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Immune checkpoint (IC) receptors play critical roles in maintaining immune homeostasis and are emerged as promising drug targets for the treatment of various cancers and autoimmune disorders. Monoclonal antibodies designed to block immune inhibitory receptors PD-1 and CTLA-4 have been approved and showed unprecedented efficacy in cancer treatment. This led to rapid expansion of drug development to many more IC receptors targeted individually or in combination. However, due to the novelty and fast speed, one of the bottleneck during immunotherapy drug development is the lack of quantitative and reproducible functional assays for potency determination when existing methods heavily rely on primary immune cells and the process are labor intensive and highly variable. To address this need, we developed a panel of cell-based reporter bioassays that can quantitatively measure the potencies of biologics targeting individual IC receptor (e.g. PD-1, LAG-3, BTLA, CTLA-4, TIGIT, TIM-3, ICOS, 4-1BB, CD40), or bispecific molecules targeting two IC receptors spontaneously (e.g. PD-1xTIGIT, PD-1xLAG-3, PD-1xCTLA-4, PD1x4-1BB). These bioassays each consist of an engineered T effector cell line that expresses T cell receptors and IC receptors of interest, and an engineered artificial antigen presenting cells (aAPC) expressing the corresponding ligands for the IC receptors. The T effector cell line also expresses a luciferase reporter driven by response elements/promoter specifically responding to TCR activation which can be co-stimulated or inhibited by the signal from the IC receptors. These bioassays are designed to reflect the mechanisms of action for the drug candidates designed for each IC receptor and the assay signals are specific. They are prequalified according to ICH guidelines and show the precision, accuracy and linearity required for relative potency determination and product stability study under cGMP environments. Therefore, these MoA-based bioassays can serve as value tools for early drug discovery, potency determination and stability study throughout immunotherapy drug development. Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, michael Beck, Jim Hartnett, Frank Fan, mei cong, Zhi-Jie Jey Cheng. MoA-based reporter bioassays enable quantitative potency determination for therapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1650.

Zusammenfassung Hintergrund Aufgrund ihrer Seltenheit sind Studien bei Orphan Diseases schwierig. Nur für wenige dieser Erkrankungen stehen kausale Therapien zur Verfügung. Die Entwicklung und Herstellung von Medikamenten wie bspw. Enzymersatztherapien (ERT) ist aufwändig, die Patientenzahl niedrig, was zu hohen Preisen führt. Am Beispiel einer Gruppe angeborener Stoffwechselerkrankungen, den lysosomalen Speichererkrankungen (LSDs), beleuchten wir die Herausforderungen bei der sektorübergreifenden Dauertherapie unter Zugrundelegung einer Literaturrecherche in Pubmed sowie eigener Erfahrungen. Viele ERTs haben ein positives Kosten-Nutzen Verhältnis. Mögliche Nebenwirkungen sind schwere allergische Reaktionen bis hin zur Anaphylaxie. ERT ist zu Lasten von GKV/PKV verschreibungsfähig, Regresse aufgrund Richtgrößenüberschreitung lassen sich mit „Praxisbesonderheiten“ umgehen. Die Verabreichung der intravenösen ERT ist weniger gut geregelt. Ein stationärer Aufenthalt zur ERT führt oft zu finanziellen Problemen (untere Grenzverweildauer), wenngleich dieser Verabreichungsmodus der sicherste ist. Ein tagesstationärer Aufenthalt ist am günstigsten, wobei bei dieser Option die Übernahme der Kosten für die ERT außerhalb der Tagesklinkpauschale durch GKV/PKV im Vorfeld zu klären ist. Eine ambulante Heimtherapie ist machbar, die Entscheidung hierfür muss für jeden Patienten sorgfältig individuell abgewogen werden. Die Durchführung der ERT wird vom behandelnden Arzt an ein Schwestern-/Pflegerteam delegiert, haftungs-, strafrechtliche sowie ethische Aspekte sind im Vorfeld zu klären. Die sektorübergreifende Therapie von LSDs ist mit (lösbaren) Herausforderungen behaftet.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare lysosomal storage disease with progressive multisystem manifestations caused by deficient activity of the enzyme iduronate-2-sulfatase. Disease-specific treatment is available in the form of enzyme replacement therapy with intravenous idursulfase (Elaprase®, Shire). Since 2005, the Hunter Outcome Survey (HOS) has collected real-world, long-term data on the safety and effectiveness of this therapy, as well as the natural history of MPS II. Individuals with a confirmed diagnosis of MPS II who are untreated or who are receiving/have received treatment with idursulfase or bone marrow transplant can be enrolled in HOS. A broad range of disease- and treatment-related information is captured in the registry and, over the past decade, data from more than 1000 patients from 124 clinics in 29 countries have been collected. Evidence generated from HOS has helped to improve our understanding of disease progression in both treated and untreated patients and has extended findings from the formal clinical trials of idursulfase. As a long-term, global, observational registry, various challenges relating to data collection, entry, and analysis have been encountered. These have resulted in changes to the HOS database platform, and novel approaches to maximize the value of the information collected will also be needed in the future. The continued evolution of the registry should help to ensure that HOS provides further insights into the burden of the disease and patient care and management in the coming years.

