-19 in patients with SLE. Due to methodologic limitations (focus on sicker patients, exclusion of asymptomatic or mild cases, limited or inaccurate viral testing), it is difficult to determine the risk and outcomes of COVID-19 in SLE patients. Corticosteroids might be associated with increased hospitalizations from COVID-19 in individuals with autoimmune rheumatic diseases. Some immune suppressive treatments do not appear to significantly increase the risk of contracting COVID-19 or poor subsequent outcomes; however, data on the safety of specific drugs remain scarce. Studies in non-autoimmune cohorts have shown more severe COVID-19 in ethnic and racial minorities, populations also more heavily impacted by SLE. Such results have been attributed to highly prevalent socioeconomic disparities and comorbidities. The complex interplay between SARS-CoV-2 and the host immunologic milieu may have particular implications for patients with SLE that remain to be explored. Concerns have been raised of COVID-19 heightening the risk of thromboembolic events in the presence of an SLE-induced procoagulant state. Summary Limitations in epidemiologic data available to date do not allow for assessing the risk and severity of COVID-19 in patients with SLE. Other than corticosteroids, prior use of some immune suppressive medications does not appear to increase the risk for infection with SARS-CoV-2 however, more comprehensive studies are needed.

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focused ultrasound during in vivo experiments using porcine models. This study illustrates how such a device could be potentially used for gastrointestinal drug delivery and the challenges to be overcome before focused ultrasound and microbubbles could be used with this device for the oral delivery of biologic therapeutics.

ObjectiveAlthough SLE disproportionately affects minority racial groups, they are significantly under-represented in clinical trials in the USA. This may lead to misleading conclusions in race-based subgroup analyses. We conducted focus groups to evaluate the perceptions of diverse patients with lupus about clinical trial participation.MethodsA qualitative research design employed three 90 min focus groups led by a trained moderator and guided by the Theory of Planned Behaviour. Open-ended questions about trial participation included advantages and disadvantages (behavioural beliefs), approving and disapproving significant others (normative beliefs), and participation enhancers and barriers (control beliefs). Discussions were recorded, transcribed and analysed to identify emerging themes.ResultsPatients with SLE (n=23) aged 21–72, with increased proportion of minority groups (65%), participated. Reported advantages of trial participation included altruism and personal benefit. Disadvantages included uncertainties, disappointment, information burden, and life–health balance. Although some patients had discussed research participation with approving or disapproving family or friends, self-approval superseded external approval. Barriers included logistics and time, and facilitators included flexibility in scheduling, advance notice of studies, streamlined forms, and hope for SLE improvement.ConclusionsKnowledge about potential benefits of clinical trial participation was high. Minority patients demonstrated confidence in making their own informed decisions, but major barriers for all participants included burdensome forms, travel, childcare, and work. These suggest a major impact on minority and all recruitment from behavioural and control aspects, which should be considered in the logistics of trial design. This does not minimise the potential importance of improved access and education about clinical research.

Inflammatory bowel disease (IBD) is a chronic and progressive disorder with destructive inflammation in the gastrointestinal tract (GIT). Biologics have changed the management of IBD, but have serious limitations, which is associated with their systemic administration via injection. Oral administration is the most accepted route of drug administration. However, the physiological barriers of the GIT pose significant challenges for oral administration of biologics, making this route of administration currently unavailable. The status of tissue barriers to oral drug delivery is altered in IBD. This may bring more challenges, but also present opportunities for oral delivery of biologics. This article provides an overview of disease-induced alterations of GIT barriers in IBD and discusses challenges, opportunities and commonly-utilised strategies for oral delivery of complex therapeutics, including biologics and nanomedicines.

Lupus disease measures such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) index are challenging to interpret. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) is intended to provide an efficient application of anchored visual analog scores, each representing the individual severity of active symptoms, with the sum of individual scores deriving an overall disease activity assessment. Our objective was to compare the performance of LFA-REAL to systemic lupus erythematosus disease activity assessments and compare scores between trained lupus clinical investigators and clinicians.Investigators scored the SLEDAI, BILAG, physician's global assessment (PGA), and LFA-REAL, while the clinicians scored the LFA-REAL. The level of agreement between physicians and instruments was determined.The study included 99 patients (93% women, 31% white, mean ± SD ages 43.4 ± 13.2 years). At the first visit, the mean ± SD SLEDAI score was 5.5 ± 4.5, BILAG score 6.7 ± 7.8, and PGA score 33.6 ± 24.5. The mean ± SD investigator LFA-REAL score was 46.2 ± 42.9, and clinician LFA-REAL score 56.1 ± 53.6. At the second visit, the mean ± SD investigator LFA-REAL score was 41.3 ± 36.7, and clinician LFA-REAL score 48.3 ± 42.6. Total LFA-REAL scores correlated positively with PGA, SLEDAI, and BILAG (ρ = 0.58-0.88, P0.001). LFA-REAL scores produced correlation coefficients of ρ0.7 for musculoskeletal, mucocutaneous, and renal BILAG domains. The intraclass correlation coefficient between the LFA-REAL scores of investigators and clinicians was 0.79 for visit 1 (P0.001) and 0.86 for visit 2 (P0.001).The LFA-REAL provides a reliable surrogate for more complicated disease activity measures when used by lupus clinical investigators or clinicians.

Patient: Male, 7 Final Diagnosis: Echinococcosis Symptoms: Cough • fever Medication: — Clinical Procedure: Medical treatment and RFA of liver cyst Specialty: Pediatrics and Neonatology Objective: Unusual setting of medical care Background: Radiofrequency ablation has been established as a treatment method for malignancies and some particular cystic lesions, especially in adults. Experience with radiofrequency ablation in the treatment of hydatid cysts, especially in children, is limited. Case Report: Although echinococcosis is rare, especially in children, we describe a 7-year-old boy with lung and liver cystic echinococcosis. Diagnosis was established by clinical history and imaging findings and confirmed by positive antiechinococcal antibodies. After 6 months of chemotherapy with albendazole, the liver lesion remained and a radiofrequency ablation under computed tomography guidance was obtained. The procedure was performed with a new type of ablation electrode in order to minimize handling and procedure duration and to achieve the best clinical result in only 1 session. This type of electrode provides the ability to simultaneously drain and ablate the cyst and the ability to monitor the desired ablation temperature in real time. Conclusions: Our patient is the first pediatric case with hepatic hydatid cyst treated successfully with the use of a new type of radiofrequency ablation electrode under computed tomography guidance.

Purpose An etiological treatment is currently lacking for Langerhans Cell Histiocytosis (LCH). Receptor activator of nuclear factor κB ligand (RANKL) appears to play a central role in the lesional immunological process inducing compensatory osteoprotegerin (OPG) activation. In a preliminary study we aimed to evaluate for the first time the use of denosumab, a RANKL inhibitor, as a targeted treatment strategy in LCH in order to support and enhance endogenous OPG action in order to control or alter the lesional immunological process. Procedures Two adult female patients with painful osteolytic bone lesions and concomitant pulmonary involvement received bimonthly denosumab 120 mg in a total of 4 doses. Results Both patients reported an immediate pain relief within the first two weeks following the 1st dose of denosumab. One month following the last dose an almost full remission of the initial osteolytic and lung lesions was observed, although an apparent new bone lesion was detected in one patient that was treated with a single intralesional steroid injection. No adverse events were recorded throughout the treatment period. Both patients have no active disease 6 months following the last denosumab dose. Conclusions Denosumab could be considered an effective treatment option in adults with multisystem LCH also exerting a significant analgesic effect in bone lesions, warranting further investigation.

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in-vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focussed ultrasound. These findings suggest that the use of focused ultrasound together with microbubbles could play a role in the oral delivery of biologic therapeutics.

ObjectiveTo evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care.MethodsPatients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering.ResultsIFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (pConclusionsIFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering.Trial registration numberNCT02665364.

Background Abatacept (ABA) is a fusion protein of the extracellular domain of CTLA4 and the Fc domain of human IgG1, constructed to inhibit B/T cell co-stimulation. Previous studies of ABA in lupus failed to show benefit in overall disease activity, but improvement in arthritis was suggested. Objectives This 6-month randomized, double-blind, placebo-controlled (PBO) study withdrew background medications to facilitate the assessment of ABA in patients with SLE arthritis. Methods Patients were entered with moderate to severe arthritis [BILAG A or B with ≥3 swollen and ≥3 tender joints (28 joint count)]. All DMARDs except prednisone (up to 20mg daily) were withdrawn by baseline and patients were randomized 1:1 to weekly sc ABA or PBO. One or more DepoMedrol injections (≤320mg total) was allowed by end of Month 2. Additional steroids or immune suppressants (IMS) at any time, and transition to open label ABA at Month 3 or later, were allowed, but designated non-response. The primary endpoint was BICLA response at Month 6 compared to screening. Secondary objectives included SRI-4, SLEDAI 4-point improvement, SLEDAI arthritis resolution, BILAG A/B musculoskeletal (MSK) improvement, as well as low disease activity defined by either SLEDAI 2 or Lupus Low Disease Activity State (LLDAS) at Month 6. Flares were evaluated by the modified SELENA-SLEDAI flare index (1) in patients followed after baseline. Results 66 patients were randomized and received at least one dose of the study drug, 31 ABA and 35 PBO. 7 withdrew prior to Month 6. Placebo response rates were lower than in most SLE trials, but no primary or secondary endpoints were met, see table (Fischer’s exact test). Flares were evaluable in 64 patients (31 on ABA, 33 on PBO). 14 (45%) patients on ABA vs. 18 (55%) on PBO had a moderate/severe flare by Month 6. 22 (71%) patients on ABA vs. 23 (70%) on PBO experienced flare or treatment failure (early drop off or off protocol steroids or IMS) by Month 6. Rates of flare and treatment failure by Month 6 did not differ between groups (Log-Rank test, p=0.688 and p=0.631, respectively). The safety profile of ABA was consistent with known effects of the treatment. Conclusion ABA did not demonstrate improvement vs placebo in controlling disease activity or flare in SLE patients in a protocol that mandated IMS withdrawal. Placebo response rates of ≤23% support the validity of these results. Since some evidence suggests potential efficacy of ABA for certain biologic subsets of SLE (2), immunophenotyping may prove helpful. References [1] Thanou A, Chakravarty E, James JA, Merrill JT. Rheumatology (Oxford) 2014;53(12):2175-81. [2] Bandyopadhyay S, Connolly SE, Jabado O, Ye J, Kelly S, Maldonado MA, Westhovens R, Nash P, Merrill JT, Townsend RM. Lupus Sci Med. 2017 4 (1): e000206. Disclosure of Interests Aikaterini Thanou Grant/research support from: Bristol-Myers Squibb, Consultant for: Neovacs, Cristina Arriens Grant/research support from: Bristol-Myers Squibb, GSK/HGS, Consultant for: GSK, AstraZeneca, Teresa Aberle: None declared, Eliza Chakravary: None declared, Samera Vaseer: None declared, Joe Rawdon: None declared, Judith A. James: None declared, Joan Merrill Grant/research support from: Genentech, UCB, GSK, EMD Serono, Pfizer, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Amgen, Xencor, Neovacs, Consultant for: Genentech, UCB, GSK, EMD Serono, Pfizer, RemeGen, Celgene, Exagen, Bristol Myers Squibb, Medimmune/Astra Zeneca, Lilly, Immupharma, Amgen, Janssen, Sanofi, Neovacs, Anthera, Speakers bureau: UCB, GSK, EMD Serono, Bristol Myers Squibb, Medimmune/Astra Zeneca, Janssen

While the prevalence of Autism Spectrum Disorder (ASD) is increasing, research continues in an effort to identify common etiological and pathophysiological bases. In this regard, modern machine learning and network science pave the way for a better understanding of the neuropathology and the development of diagnosis aid systems. The present work addresses the classification of neurotypical and ASD subjects by combining knowledge about both the structure and the functional activity of the brain. In particular, we model the brain structure as a graph, and the resting-state functional MRI (rs-fMRI) signals as values that live on the nodes of that graph. We then borrow tools from the emerging field of Graph Signal Processing (GSP) to build features related to the frequency content of these signals. In order to make these features highly discriminative, we apply an extension of the Fukunaga-Koontz transform. Finally, we use these new markers to train a decision tree, an interpretable classification scheme, which results in a final diagnosis aid model. Interestingly, the resulting decision tree outperforms state-of-the-art methods on the publicly available Autism Brain Imaging Data Exchange (ABIDE) collection. Moreover, the analysis of the predictive markers reveals the influence of the frontal and temporal lobes in the diagnosis of the disorder, which is in line with previous findings in the literature of neuroscience. Our results indicate that exploiting jointly structural and functional information of the brain can reveal important information about the complexity of the neuropathology., (c) 2021 Elsevier B.V. All rights reserved.