Introduction The purpose of this retrospective case-control study was to compare the treatment effectiveness and efficiency of the Invisalign system with conventional fixed appliances in treating orthodontic patients with mild to moderate malocclusion in a graduate orthodontic clinic. Methods Using the peer assessment rating (PAR) index, we evaluated pretreatment and posttreatment records of 48 Invisalign patients and 48 fixed appliances patients. The 2 groups of patients were controlled for general characteristics and initial severity of malocclusion. We analyzed treatment outcome, duration, and improvement between the Invisalign and fixed appliances groups. Results The average pretreatment PAR scores (United Kingdom weighting) were 20.81 for Invisalign and 22.79 for fixed appliances ( P = 1.0000). Posttreatment weighted PAR scores between Invisalign and fixed appliances were not statistically different ( P = 0.7420). On average, the Invisalign patients finished 5.7 months faster than did those with fixed appliances ( P = 0.0040). The weighted PAR score reduction with treatment was not statistically different between the Invisalign and fixed appliances groups ( P = 0.4573). All patients in both groups had more than a 30% reduction in the PAR scores. Logistic regression analysis indicated that the odds of achieving "great improvement" in the Invisalign group were 0.329 times the odds of achieving "great improvement" in the fixed appliances group after controlling for age ( P = 0.0150). Conclusions Our data showed that both Invisalign and fixed appliances were able to improve the malocclusion. Invisalign patients finished treatment faster than did those with fixed appliances. However, it appears that Invisalign may not be as effective as fixed appliances in achieving "great improvement" in a malocclusion. This study might help clinicians to determine appropriate patients for Invisalign treatment.

Background/ Aims: This study was performed to reveal signaling pathways exploited by pigment epithelium-derived factor (PEDF) derived from retinal (glial) Müller cells to protect retinal ganglion cells (RGCs) from cell death. Methods: The survival of RGCs was determined in the presence of conditioned culture media (MCM) from or in co-cultures with Müller cells. The significance of PEDF-induced STAT3 activation was evaluated in viability assays and using Western blotting analyses and siRNA-transfected cells. Results: Secreted mediators of Müller cells increased survival of RGCs under normoxia or hypoxia to a similar degree as of PEDF- or IL-6-exposed cells. PEDF and MCM induced an increased STAT3 activation in RGCs and R28 cells, and neutralization of PEDF in MCM attenuated STAT3 activation. Inhibition of STAT3 reduced PEDF-promoted survival of RGCs. Similar to IL-6, PEDF induced STAT3 activation, acting in a dose-dependent manner via the PEDF receptor (PEDF-R) encoded by the PNPLA2 gene. Ablation of PEDF-R attenuated MCM-induced STAT3 activation and compromised the viability of PEDF-exposed R28 cells. Conclusions: Müller cells are an important source of PEDF, which promotes RGC survival through STAT3 activation and, at least in part, via PEDF-R. Enhancing the secretory function of Müller cells may be useful to promote RGC survival in retinal neurodegenerative diseases.

Split reporters based on fluorescent proteins and luciferases have emerged as valuable tools for measuring interactions in biological systems. Relatedly, biosensors that transduce measured input signals into outputs that influence the host system are key components of engineered gene circuits for synthetic biology applications. While small molecule-based imaging agents are widely used in biological studies, and small molecule-based drugs and chemical probes can target a range of biological processes, a general method for generating a target small molecule in a biological system based on a measured input signal is lacking. Here, we develop a proximity-dependent split esterase that selectively unmasks ester-protected small molecules in an interaction-dependent manner. Exploiting the versatility of an ester-protected small molecule output, we demonstrate fluorescent, chemiluminescent, and pharmacological probe generation, each created by masking key alcohol functional groups on a target small molecule. We show the split esterase system can be used in combination with ester-masked fluorescent or luminescent probes to measure a protein-protein interactions and protein-protein interaction inhibitor engagement. We demonstrate the esterase-based reporter system is compatible with other commonly-used split reporter imaging systems for the simultaneous detection of multiple protein-protein interactions. Finally, we develop a system for selective small molecule-dependent cell killing by unmasking a cytotoxic molecule using an inducible split esterase. Presaging utility in future synthetic biology-based therapeutic applications, we also show the system can be used for intercellular cell killing via a bystander effect, where one activated cell unmasks a cytotoxic molecule and kills cells physically adjacent to the activated cells. Collectively, this work illustrates that the split esterase system is a valuable new addition to the split protein toolbox, with particularly exciting potential in synthetic biology applications.

Split reporters based on fluorescent proteins and luciferases have emerged as valuable tools for measuring interactions in biological systems. Relatedly, biosensors that transduce measured input signals into outputs that influence the host system are key components of engineered gene circuits for synthetic biology applications. While small molecule-based imaging agents are widely used in biological studies, and small molecule-based drugs and chemical probes can target a range of biological processes, a general method for generating a target small molecule in a biological system based on a measured input signal is lacking. Here, we develop a proximity-dependent split esterase that selectively unmasks ester-protected small molecules in an interaction-dependent manner. Exploiting the versatility of an ester-protected small molecule output, we demonstrate fluorescent, chemiluminescent, and pharmacological probe generation, each created by masking key alcohol functional groups on a target small molecule. We show the split esterase system can be used in combination with ester-masked fluorescent or luminescent probes to measure a protein-protein interactions and protein-protein interaction inhibitor engagement. We demonstrate the esterase-based reporter system is compatible with other commonly-used split reporter imaging systems for the simultaneous detection of multiple protein-protein interactions. Finally, we develop a system for selective small molecule-dependent cell killing by unmasking a cytotoxic molecule using an inducible split esterase. Presaging utility in future synthetic biology-based therapeutic applications, we also show the system can be used for intercellular cell killing via a bystander effect, where one activated cell unmasks a cytotoxic molecule and kills cells physically adjacent to the activated cells. Collectively, this work illustrates that the split esterase system is a valuable new addition to the split protein toolbox, with particularly exciting potential in synthetic biology applications.

We investigate the influence of Auger electrons on the efficiency of optical spin pumping of donor bound electrons in isotopically enriched silicon by means of time-resolved pump-probe absorption spectroscopy. The experimentally observed drastic shortening of the spin relaxation time with increasing optical excitation results from inelastic scattering between free and localized electrons and an interconnected Orbach-type spin relaxation process. The maximal steady-state degree of polarization of the localized electron spins and the probe-beam-induced depolarization dynamics reveal that the fast, nonthermal energy dissipation of the conduction band electron distribution is detrimental for efficient optical spin initialization. In fact, each absorbed photon creates an Auger electron with enough energy to depolarize the spin of $\ensuremath{\approx}30$ donor bound electrons but the fast, nonthermal energy dissipation by phonons reduces this spin relaxation efficiency to approximately unity.

In the last decades, it has become more and more evident that lysosomal storage disorders and common neurodegenerative diseases such as Alzheimer and Parkinson diseases have clinical, neuropathological, and genetic features in common, including lysosomal dysfunction and impaired autophagy. Patients with Gaucher and even carriers of Gaucher disease have an increased risk to develop Parkinson disease. Likewise, individuals who are heterozygous for a mutation of a gene that causes an adult form of neuronal ceroid lipofuscinosis are more likely to be affected by a form of frontotemporal dementia in their later life. A further example is the gene NAGLU encoding the enzyme α-N-acetylglucosaminidase, which is deficient in patients with mucopolysaccharidosis type IIIB. Mutations of the NAGLU gene have been observed in patients affected by an axonal neuropathy. An interesting unexpected finding was the link between stuttering and genes that are essential for the function of all lysosomal enzymes. This review will present some example of the association of lysosomal storage disorders and neurodegenerative disease and discuss possible pathogenic mechanisms that are common to both conditions. The understanding of the pathophysiology of the endosomal–lysosomal–autophagic system may help to develop drugs, which might provide benefit not only for patients with rare lysosomal storage disorders but also for individuals affected by more common diseases.

Purpose Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Patients and methods FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Results Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9–67.3) for females (n=62), 34.4 (18.0–66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; −0.55 [−1.12, +0.01]) and slightly declined in males (n=79; −1.99 [−2.45, −1.54]). With impaired kidney function (eGFR 48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [−0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. Conclusion Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.

Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age 70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P

To determine if a lean intervention improved emergency department (ED) throughput and reduced ED boarding by improving patient discharge efficiency from a tertiary care children's hospital.The study was conducted at a tertiary care children's hospital to study the impact lean that changes made to an inpatient pediatric service line had on ED efficiency. Discharge times from the general pediatrics' service were compared to patients discharged from all other pediatric subspecialty services. The intervention was multifaceted. First, team staffing reconfiguration permitted all discharge work to be done at the patient's bedside using a new discharge checklist. The intervention also incorporated an afternoon interdisciplinary huddle to work on the following day's discharges. Retrospectively, we determined the impact this had on median times of discharge order entry, patient discharge, and percent of patients discharged before noon. As a marker of ED throughput, we determined median hour of day that admitted patients left the ED to move to their hospital bed. As marker of ED congestion we determined median boarding times.For the general pediatrics service line, the median discharge order entry time decreased from 1:43pm to 11:28am (p 0.0001) and the median time of discharge decreased from 3:25pm to 2:25pm (p 0.0001). The percent of patients discharged before noon increased from 14.0% to 26.0% (p 0.0001). The discharge metrics remained unchanged for the pediatric subspecialty services group. Median ED boarding time decreased by 49 minutes (p 0.0001). As a result, the median time of day admitted patients were discharged from the ED was advanced from 5 PM to 4 PM.Lean principles implemented by one hospital service line improved patient discharge times enhanced patient ED throughput, and reduced ED boarding times.

A promising approach for increasing the energy efficiency of domestic households and buildings is to optimize the whole energy system by coupling of different heat sources and sinks. This procedure, known as heat integration, is state of the art in the industrial sector and is now applied to the residential sector. In this work several options for increasing the energy efficiency and for recovering waste heat are discussed. In order to reduce the primary energy demand different waste heat sources like domestic hot water or household appliances (refrigerators or freezers) were evaluated. The first step is the development of an advanced form of the stationary Pinch Analysis. This was subsequently applied to determine the thermodynamically possible energy saving for a single family home.

In this paper a thermodynamic analysis of a concept approach based on a possible form of load management for photovoltaic energy is presented. By using the surplus electricity for driving a compression chiller it is possible to load a low temperature thermal storage. This cold storage can be used to cover the cooling demand of domestic refrigerator and freezers. A parameter study was performed to evaluate the energetic efficiency for this system in a single family home. A short economic evaluation compares the concept to a system without storage and to a system with battery storage.

Seit Einfuhrung in die klinische Routine in den 70er Jahren stellt die Skelettszintigrafie eines der haufigsten nuklearmediznischen Untersuchungsverfahren dar. Ihre Sensitivitat bei der Detektion skelettaler Lasionen ist sehr hoch, Spezifitat als auch raumliche Auflosung sind hingegen limitiert. Dies gilt auch, wenn die Skelettszintigrafie durch eine Einzelphotonenemissionscomputertomografie (SPECT) erganzt wird. Hybridkameras, welche die Akquisition eines SPECT und einer Rontgencomputertomografie (CT) in einem Untersuchungsgang erlauben, stehen seit ca. 10 Jahren kommerziell zur Verfugung. Die SPECT/CT verbessert die Genauigkeit der Knochenszintigrafie beim Staging von Tumorerkrankungen erheblich. Auch bei der Diagnostik gutartiger Veranderungen des Skeletts ergeben sich gegenuber der konventionellen nuklearmedizinischen Bildgebung deutliche Vorteile der Hybriddiagnostik. Die Moglichkeit der Quantifizierung des regionalen Traceruptakes in absoluten Einheiten und sog. multimodale Rekonstruktionstechniken stellen jungste methodische Fortschritte dar.