Background: Treatment of adrenal metastasis from lung carcinoma may prolong survival in the selected patients. However, not all patients can undergo surgery; thus, minimally invasive ablation procedures such as radiofrequency ablation (RFA) and microwave ablation (MWA) have gained acceptance as alternative treatment methods. This study summarized a 5-year single-center experience regarding the evaluation of safety and efficacy of computed tomography (CT)-guided thermal ablation in the management of adrenal metastasis originating from non-small cell lung cancer (NSCLC). Methods: The data of NSCLC patients ablated for adrenal metastasis at the Department of Diagnostic Imaging and Interventional Radiology, General Hospital Sotiria, were retrospectively analyzed. Patients were divided into two groups: RFA group and MWA group according to the therapeutic approaches. Preprocedural blood tests included measurement of international normalized ratio, partial thromboplastin time, and platelet enumeration. A dual-phase contrast-enhanced spiral CT was performed immediately after the procedure to assess the immediate response after ablation and to screen for related complications. Follow-up was performed with CT or magnetic resonance imaging at 1, 3, 6 months and 1 year after ablation and every 6 months thereafter. Results: A total of 99 ablation sessions in 71 patients with adrenal metastasis originating from NSCLC were included in the final analysis. Self-limited, postablation syndrome occurred in 16/99 (16.1%) of ablation sessions. All procedures were technically successful. Immediate postablation imaging showed no contrast enhancement of the ablated tumor in all patients. Follow-up imaging at 3 months revealed local tumor progression in 8 (22.8%) patients of the RFA group and 7 (19.4%) patients of MWA group, all of them underwent a second session successfully. The 1-year assessment revealed local recurrence of the ablated tumor in six patients (17.1%) of RFA group and seven patients (19.4%) of MWA group. Among these 71 patients, those with tumor size >3.5 cm had a higher local recurrence rate (65.2%, 15/23) than those with tumors ≤3.5 cm (16.7%, 8/48; P = 0.012). There was no significant difference in the median survival time between RFA (14.0 months) and MWA (14.6 months) groups (P > 0.05). Conclusions: RFA and MWA showed comparable efficacy and safety in adrenal metastasis treatment.

SLE is a clinically heterogeneous disease characterized by an unpredictable relapsing-remitting disease course. Although the etiology and mechanisms of SLE flares remain elusive, Epstein-Barr virus (EBV) reactivation is implicated in SLE pathogenesis. This study examined the relationships between serological measures of EBV reactivation, disease activity, and interferon (IFN)-associated immune pathways in SLE patients. Sera from adult SLE patients (n = 175) and matched unaffected controls (n = 47) were collected and tested for antibodies against EBV-viral capsid antigen (EBV-VCA; IgG and IgA), EBV-early antigen (EBV-EA; IgG), cytomegalovirus (CMV; IgG), and herpes simplex virus (HSV-1; IgG). Serological evidence of EBV reactivation was more common in SLE patients compared to controls as demonstrated by seropositivity to EBV-EA IgG (39% vs 13%; p = 0.0011) and EBV-VCA IgA (37% vs 17%; p = 0.018). EBV-VCA, CMV1, and HSV-1 IgG seropositivity rates did not differ between SLE patients and controls. Furthermore, concentrations of EBV-VCA (IgG and IgA) and EBV-EA (IgG) were higher in SLE patients. SLE patients with high disease activity had increased concentrations of EBV-VCA IgA (mean ISR 1.34 vs. 0.97; p = 0.041) and EBV-EA IgG levels (mean ISR 1.38 vs. 0.90; p = 0.007) compared with those with lower disease activity. EBV reactivation was associated with enhanced levels of the IFN-associated molecule IP-10 (p, Highlights • Serologic markers of EBV reactivation are more common in SLE patients. • Elevated EBV reactivation is associated with higher SLE disease activity. • EBV serologic reactivation correlates with elevated IP-10, IL-10, and BLyS levels. • EBV reactivation occurs in SLE clusters with robust inflammatory and IFN responses.

The sheep and goats brucellosis program is one of the most important animalhealth programs with significant animal health, public health, and internationaltrade consequences. Several factors are involved in the implementation of thisprogram, while its success depends on the availability of an effective, well-trained,and fully engaged staff. Considering the poor results of sheep and goats brucellosisprogram in Greece mainly related to the limited number of veterinarians workingin the regional veterinary services, the present study aims to approach the numberof the human resources and more precisely of veterinarians that are essential forthe effective and efficient brucellosis control strategy in Greece. Therefore, the dataderived by the performance of the program for the years 2012 to 2015 are analyzed.Finally, economic and political circumstances – external factors that affect thefunctionality of the program as well as all relevant bottlenecks are being discussed.The findings of the present study indicate that approximately 485 veterinarians with485 assistants working for the needs of the brucellosis program would significantlyassist on the complete implementation of the brucellosis control and eradication ofthe disease in Greek sheep and goat holdings.

As a well-established method for clinical imaging, ultrasound can also be used as source of focused waves to selectively affect tissues by activating drug carriers and/or improving drug uptake in tumors providing a novel strategy for targeted treatment [1]. In this chapter we describe the design of nanoparticles that can respond to effects induced by focused ultrasound that can be used in cancer therapy.

Traditional prototype development and optimization is a long and costly process. Customization of those products is either very difficult or unfeasible. Healthcare implants are often chosen by the surgeon, much like shoes, for the ‘best fit’. In addition to synthetic implant issues, there is a considerable lack of tissue and organs for transplant. When we consider the development and testing of new drugs, many in vitro models are poor predictors for drug efficacy. Cell and tissue growth on commonly used plastics, in 2 dimensions, may be part of this issue. Looking at drug delivery, the release and stability are often poorly optimized, with controlled drug delivery and release kinetics often unaddressed. In addition to these healthcare related issues, the world is facing increased pressure for resources due to both population growth and standard of living increases.