The thermal properties of Light Emitting Diode (LED) products have a significant impact on their longevity and overall performance. Products which are unable to adequately dissipate heat degrade, shortening the projected lifespan. A testing apparatus has been constructed to characterize the thermal behavior of MR-16 LED products. This paper documents the testing setup and measurement results for 9 separate products, and identifies product characteristics which demonstrate higher success at heat dissipation. The thermal performance was quantified using experimental data and heat transfer models. Calculations to quantify the magnitude of heat transferred through radiation and convection in each LED product were performed. Results indicate some of the products are better optimized to enhance convection heat transfer.

The human immune system is regulated by a complex network of inhibitory and stimulatory immune checkpoint receptors that regulate T Cell function. These receptors are promising new immunotherapy targets for the treatment of a variety of cancers and autoimmune disorders. Novel therapies employing a variety of strategies have been developed that rely on releasing the brakes on the immune system, with the aim of eliminating tumor cells even more efficiently. Immunotherapies designed to block co-inhibitory receptors (e.g. PD-1, CTLA-4) are showing unprecedented efficacy in the treatment of cancer. However, not all patients and tumor types respond to this approach. This has resulted in broadening of immunotherapy research programs to target additional co-inhibitory (e.g. LAG-3, TIM-3, TIGIT) and co-stimulatory (e.g. 4-1BB, GITR, OX40, ICOS) receptors, individually and in combination. A major challenge in the development of antibody-based biologics is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable and fail to yield data required for drug development in a quality-controlled environment. To address this need, we have developed a suite of cell-based functional bioassays to interrogate modulation of immune checkpoint receptors individually (e.g. PD-1, LAG-3, TIM-3, GITR, 4-1BB) and in combination (e.g. PD-1+CTLA-4, PD-1+LAG-3). These bioassays consist of stable cell lines that express luciferase reporters driven by response elements under the precise control of mechanistically relevant intracellular signals from TCR and immune checkpoint receptors. Thus, these bioassays reflect mechanisms of action for drug candidates designed for each immune checkpoint receptor and demonstrate high specificity, sensitivity and reproducibility. The bioassays are prequalified according to ICH guidelines and show the precision, accuracy and linearity required for routine use in potency and stability studies. Here we describe the application of MoA-based immune checkpoint receptor bioassays as tools for biologics drug discovery, development, potency and stability studies. Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based reporter bioassays for functional characterization of immunotherapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 944.

Quenzel, G., & Hurrelmann, K. (Hrsg.). (2019). Handbuch Bildungsarmut (S. 491-522). Wiesbaden: Springer Fachmedien Wiesbaden, S. 491-522, Der Artikel untersucht Bildungsarmut im Schweizer Schulsystem dahingehend, ob sich auftretende Unterschiede nach Migrationshintergrund bei Übertritten im Sinne von Chancengerechtigkeit durch Schulleistungen erklären lassen oder ob Residualeffekte im Sinne allfälliger Diskriminierung auftreten. Während beim Übergang Primar-Sekundarschule keine Effekte erkennbar sind, zeigen sich solche beim (Nicht-)Übertritt in die nachobligatorische Ausbildung zu Ungunsten südosteuropäischer Herkunftsgruppen.

Objective The aim of this study was to evaluate expression of cornulin in oral mucosa as an adjunct to histopathologic grading of oral epithelial dysplasia (OED). Study Design Biomarker expression was assessed in normal oral mucosa, low-grade OED (LD), high-grade OED (HD), and oral squamous cell carcinoma (OSCC) by using immunohistochemistry. Photomicrographs were evaluated with Aperio Imagescope using a positive-pixel-counting algorithm. A histo-score (H-score) was calculated on the basis of staining intensity and the percentage of positive cells (%-staining). Intrarater reliability for H-score and %-staining was determined by calculating interclass correlation coefficients. Mean differences in H-scores and %-percent staining values were each analyzed by using an analysis of variance and Tukey's post hoc procedure. Results Cornulin expression progressively diminished with increasing grades of dysplasia and OSCC. Interclass correlation coefficients for H-score and %-staining were each greater than 0.99. Except for OSCC versus HD, all other pairwise comparisons were statistically significant (P Conclusions Cornulin expression helped differentiate between low-grade and high-grade oral epithelial dysplasia, making it a potential adjunct for grading oral OEDs and a potential biomarker for risk of lesion progression. Longitudinal studies evaluating risk stratification based on cornulin expression may be warranted.

The aim was to evaluate the outcome of treatment-naive patients with synchronous metastatic rectal cancer after chemotherapy with FOLFOXIRI followed by local therapeutic procedures of all tumor lesions as complete as possible. We reviewed data of 30 patients with synchronous distant metastatic rectal cancer who underwent chemotherapy with FOLFOXIRI and subsequent local therapy in our institution. Median follow-up was 28 months (range: 8; 74). Cumulative overall survival (OS) and progression-free survival (PFS) was 93.3, 76.9, 55.6% and 46.2, 29.7, 29.7% after 1, 2, 4 years. Non-response to chemotherapy with FOLFOXIRI was associated with a highly significant decreased OS (p

Approximately 20% of the nationally reported tetanus infections in children aged 0 to 14 years that occurred in the United States between 2005 and 2015 were treated at Penn State Children’s Hospital. With an electronic medical record search, we identified 5 cases of pediatric tetanus; 100% of these cases occurred in unimmunized children. Their median length of stay was 10 days, and the costs were significant.