Background Existing methods for grading lupus flares or improvement in disease activity require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analyzed the performance of two scales, the SELENA SLEDAI Physician’s Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REALTM) as measures of progress in SLE. Methods Prospectively, we evaluated the agreement between collected disease activity (SLEDAI, BILAG-2004, CLASI, SSPGA and LFA-REALTM) and response (SRI-4 and BICLA) measures in an ongoing clinical trial. Results 50 patients (47 females, mean age 45±11.6 years) were assessed at 528 consecutive visits (average 10.6±4.1 visits per patient). Changes in disease activity compared to baseline were examined in 478 visit pairs. SSPGA and LFA-REALTM correlated with each other (r=0.936), and with SLEDAI and BILAG [SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REALTM: r=0.778 (SLEDAI), r=0.813 (BILAG); all p Conclusions SSPGA and LFA-REALTM are reliable surrogates of common SLE trial endpoints and could be used as continuous or dichotomous response measures. Additionally, LFA-REALTM can provide individualized scoring at the symptom or organ level. Acknowledgements We thank the patients for their participation in the study. Clarification of Abatacept Effects in SLE with Integrated Biologic and Clinical Approaches (The ABC Study) is an ongoing, investigator-initiated, clinical trial, conducted at the Oklahoma Medical Research Foundation (OMRF), with funding from Bristol Myers Squibb (NCT02270957).

Introduction: Research into oral delivery of biologics has a long and rich history but has not produced technologies used in the clinic. The area has evolved in terms of strategies to promote oral biologics delivery from early chemical absorption enhancers to nanomedicine to devices. Continued activity in this area is justifiable considering the remarkable proliferation of biologics.Areas covered: The article discusses some physiological barriers to oral delivery of biologics, with a special focus on less characterised barriers such as the basement membrane. Recent progress in oral delivery of biologics via nanomedicine is subsequently covered. Finally, the emerging field of device-mediated gastrointestinal delivery of biotherapeutics is discussed.Expert opinion: Oral delivery of biologics is considered a ‘panacea’ in drug delivery. Almost century-old approaches of utilising chemical absorption enhancers have not produced clinically translated technologies. Nanomedicine for oral biologics delivery has demonstrated potential, but the field is relatively new, and technologies have not progress to the clinic. Device-mediated oral biologics delivery (e.g. ultrasound or microneedles) is in its infancy. However, this space is likely to intensify owing to advances in electronics and materials, as well as the challenges and history related to clinical translation of alternative approaches.

Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease oftentimes characterised by a waxing and waning disease course. However, mechanisms of disease flare remain elusive. Objectives This study examined relationships between SLE disease activity, immune pathways, and serologic evidence of viral exposures and reactivation within molecular subsets of SLE patients. Methods Serial or single samples of plasma, serum and RNA (n=290) were collected from 184 adult SLE patients who met ACR classification and cohort-matched controls (n=49). Disease activity was assessed by modified SELENA-SLEDAI. Immune pathways were evaluated by modular transcriptional analysis of Illumina Beadchip Microarray gene expression data, as well as by plasma soluble mediators (n=32) by multiplex, bead-based assay and ELISAs. This information was used to subset patients into seven molecular-defined categories by random forest modelling. Viral seropositivity and antibody concentrations were detected by ELISA for antibodies against EBV-Viral Capsid Antigen (VCA) (IgG and IgA), EBV-Early Antigen (EA) (IgG), Cytomegalovirus (CMV) (IgG), and Herpes Simplex Virus (HSV-1) (IgG). Results Serologic evidence of EBV reactivation was more common in SLE patients compared to controls, as measured by antibodies against EBV-EA [IgG] (40% vs 13%; OR=4.57, p=0.0006) or EBV-VCA [IgA] (36% vs 17%; OR=2.70, p=0.019). No differences were noted in CMV or HSV1 seropositivity rates between patients and controls. IgG responses against EBV-VCA were nearly universal among these adult patients and controls; however, concentrations of EBV-VCA IgG were higher in SLE patients compared to controls (ISR=4.44 vs 3.52; p=0.0021), as were EBV-VCA IgA and EBV-EA IgG antibody responses. In cross sectional analysis, SLE patients with higher disease activity (SLEDAI ≥6; n=126) had higher concentrations of EBV-EA IgG than patients with lower (n=166) disease activity (ISR=0.822 vs 0.540; p=0.033). SLE patients with serologic evidence of EBV reactivation by EA IgG responses had higher levels of interferon associated molecules, IP10 (p=3.4×10–14), BLyS (5.5×10–5), and IL-10 (p=0.00013). HSV1 IgG positive SLE patients also showed higher levels of IP10 (2.2×10–7). Antibody responses toward EBV-EA were enriched in molecularly defined patient clusters with higher expression levels of interferon and inflammatory modules, as well as with interferon and inflammatory soluble mediators. Patients within these clusters were also more likely to have major organ involvement, such as renal or neurologic disease. Conclusions Serologic evidence of EBV reactivation is more common in SLE patients compared to healthy controls. EBV-EA IgG responses are elevated in SLE patients with active disease and correspond with increases in interferon-associated mediators. This study provides serologic evidence suggesting a possible role for viral reactivation in SLE disease activity. Acknowledgements This work was supported in part by grants from the National Institutes of Health: U19AI082714, U01AI101934, U54GM104938, P30AR053483, R01AR072401. Disclosure of Interest None declared

Background Systemic lupus erythematosus (SLE) is characterised by remarkable clinical and pathophysiological diversity, hindering diagnosis, treatment and treatment development. Subsetting of patients based upon clinical presentations alone has not identified homogeneous groups of patients best treated with a directed therapeutic. Objectives To cluster SLE patients into more homogeneous subsets with common molecular pathway signatures, and to assess the clinical, therapeutic, and demographic features enriched in each cluster. Methods Serial or single plasma, serum and RNA samples (n=290) were collected from 198 SLE patients who met ACR classification. Disease activity was assessed by modified SELENA-SLEDAI at an average of 17 visits per patient. Transcriptional co-expression signature module scores were calculated from Illumina Beadchip Microarray gene expression data for 29 immune pathway related modules. Plasma soluble mediators (n=23) and 12 antinuclear autoantibodies (anti-dsDNA, chromatin, ribosomal P, Sm, Sm, SmRNP, RNP, Ro/SSA, La/SSB, centromere B, Scl-70 and Jo-1) were assessed by multiplex bead-based assay and ELISA. Spearman correlations were used for univariate and multivariate analysis using R. Patients were clustered on module signature scores and soluble mediators using random forest and tSNE. Results SLEDAI scores strongly correlated with interferon modules and were modestly correlated with plasmablast and select cell cycle signatures in this adult lupus collection. SLEDAI scores also correlated with soluble levels of IFNa, IL21, IL1a, IL17A, IP10 and MIG. Random forest defined seven clusters of SLE patients with unique molecular phenotypes based upon gene co-expression module signatures and soluble mediators. Inflammation and interferon (IFN) signatures were elevated in Clusters 1 (moderately) and 4, with decreased T cell signatures in Cluster 4. The other clusters had lower IFN and inflammation signatures, but differed in their monocyte, plasmablast and T cell signatures. Clusters 1 and 4 had the highest SLEDAI scores, with high rates of anti-dsDNA, low complement, proteinuria and hematuria; these features were also prominent in Cluster 3, which lacked the IFN and inflammation signatures. Cluster 6 had the highest plasmablast module score, highest IL1a levels, and SLEDAI scored rashes, but only moderate IFN and inflammation module scores. Cluster 2 had higher rates of SLEDAI scored alopecia, a slightly elevated inflammation signature, but lower interferon signature and lower soluble mediator levels. Conclusions SLE subsets can be distinguished by a range of molecular profiles encompassing IFN, T cell, neutrophil, plasmablast, and inflammation co-expression signatures, as well as soluble mediators that vary with disease activity. Prospective longitudinal studies of these molecular profiles may inform clinical trial design and personalised disease management. Acknowledgements This work was supported in part by grants from the National Institutes of Health: U19AI082714, U01AI101934, U54GM104938, and P30AR053483. Disclosure of Interest None declared