The center of pressure (CoP) is one of the most utilized quantitative measurements describing postural competency. Due to the complexity and biological variability of postural regulatory systems, a myriad of different methods and parameters have been established describing the CoP trajectory. Besides procedural variables, such as foot position, visual condition, and sampling duration, the method of data collection itself has a relevant effect on the result of the measurement. Furthermore, different methods for recording the measured data have been developed, which differ regarding the filters, frequencies, and test durations used. The goal of this study was the methodical comparison of various filters, measurement frequencies, and measurement duration, with respect to their effects on the CoP trajectory. Based on the results presented, we demonstrate that the Butterworth and Bessel filters can be recommended for analysis of CoP data, and at the very least, a second-order filter should be chosen for the process. For assessment of the cutoff frequency, a technical pendulum was used to show that a cutoff frequency of 13 Hz provided reliable data and it can be inferred that a 100 Hz sampling rate would be the minimum requirement.

The gut microbiome is strongly interwoven with human health. Conventional gut microbiome analysis generally involves 16S rRNA gene targeting next generation sequencing (NGS) of stool microbial communities, and correlation of results with clinical parameters. However, some microorganisms may not be alive at the time of sampling, and thus their impact on the human health is potentially less significant. As conventional NGS methods do not differentiate between viable and dead microbial components, retrieved results provide only limited information.Propidium monoazide (PMA) is frequently used in food safety monitoring and other disciplines to discriminate living from dead cells. PMA binds to free DNA and masks it for subsequent procedures. In this article we show the impact of PMA on the results of 16S rRNA gene-targeting NGS from human stool samples and validate the optimal applicable concentration to achieve a reliable detection of the living microbial communities.Fresh stool samples were treated with a concentration series of zero to 300 μM PMA, and were subsequently subjected to amplicon-based NGS. The results indicate that a substantial proportion of the human microbial community is not intact at the time of sampling. PMA treatment significantly reduced the diversity and richness of the sample depending on the concentration and impacted the relative abundance of certain important microorganisms (e.g. Akkermansia, Bacteroides). Overall, we found that a concentration of 100 μM PMA was sufficient to quench signals from disrupted microbial cells.The optimized protocol proposed here can be easily implemented in classical microbiome analyses, and helps to retrieve an improved and less blurry picture of the microbial community composition by excluding signals from background DNA.

Background Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. Methods We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents’ DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. Results The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. Conclusions For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions. Electronic supplementary material The online version of this article (10.1186/s13023-018-0763-0) contains supplementary material, which is available to authorized users.

The great majority of electronic and optoelectronic devices depend on interfaces between p-type and n-type semiconductors. Finding matching donor-acceptor systems in molecular semiconductors remains a challenging endeavor because structurally compatible molecules may not necessarily be suitable with respect to their optical and electronic properties, and the large exciton binding energy in these materials may favor bound electron-hole pairs rather than free carriers or charge transfer at an interface. Regardless, interfacial charge-transfer exciton states are commonly considered as an intermediate step to achieve exciton dissociation. The formation efficiency and decay dynamics of such states will strongly depend on the molecular makeup of the interface, especially the relative alignment of donor and acceptor molecules. Structurally well-defined pentacene-perfluoropentacene heterostructures of different molecular orientations are virtually ideal model systems to study the interrelation between molecular packing motifs at the interface and their electronic properties. Comparing the emission dynamics of the heterosystems and the corresponding unitary films enables accurate assignment of every observable emission signal in the heterosystems. These heterosystems feature two characteristic interface-specific luminescence channels at around 1.4 and 1.5 eV that are not observed in the unitary samples. Their emission strength strongly depends on the molecular alignment of the respective donor and acceptor molecules, emphasizing the importance of structural control for device construction.

Summary Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

Zusammenfassung Für einige lysosomale Speicherkrankheiten steht eine Enzymersatz-Therapie zur Verfügung oder wird derzeit entwickelt. Um zu erreichen, dass intravenös applizierte Enzyme das Zentralnervensystem erreichen, werden Methoden entwickelt, durch Modifizierung der Enzyme oder durch Anwendung von Nanopartikeln die Bluthirnschranke zu überwinden. Eine andere Therapie-Option besteht in der Anwendung von Substrathemmern, die für den M. Gaucher und den M. Niemann-Pick Typ C eingesetzt werden. Derzeit werden Chaperone für verschiedene lysosomale Speicherkrankheiten entwickelt, die jedoch den Nachteil haben, dass sie nur bei bestimmten Mutationen eingesetzt werden können. „Read-Through“ Substanzen werden lediglich bei Vorliegen einer Nonsense-Mutation wirksam sein können. Auf dem Gebiet der lysosomalen Speicherkrankheiten wird eine Gen-Therapie derzeit nur im Rahmen klinischer Studien durchgeführt. Bevor dieses Behandlungs-Prinzip breite Anwendung finden kann, sollten jedoch noch Fragen zum Beispiel bezüglich der Langzeit-Sicherheit, der möglichen Immun-Reaktion und der Organ-Spezifität des für die Insertion verwendeten Vektors beantwortet werden. Um eine Behandlung einleiten zu können, bevor irreversible Organschäden auftreten, ist in vielen Ländern ein Neugeborenen-Screening für lysosomale Speicherkrankheiten eingeführt worden. Da jedoch damit mehr Mutationsträger diagnostiziert wurden als auf Grund epidemiologischer Untersuchungen zu erwarten war, muß angenommen werden, dass auch sehr leicht betroffene Patienten damit erfaßt werden. Eine sichere Aussage über den zu erwartenden Schweregrad kann jedoch auch durch eine Gen-Analyse nicht gemacht werden, so dass eine Therapie-Entscheidung im Einzelfall eventuell sehr schwierig ist. Für dieses Dilemma ist bisher noch keine Lösung gefunden worden.