Background Clinical trial evaluations in SLE are problematic, in part due to glossary-based outcome measures with imperfect granular relevance. Visual analogue scales (VAS) allow real world scaling of disease severity, but may be inconsistent when used over time or by different raters. The SELENA SLEDAI Physician’s Global Assessment (SSPGA) is a VAS with severity anchors and instructions to promote consistent, transitional scoring. The Rapid Evaluation of Activity in Lupus (LFA-REALTM) extends the SSPGA by scoring each active feature separately, allowing additive impact of each manifestation within organs, and a global score with meaningful weighting of multiple symptoms. It differs from previous constructions that combine PGA with component scoring1 by incorporating all manifestations of lupus and refining scaling of the SSPGA2. Objectives To compare performance of SSPGA and LFA-REALTM to accepted SLE trial outcome measures during an ongoing trial in SLE, using a strict protocol for transitional scoring. Methods Disease activity, SLEDAI, BILAG 2004 CLASI, SSPGA and LFA-REALTM) was evaluated at monthly visits in an investigator-initiated, double-blind, placebo controlled study of abatacept (trial results pending). Validation of total scores and change in SSPGA and REAL vs SLEDAI and BILAG were examined by Spearman Correlation. ROC curve analysis compared changes in SSPGA and LFA-REALTM to the dichotomous SLE trial endpoints, SRI-4 and BICLA. Results 50 adult SLE patients, 47 female, were assessed at 528 visits. Changes in disease activity compared to screening were examined in 478 visit pairs. Total SSPGA and REAL scores strongly correlated to each other (r=0.932), as well as to total SLEDAI and BILAG [SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); REAL: r=0.776 (SLEDAI), r=0.813 (BILAG); all p Conclusions Both the SSPGA and LFA-REALTM are reliable surrogates of commonly used endpoints in SLE trials. Both instruments are easy to score and understand, and could be employed as continuous or dichotomous endpoints. The LFA-REALTM allows individualised scoring at the symptom or organ level, and each symptom contributes its exact severity to a global score. The simplicity of PGA scoring is accompanied by gains in versatility. References [1] Askanase AD, et al. Arthritis Care Res2017Oct 9. doi:10.1002/acr.23445 [2] Petri M, et al. J Rheumatol1992;19:53–9. Disclosure of Interest None declared

To review progress in the field of clinical trials for SLE. Treatment development for SLE has been marked by failures of many later phase studies, representing billions of dollars of lost research and development funding. Recently, more successful Phase II trials have tested reductions in background medications, novel stringent endpoints, and identification of informative immunologic subsets to achieve greater treatment effects. A large number of agents with promising novel biologic mechanisms have continued to enter clinical development, and momentum is building to capitalize on newer strategies for trial designs. Widespread SLE drug development is proceeding despite setbacks and controversies. Approaches focusing on patients with high disease activity, reduction of background polypharmacy, or increased endpoint stringency provide strategies that might improve interpretation of trial results. Pharmacodynamics of immune-modulation is a field in its infancy, but ripe for development.

The coverage control problem for mobile sensor networks in non-convex environments is addressed in this article. The sensing model of each node is assumed identical and radial either in the geodesic or the Euclidean sense. Depending on the selected metric, the partitioning of the non-convex domain can result either in the geodesic or the Euclidean Voronoi diagram. The coverage problem is examined from a two-fold aspect: based on a) proper selection of the sensing model, and b) the partitioning scheme, as directed by the application itself. Distributed collaborative control schemes are developed, further validated via extensive numerical studies.

BACKGROUND: Antenatal corticosteroid therapy recently has been considered for term and near-term infants, in addition to preterm infants, delivered by elective cesarean section, with the aim of preventing an adverse respiratory outcome.OBJECTIVES: The objective of this study was to investigate hormonal and metabolic effects of antenatal betamethasone when administered to term fetuses.METHODS: Cord blood levels of cortisol, C-peptide, insulin-like growth factor I and its binding protein 3, and 5 more analytes including glucose were measured in singleton newborns of over 35 weeks of gestational age. In anticipation of a cesarean delivery, the mother was either treated or not treated with 12 mg of intramuscularly administered antenatal betamethasone approximately 24 hours prior to birth. Babies of comparable gestational age, sex, and nutritional status who were not treated antenatally served as controls.RESULTS: Cord serum cortisol levels of the betamethasone-treated fetuses were suppressed to CONCLUSIONS: Prophylactic betamethasone therapy causes immediate hormonal alterations, which might interfere with the metabolic adaptation of the newborn. This issue deserves thorough investigation.

Background Pulmonary histoplasmosis is a fungal infection caused by histoplasma capsulatum, rarely diagnosed in non endemic areas and/or immunocompromised patients. Complication of pulmonary histoplasmosis with bronchocentric granulomatosis is extremely rare. Case Report A 48-year-old man with prolonged fever and nausea was admitted to our hospital. Clinical examination revealed pathological auscultatory sounds to the left lung. Computed tomography was performed and revealed a large solid mass of the left upper lobe, limited pleural and pericardial effusion and calcified lymphadenopathy of mediastinum. A computed tomography guided core biopsy of the lung lesion was performed and three samples were obtained. Culture and polymerase chain reaction (PCR) revealed Histoplasma capsulatum . Histological findings were compatible with bronchocentric granulomatosis. Extended laboratory investigation excluded immunosuppresion. Our patient although immunocompetent was diagnosed with chronic pulmonary histoplasmosis complicated with bronchocentric granulomatosis and treatment with antifungal medication and methylprednisoline started. Conclusion Description of a rare case of chronic pulmonary histoplasmosis in a non endemic area like Greece, with atypical radiological findings, complicated with bronchocentric granulomatosis.

The field of image guided drug delivery has attracted significant interest for researchers from various disciplines. Imaging is used to guide ultrasound to mediate drug delivery improving drug disposition and achieve tissue or organ specific delivery. Targeting drug delivery can be largely beneficial for diseases usually treated with cytotoxic drugs such as chemotherapy or drugs that may affect healthy functions of organs or cells. The term “focal” drug delivery has been introduced to describe the focal targeting of drugs in specific regions with the help of imaging. An example of this method is the use of imaging and a novel non-invasive technique named focused ultrasound (FUS) in combination with Magnetic Resonance Imaging (MRI). The increased temperature induced by FUS (hyperthermia) can improve blood supply in tissues and therefore improve drug distribution. FUS has also been studied for effects on physiological barrier permeability such as the blood brain barrier (BBB). FUS has been utilised in combination with imaging and theranostics, such as labelled liposomes that respond to temperature increase. This strategy aims to trigger nanoparticles to release their cargo locally when hyperthermia is induced by FUS. MRI guided FUS drug delivery can improve drug bioavailability at targeted tissues and therefore improve the therapeutic profiles of drugs. This strategy can be translated to the clinic as MRgFUS is an established clinically approved approach. However, more basic research is required to understand its physiological mechanisms.

Purpose. We examined current osteoporosis prevention practices in patients with inflammatory bowel disease (IBD) on chronic steroid using the 2003 American Gastroenterological Association guidelines as standard of care. Methods. We identified all IBD patients followed at the Oklahoma City VA Medical Center from January 2003 to December 2010, who had been on daily oral steroids (prednisone ≥5 mg or budesonide ≥6 mg) for ≥3 consecutive months. Associations of calcium and vitamin D (vitD) prescribing and bone mineral density (BMD) testing with patient characteristics were examined by logistic regression. Results. Sixty-three of 384 consecutive patients met inclusion criteria. Among 86 steroid courses, calcium and vitD were concurrently prescribed in 46%, and BMD was tested in 30%. There was no association of demographic and clinical characteristics with calcium/vitD prescribing and BMD testing. By multivariate analysis, steroid initiation after 2006, compared to before 2006, was associated with a significant increase in calcium (OR = 3.17 and P = 0.02) and vitD (OR = 2.96 and P = 0.02) prescribing and BMD testing (OR = 4.63 and P = 0.004). Conclusions. We observed a low, yet increasing, adherence to osteoporosis prevention guidelines in IBD since 2003, which highlights the need for continued physician education to enhance guideline awareness and implementation.

This paper introduces a self-organizing museum visitor communities' formation exploiting their personal characteristics and social interactions, aiming at enhancing their visiting experience based on a participatory action research (PAR) process. Initially, visitors' (a) interest and social ties, (b) expertise and willingness for participation in communities and (c) physical ties, are captured towards formulating their communities, and selecting the facilitator of each community. The latter will lead the PAR process, the outcome of which will be adopted by the members of each community. A museum touring framework is proposed towards maximizing visitors' perceived Quality of Experience (QoE), while three different community formation alternatives are studied and evaluated.

Background We previously observed an association between systemic lupus erythematosus (SLE) disease activity and heart rate variability (HRV) with a preliminary observation of consistency between these two measures when disease activity changed between two timepoints (1). Objectives To prospectively test the hypothesis that HRV reflect longitudinal changes in clinical status and patient reported outcomes. Methods The current project evaluated HRV measurements using a 5 min ECG in SLE patients who completed a minimum of 2 visits in an ongoing clinical trial. HRV parameters were calculated in the time domain (RMSSD and pNN50) and the frequency domain [high frequency (HF) as well as low frequency to high frequency (LF/HF) ratio]. A mixed effects linear model, with generalized estimating equations to account for clustering of visits for each patient, was used to compare changes in HRV between paired visits and to examine linear associations between HRV parameters and clinical scores. All models were adjusted for baseline values of each HRV parameter. Results Forty nine patients (age 44.9±11.7, 46 female), followed in a total of 413 paired visits (median time between visits 1 month), were included. Global BILAG score was inversely associated with RMSSD (regression coefficient β=-1.39±0.01; p Changes in Physical Component Summary (PCS) of SF36v2 were inversely related to changes in SLEDAI and PGA (β=-0.39±0.14; p=0.006 and -0.19±0.02; p Conclusions Changes in HRV reflect changes in clinical status and patient reported outcomes in patients with SLE. These data suggest that HRV may be a simple non-invasive tool used to gage or predict clinical improvement in SLE. Further studies are warranted. References Thanou A, Stavrakis S, Dyer JW, Munroe ME, James JA, Merrill JT. Impact of heart rate variability, a marker for cardiac health, on lupus disease activity. Arthritis Res Ther. 2016 Sep 2;18:197. Disclosure of Interest None declared

Purpose – The purpose of this paper is to add to the existing literature by examining a number of hypotheses relating to the capital structure decision in relation to the firms’ size, namely by distinguishing among micro, small and medium firms. Design/methodology/approach – The paper examines the hypothesis that the factors determining capital structure are different for firms belonging to different size groups. The authors use a panel data model capturing the dynamic concept of capital structure. Findings – The authors find that whereas the size of the firm does affect how much debt a firm will issue, it does not influence the relationship between the other regressors and debt usage. Research limitations/implications – The paper examines the small and medium enterprises (SMEs). Does not examine the large firms. Practical implications – During the last decade there has been a gradually increasing interest shown in the field of SMEs. These enterprises represent important parts of all economies in terms of both their total number and their job offer and job creation. For example, in the European Union (EU), in 2005, SMEs accounted for 99.8 percent of the total number of enterprises operating in EU-27, covering 66.7 of total employment in the non-financial business economy sector. Social implications – This paper relates capital structure decision to firms’ size distinguishing them among micro, small and medium firms. Originality/value – The paper tests differences in capital structure determination among different size groups of enterprises in a dynamic framework for more than one year.