Eine thermodynamische Analyse zum Einsatz von Kaltespeichern und der Abwarmenutzung bei Kuhl- und Gefrieranwendungen wird vorgestellt. Die Energieeffizienz der betrachteten Systeme steht dabei im Fokus. Zudem wird die Umgebung als unendliche Warmesenke zur direkten Ableitung der Warme aus dem Kuhlschrank untersucht. Es werden funf verschiedene Konzepte beschrieben und anhand ihres Jahresenergie- und Jahresprimarenergiebedarfs verglichen.

Objective The objective of this pilot study is to determine the prevalence of pseudoxanthoma elasticum (PXE)–like connective changes in an oral biopsy service and compare it with the estimated prevalence of PXE as well as to the prevalence of the mutated PXE gene ABCC6. Study Design This prevalence study utilized 500 oral mucosal biopsy specimens received from the biopsy service of the Oral Pathology Consultants at the Ohio State University. Each specimen was microscopically evaluated using hematoxylin and eosin, Verhoeff-van Gieson and von Kossa stains. Results A prevalence of 9.8% was identified for PXE-like changes in the connective tissue of oral biopsy specimens submitted to this service. Conclusions The overall prevalence of PXE-like connective tissue changes found in routine oral mucosal biopsy specimens (9.8%) was much higher than either the suspected prevalence of PXE (0.001%-0.004%) or the estimated prevalence of the mutated gene ABCC6 (0.625%-1.25%).

There is disagreement in the literature concerning the importance of the mouth in overall facial attractiveness. Eye tracking provides an objective method to evaluate what people see. The objective of this study was to determine whether dental and facial attractiveness alters viewers' visual attention in terms of which area of the face (eyes, nose, mouth, chin, ears, or other) is viewed first, viewed the greatest number of times, and viewed for the greatest total time (duration) using eye tracking.Seventy-six viewers underwent 1 eye tracking session. Of these, 53 were white (49% female, 51% male). Their ages ranged from 18 to 29 years, with a mean of 19.8 years, and none were dental professionals. After being positioned and calibrated, they were shown 24 unique female composite images, each image shown twice for reliability. These images reflected a repaired unilateral cleft lip or 3 grades of dental attractiveness similar to those of grades 1 (near ideal), 7 (borderline treatment need), and 10 (definite treatment need) as assessed in the aesthetic component of the Index of Orthodontic Treatment Need (AC-IOTN). The images were then embedded in faces of 3 levels of attractiveness: attractive, average, and unattractive. During viewing, data were collected for the first location, frequency, and duration of each viewer's gaze.Observer reliability ranged from 0.58 to 0.92 (intraclass correlation coefficients) but was less than 0.07 (interrater) for the chin, which was eliminated from the study. Likewise, reliability for the area of first fixation was kappa less than 0.10 for both intrarater and interrater reliabilities; the area of first fixation was also removed from the data analysis. Repeated-measures analysis of variance showed a significant effect (P0.001) for level of attractiveness by malocclusion by area of the face. For both number of fixations and duration of fixations, the eyes overwhelmingly were most salient, with the mouth receiving the second most visual attention. At times, the mouth and the eyes were statistically indistinguishable in viewers' gazes of fixation and duration. As the dental attractiveness decreased, the visual attention increased on the mouth, approaching that of the eyes. AC-IOTN grade 10 gained the most attention, followed by both AC-IOTN grade 7 and the cleft. AC-IOTN grade 1 received the least amount of visual attention. Also, lower dental attractiveness (AC-IOTN 7 and AC-IOTN 10) received more visual attention as facial attractiveness increased.Eye tracking indicates that dental attractiveness can alter the level of visual attention depending on the female models' facial attractiveness when viewed by laypersons.

Introduction: Mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes that are responsible for the stepwise degradation of complex carbohydrates, the glycosaminoglycans. Whereas in the past the treatment of MPS consisted mainly of palliative care, enzyme replacement therapy (ERT) is now possible for some MPS disorders, and in the future many other therapeutic options will become available.Areas covered: This review, based on personal experience and the currently available literature, will give an overview on the efficacy and limitations of ERT and will discuss new therapeutic approaches, such as anti-inflammatory drugs, substrate reduction therapy, chaperones and gene therapy.Expert opinion: The therapeutic strategies available nowadays for MPS patients, namely ERT and hematopoietic stem cell transplantation, have their limitations, particularly in regard to the bone and CNS manifestation. Small molecules such as substrate inhibitors or chaperones that are capable o...

Although several reports suggest an increased thromboembolic event rate, especially regarding strokes and TIAs at early age in patients with Fabry disease (FD), the risk for patients with FD to experience these events, the clinical relevance of additional risk factors including the concurrence of factor V Leiden (FVL), and the benefit of enzyme replacement therapy (ERT) regarding these events remain unclear.Three hundred four consecutively recruited patients with FD were evaluated for their lifetime occurrence of thromboembolic events such as stroke, TIA, deep vein thrombosis, and pulmonary embolism. The thromboembolic risk was determined in patients with FD and concurrent FVL, and the impact of ERT was assessed.The 304 patients with FD had a median age of 41 years and 53 (17.4%) had experienced at least one thromboembolic event during their lifetime. Among 226 patients with FD screened for FVL, 16 gene carriers were identified (7.1%). The occurrence of thromboembolic events in patients with FD and concurrent FVL was significantly increased compared to those without FVL (hazard ratio = 5.45, 95% confidence interval 2.29-12.99; p0.001). Patients with FD receiving ERT had a significantly decreased risk of thromboembolic events compared to those without ERT (hazard ratio = 0.362, 95% confidence interval 0.132-0.992; p = 0.0422).This observational study confirms that patients with FD have a high risk of clinically relevant thromboembolic events, which could be aggravated by a concurrence of FVL. ERT might be of benefit in preventing vascular events in patients with FD. The latter observation needs confirmation, however, by randomized and controlled clinical trials.

This chapter presents novel approaches for the efficient generation, storage, and usage of energy in the smart home environment and their link to the smart grid. It also demonstrates innovative concepts and their feasibility for these purposes. The generation of renewable energy on the level of individual homes and housing estates is achieved by aerodynamically and aeroacoustically optimized small wind turbines as well as combined heat and power (CHP) micro plants using organic Rankine cycles (ORCs) to complement solar energy. The chapter further discusses the intelligent distribution of electric energy between the smart home and the smart grid. In order to tackle the transition of the electric power supply toward a renewable‐based generation plant system, it is necessary to fully exploit locally available energy sources and to generate production surpluses in rural areas for the supply of urban agglomerations and industrial centers.

Recently, greater emphasis has been placed on smile esthetics in dentistry. Eye tracking has been used to objectively evaluate attention to the dentition (mouth) in female models with different levels of dental esthetics quantified by the aesthetic component of the Index of Orthodontic Treatment Need (IOTN). This has not been accomplished in men. Our objective was to determine the visual attention to the mouth in men with different levels of dental esthetics (IOTN levels) and background facial attractiveness, for both male and female raters, using eye tracking.Facial images of men rated as unattractive, average, and attractive were digitally manipulated and paired with validated oral images, IOTN levels 1 (no treatment need), 7 (borderline treatment need), and 10 (definite treatment need). Sixty-four raters meeting the inclusion criteria were included in the data analysis. Each rater was calibrated in the eye tracker and randomly viewed the composite images for 3 seconds, twice for reliability.Reliability was good or excellent (intraclass correlation coefficients, 0.6-0.9). Significant interactions were observed with factorial repeated-measures analysis of variance and the Tukey-Kramer method for density and duration of fixations in the interactions of model facial attractiveness by area of the face (P 0.0001, P 0.0001, respectively), dental esthetics (IOTN) by area of the face (P 0.0001, P 0.0001, respectively), and rater sex by area of the face (P = 0.0166, P = 0.0290, respectively). For area by facial attractiveness, the hierarchy of visual attention in unattractive and attractive models was eye, mouth, and nose, but for men of average attractiveness, it was mouth, eye, and nose. For dental esthetics by area, at IOTN 7, the mouth had significantly more visual attention than it did at IOTN 1 and significantly more than the nose. At IOTN 10, the mouth received significantly more attention than at IOTN 7 and surpassed the nose and eye. These findings were irrespective of facial attractiveness levels. For rater sex by area in visual density, women showed significantly more attention to the eyes than did men, and only men showed significantly more attention to the mouth over the nose.Visual attention to the mouth was the greatest in men of average facial attractiveness, irrespective of dental esthetics. In borderline dental esthetics (IOTN 7), the eye and mouth were statistically indistinguishable, but in the most unesthetic dental attractiveness level (IOTN 10), the mouth exceeded the eye. The most unesthetic malocclusion significantly attracted visual attention in men. Male and female raters showed differences in their visual attention to male faces. Laypersons gave significant visual attention to poor dental esthetics in men, irrespective of background attractiveness; this was counter to what was seen in women.

Introduction Recent technological advances have made intraoral scans and digital models a possibility and a promising alternative to conventional alginate impressions. Several factors should be examined when considering an intraoral scanner, including patient acceptance and efficiency. The objectives of this study were to assess and compare patient satisfaction and time required between 2 intraoral scanners and conventional alginate impressions. Methods An initial pilot study was completed to create a valid and reliable survey instrument that would measure 3 areas of patient satisfaction with the impression experience. A visual analog scale survey was developed and administered to 180 orthodontic patients receiving 1 of 3 types of impressions: (1) iTero Element intraoral scan (Align Technologies, San Jose, Calif), n = 60; (2) TRIOS Color intraoral scan (3Shape, Copenhagen, Denmark), n = 60; and (3) conventional alginate impression (imprEssix Color Change; Dentsply Sirona, York, Pa), n = 60, and the time required to obtain the impressions was recorded. Results Reliability was evaluated with intraclass correlation coefficient values for 17 paired questionnaires, and all questions were found to be reliable (intraclass correlation coefficient, ≥0.65). For the main study, 180 subjects completed timed impressions and surveys. Data indicated that subjects receiving intraoral scans preferred the digital impressions, and subjects receiving alginate impressions were neutral regarding impression preference, and that efficiency varied based on the impression method. Conclusions Intraoral scanners are accepted by orthodontic patients, and they have comparable efficiency with conventional impression methods depending on the type of scanner.