A proportional–integral–derivative (PID) control model of an active hydromagnetic journal bearing (AHJB) is presented here and its design guidelines are explicitly described. The nonlinear rotor equations of motion, is introduced. Then, the linearization of these equations in the bearing specific equilibrium point is performed and presented along with the appropriate PID gains. Consequentially, the linear equation is transformed via Laplace method and the control model of the AHJB is finally developed. The multiphysics module of Ansys is used to calculate the forces that the hydrodynamic lubrication applies to the rotor, in every position of the rotor, during its movement inside the bearing. This has been done, in order not to have linear equations of the hydrodynamic forces, but the real, nonlinear equations. The nonlinear equations are used for the electromagnetic forces too. The Matlab software is used to simulate the components that the AHJB is consisted of. The P, I, and D gains are the obtained results of this simulations, which are produced via robust control method, in single-input-single-output tool module. Finally, the Simulink module of Matlab is energized to check the control characteristics of the developed AHJB system, taking into account the nonlinear equations of motion of the system, in combination with the rotor unbalance and gyroscopic effects and the saturation of the coils. The rotor response, the overshoot, the rotor center vibration are controlled using the above produced P, I, and D gains. Several plots are constructed and presented, such as the rotor orbits, to show the possibility of the AHJB control.

In sparse signal representation, the choice of a dictionary often involves a tradeoff between two desirable properties – the ability to adapt to specific signal data and a fast implementation of the dictionary. To sparsely represent signals residing on weighted graphs, an additional design challenge is to incorporate the intrinsic geometric structure of the irregular data domain into the atoms of the dictionary. In this work, we propose a parametric dictionary learning algorithm to design data-adapted, structured dictionaries that sparsely represent graph signals. In particular, we model graph signals as combinations of overlapping local patterns. We impose the constraint that each dictionary is a concatenation of subdictionaries, with each subdictionary being a polynomial of the graph Laplacian matrix, representing a single pattern translated to different areas of the graph. The learning algorithm adapts the patterns to a training set of graph signals. Experimental results on both synthetic and real datasets demonstrate that the dictionaries learned by the proposed algorithm are competitive with and often better than unstructured dictionaries learned by state-of-the-art numerical learning algorithms in terms of sparse approximation of graph signals. In contrast to the unstructured dictionaries, however, the dictionaries learned by the proposed algorithm feature localized atoms and can be implemented in a computationally efficient manner in signal processing tasks such as compression, denoising, and classification.

ObjectiveExisting methods for grading lupus flares or improvement require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analysed the performance of the SELENA SLEDAI Physician’s Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) as measures of improvement or worsening in SLE.MethodsWe evaluated the agreement between prospectively collected measures of lupus disease activity [SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index 2004 (BILAG 2004), Cutaneous Lupus Area and Severity Index (CLASI), SSPGA and LFA-REAL] and response [(SLE Responder Index (SRI)-4 and BILAG-Based Combined Lupus Assessment (BICLA)] in a clinical trial.ResultsFifty patients (47 females, mean age 45 (±11.6) years) were assessed at 528 consecutive visits (average 10.6 (±4.1) visits/patient). Changes in disease activity compared with baseline were examined in 478 visit pairs. SSPGA and LFA-REAL correlated with each other (r=0.936), and with SLEDAI and BILAG (SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REAL: r=0.778 (SLEDAI), r=0.813 (BILAG); all pConclusionSSPGA and LFA-REAL are reliable surrogates of common SLE trial end points and could be used as continuous or dichotomous response measures. Additionally, LFA-REAL can provide individualised scoring at the symptom or organ level.Trial registration numberNCT02270957.

Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.

Purpose. We examined current osteoporosis prevention practices in patients with inflammatory bowel disease (IBD) on chronic steroid using the 2003 American Gastroenterological Association guidelines as standard of care. Methods. We identified all IBD patients followed at the Oklahoma City VA Medical Center from January 2003 to December 2010, who had been on daily oral steroids (prednisone ≥5 mg or budesonide ≥6 mg) for ≥3 consecutive months. Associations of calcium and vitamin D (vitD) prescribing and bone mineral density (BMD) testing with patient characteristics were examined by logistic regression. Results. Sixty-three of 384 consecutive patients met inclusion criteria. Among 86 steroid courses, calcium and vitD were concurrently prescribed in 46%, and BMD was tested in 30%. There was no association of demographic and clinical characteristics with calcium/vitD prescribing and BMD testing. By multivariate analysis, steroid initiation after 2006, compared to before 2006, was associated with a significant increase in calcium (OR = 3.17 and P=0.02) and vitD (OR = 2.96 and P=0.02) prescribing and BMD testing (OR = 4.63 and P=0.004). Conclusions. We observed a low, yet increasing, adherence to osteoporosis prevention guidelines in IBD since 2003, which highlights the need for continued physician education to enhance guideline awareness and implementation.

Spontaneous rapture with consequent retroperitoneal hemorrhage (Wunderlich’s syndrome) is the complication mostly feared from large renal angiomyolipomas (RAMLs). In hemodynamic stable patients, minimal invasive therapies have superseded open surgery as the mainstay of treatment, with contemporary cases mostly treated by selective arterial embolization. Robotic-assisted laparoscopic partial nephrectomy (RALPN) is an established minimal access treatment that has been used in the past for benign and malignant lesions of the kidney in the elective setting, but rarely in urgent situations as primary treatment. We present a case of a ruptured RAML in a young female treated effectively by RALPN.

This paper introduces a holistic approach in the formulation and optimization of museum visitors' Quality of Experience (QoE). The most influential parameters on visitors QoE have been identified and quantified via performing an empirical study based on a questionnaire answered by experts in the field of arts and museums. Individual QoE functions with respect to each of the identified parameters have been formulated for different museum visitors' style, towards capturing visitors' perceived satisfaction in a formal manner and providing them a customized and personalized experience. Visitors' total QoE function is formulated considering the different weight of the parameters and optimized in order to determine the optimal conditions that maximize museum visitors' satisfaction. Detailed numerical results are provided towards illustrating the applicability of the proposed framework under different scenarios.

Ultrasound is a well-established imaging modality used in clinics worldwide for many different applications. It has also experienced recent growth in interest for therapeutic applications in the form of high-intensity focused ultrasound (HIFU) or focused ultrasound (focused-US), including in capsules for use in drug delivery in the gut. The work described here aimed to support the investigation of its usefulness for drug delivery further. An in vitro sonication system was designed, comprising a focused-US transducer, a cell plate on a vertical stage and transepithelial electrical resistance (TER) meter. Miniature focused-US transducers were fabricated with PZ26 and PZ54 materials (Meggitt Sensing Systems, Kvistgaard, Denmark). The active elements in both transducers have outer diameter, OD = 5 mm, and radius of curvature, R C = 15 mm. US field mapping indicated that output acoustic pressures are in the range 25 kPa ac ac < 80 mW. Feasibility testing with Caco-2 colon cancer cells involved measuring TER during and after sonication. Sonication produced a drop in TER of 6.7% after 6 min. Recovery to the starting TER value was observed 14 min after sonication indicating that the sonication system can be used to measure the effect of ultrasound on tissue barrier function as expected.

Objective Molecular medicine raised expectations for strategically targeted biologic agents in systemic lupus erythematosus (SLE), but clinical trial results have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard therapy immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus remains controversial. We undertook the Biomarkers of Lupus Disease study to test withdrawal of immunosuppressants as a novel approach to rendering SLE trials interpretable. Methods In 41 patients with active, non–organ-threatening SLE flare (group A), temporary steroids were given while background immunosuppressants were withdrawn. Time to loss of disease suppression (time to disease flare) and safety were evaluated; standard therapy was immediately resumed when symptoms recurred. Immunologic impacts of standard therapy were studied at baseline by multiplex assay, enzyme-linked immunosorbent assay, and messenger RNA array in group A patients plus 62 additional patients donating a single sample (group B). Results Patients with lower or higher baseline disease activity had median times to flare of 71 or 45 days, respectively; 40 of 41 patients (98%) had disease flares by 6 months. All flares were treated and resolved within 6 weeks. No serious adverse events occurred from flare or infection. Type I interferon (IFN), Th17, and B lymphocyte stimulator pathways tracked together. Baseline immunosuppressants had distinct impacts on Th17 and B lymphocyte stimulator, depending on IFN signature. Conclusion Trials in active, non–organ-threatening SLE can safely withdraw background treatments if patients who have disease flares are designated nonresponders and returned to standard therapy. Immunologic effects of standard therapy vary between IFN-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care.

Image guided drug delivery has gained significant attention during the last few years. Labelling nanoparticles or macromolecules and monitoring their fate in the body provides information that can be used to modulate their biodistribution and improve their pharmacokinetics. In this study we label antibodies and monitor their distribution in the tumours post intravenous injection. Using Focused Ultrasound (FUS, a non-invasive method of hyperthermia) we increase the tumour temperature to 42 °C for a short period of time (3–5 min) and we observe an increased accumulation of labelled antibody. Repetition of focused ultrasound induced hyperthermic treatment increased still further the accumulation of the antibodies in the tumour. This treatment also augmented the accumulation of other macromolecules non-specific in the tumour, such as IgG and albumin. These effects may be used to enhance the therapeutic efficiency of antibodies and/or targeted nanoparticles.

Chitosan is a natural polysaccharide that has attracted significant scientific interest during the last two decades. It is a potentially biologically compatible material that is chemically versatile (-NH2 groups and various M(w)). These two basic properties have been used by drug delivery and tissue engineering scientists to create a plethora of formulations and scaffolds that show promise in healthcare. Despite the high number of published studies, chitosan is not approved by the FDA for any product in drug delivery, and as a consequence very few biotech companies are using this material. This review will aim to provide information on these biological properties that affect chitosan's safe use in drug delivery. The term "Chitosan" represents a large group of structurally different chemical entities that may show different biodistribution, biodegradation and toxicological profiles. Here we aim to review research in this area and critically discuss chitosan's potential to be used as a generally regarded as safe (GRAS) material.

Objective To summarize data on existing and experimental therapies for primary Sjogren’s syndrome (pSS), referring both to sicca syndrome and to other systemic disease manifestations. Methods Relevant English and non-English articles acquired through Medline were reviewed. Results pSS usually has a benign clinical course, centered on sicca features and general musculoskeletal manifestations, and is managed symptomatically. However, a subset of patients develops more severe extraglandular disease that warrants close monitoring and aggressive treatment. For dry eyes and mouth, nonpharmacologic measures to preserve secretions, and tear and saliva substitutes, offer some symptomatic relief. Muscarinic agonists and topical cyclosporine yield well-documented improvement in ocular sicca features. Although traditional antirheumatic drugs are used empirically for polyarthritis and other Sjogren’s symptoms, their efficacy in pSS overall and as disease-modifying agents is limited. For the potential severe, nonexocrine manifestations complicating pSS, standard high-dose immunosuppression is used. Among the biologic agents already examined in pSS, those targeting tumor necrosis factor (TNF)-α failed to demonstrate significant benefit. Nonetheless, rituximab and other B-cell-depleting therapies appear promising. Conclusions Treatment of pSS patients with severe extraglandular disease should differ from that of patients with predominantly sicca features and/or general muscoloskeletal manifestations. pSS treatment is mainly symptomatic, primarily directed against sicca complaints. The traditional anti-rheumatic agents show limited efficacy in the systemic process and use of systemic TNF-α inhibitors has been very disappointing. B cell depleting treatments and other newer biologic therapies appear more promising.

Mobile phones are one of the most popular means of access to the internet. Users, via the telephone, connect to different services such as: Google, social networks, work accounts, banks accounts, etc. Those services, are many times, left open in their device. This enables risks, such as, loss or/and the violation of their personal data. In addition, in case of device theft after login, full access to sensitive data and applications may be fully granted. The purpose of this research is to analyze the most salient patterns characterizing user practices regarding certain behavioral modalities including: the way of using the various applications, power consumption, touch gestures and guest users' habits. To this end, we used an original questionnaire, created for the needs of the specific survey, to examine whether we can find some trends among the users. This can give us a qualitative information, for the different behaviors / "characters" of users, in order to be used in further research regarding User's Continuous Authentication.

We study the distributed processing of graph signals that are well represented by graph spectral dictionaries. We first analyze the impact of quantization noise in the distributed computation of polynomial dictionary operators that are commonly used in various signal processing tasks. We show that the impact of quantization depends on the graph geometry and on the structure of the spectral dictionaries. Then, we focus on the problem of distributed sparse signal representation that can be solved with an iterative soft thresholding algorithm. We define conditions on the dictionary structure to ensure the convergence of the distributed algorithm and finally propose a dictionary learning solution that permits to control the robustness to quantization noise. Experimental results for reconstruction and denoising of both synthetic and practical signals illustrate the tradeoffs that exist between accurate signal representation and robustness to quantization error in the design of dictionaries operators in distributed graph signal processing.