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naive MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200μg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S). Treatment is available in the form of enzyme replacement therapy (ERT) with recombinant I2S. Clinical outcomes following ≥3 years of ERT with idursulfase were investigated in a broad population of patients with MPS II enrolled in the Hunter Outcome Survey (HOS). As of January 2016, 639 patients (excluding female patients, individuals who had received a bone marrow transplant and those enrolled in the phase 1/2 [TKT018] or phase 2/3 [TKT024] clinical trial) followed prospectively in the registry had received idursulfase for ≥6 months. These individuals all had data available for ≥1 clinical parameter at baseline and ≥1 additional time point following treatment initiation. Changes in clinical parameters were assessed in the subcohorts of patients with a measurement at baseline and at year 1, 2 or 3 of treatment. Safety data from patients who started treatment at or after enrollment in HOS (n = 233) were also assessed. Median (10th, 90th percentiles) age at first treatment was 6.2 (2.1, 18.2) years and median treatment duration was 56.3 (18.2, 97.6) months. Urinary glycosaminoglycan (uGAG) levels decreased from baseline to year 3 in patients with data available at this time point (median change from baseline: −201.0 [−591.4, −21.9] μg/mg creatinine [n = 121]). Improvements in the following parameters were observed at year 3 in the subcohorts: 6-min walking test (6MWT) distance, 10.6 (−33.6, 50.8)% (n = 26); left ventricular mass index (LVMI), −9.3 (−31.5, 19.7)% (n = 52); absolute forced vital capacity (FVC), 29.7 (−13.4, 66.7)% (n = 23); absolute forced expiratory volume in 1 s (FEV1), 22.8 (−15.2, 62.1) % (n = 22); palpable liver size, −54.5 (−85.7, 50.0)% (n = 53); palpable spleen size, −33.3 (−80.0, 33.3)% (n = 17). No new or unexpected safety concerns were identified in this analysis. These findings suggest that idursulfase has a positive effect on uGAG levels, 6MWT results, LVMI, FVC, FEV1 and hepatosplenomegaly after 1, 2 and 3 years treatment.

Purpose: In this study, we aimed to describe the natural history of mucopolysaccharidosis I. Methods: Data from 1,046 patients who enrolled in the MPS I Registry as of August 2013 were available for descriptive analysis. Only data from untreated patients and data prior to treatment for patients who received treatment were considered. Age at symptom onset, diagnosis, and treatment initiation were examined by geographic region and phenotype (from most to least severe: Hurler, Hurler–Scheie, and Scheie). For each symptom, frequency and age at onset were examined. Results: Natural history data were available for 987 patients. Most patients were from Europe (45.5%), followed by North America (34.8%), Latin America (17.3%), and Asia Pacific (2.4%). Phenotype distribution was 60.9% for Hurler, 23.0% for Hurler–Scheie, and 12.9% for Scheie (3.2% undetermined) syndromes. Median age at symptom onset for Hurler, Hurler–Scheie, and Scheie syndromes was 6 months, 1.5 years, and 5.3 years, respectively; median age at treatment initiation was 1.5 years, 8.0 years, and 16.9 years, respectively. Coarse facial features and corneal clouding were among the most common symptoms in all three phenotypes. Conclusion: A delay between symptom onset and treatment exists, especially in patients with attenuated mucopolysaccharidosis I. A better understanding of disease manifestations may help facilitate prompt diagnosis and treatment and improve patient outcomes.

The objective of the present study was to examine the grey value parameters and their magnitudes produced by CBCT and whether they are influenced by different scanners with various scanning conditions.An ATOM Max dental and diagnostic artificial head was scanned by two CBCT scanners (Planmeca and iCAT). Under full field of view with normal dose and ultralow-dose (ULD) conditions, the Planmeca scanner was examined for three scanning resolutions (200, 400, and 600 micron voxel sizes) and the iCAT scanner was tested for four scanning resolutions (200, 250, 300 and 400 micron voxel sizes). After 9 weeks, the artificial head was scanned again by the Planmeca scanner with the same scanning conditions. In addition, two hydroxyapatite phantoms (1220 and 1540 mg cmThe different scanning conditions and the bilateral locations of the artificial head did not have significant effects on measurements of the grey value parameters (p 0.436) with excellent repeatability. However, the iCAT scanner produced significantly different grey values from the Planmeca scanner (p 0.001).CBCT can assess BMD, while calibration of absolute measures is necessary to obtain comparable values between different scanners that are currently used to assess oral bone quantity and quality.

The purposes of this study were to assess the role of dental attractiveness in background facial attractiveness and to evaluate how facial and dental attractiveness influenced raters' opinions of the integrity, social attractiveness, and intellectual attractiveness of the models.Photographs of male and female individuals rated by peers as unattractive, average, and attractive were combined with oral images of 4 different levels of dental attractiveness (Index of Orthodontic Treatment Need [IOTN] 1, 5, 7, and 10). Sixty-seven participants meeting the inclusion criteria were recruited as raters. Raters viewed closed-lip smile and open-lip, posed smile of 24 models and rated them for facial attractiveness and integrity and multiple social/intellectual attractiveness dimensions using a Visual Analog Scale.Intrarater reliability was fair to excellent. Analysis of variance showed significant 3-way interactions (P 0.0001=aim 1; P 0.005=aim 2) for model sex, facial attractiveness, and dental attractiveness. The contribution of dental attractiveness to facial attractiveness was not fixed or linear, but dependent on dental attractiveness level, background facial attractiveness, and model sex. For both sexes, dental impact on facial attractiveness was neutral or negative when teeth were less than ideal, beginning at IOTN 5 for all background facial attractiveness levels. The impact of dental attractiveness on integrity and social and intellectual attractiveness was also dependent on dental attractiveness level, background facial attractiveness, and model sex. Dental attractiveness can make dramatic differences in Average and Attractive male individuals.The impact of dental attractiveness on facial attractiveness and integrity and social and intellectual attractiveness was dependent on dental attractiveness level, background facial attractiveness, and model sex. The effect of dental esthetics on facial attractiveness was neutral or negative for both male and female individuals when there was a need for treatment (IOTN 5 or higher) for all levels of facial attractiveness. For both male and female models, lower dental esthetics had a greater effect on more attractive faces. Judgments about integrity and social and intellectual attractiveness were strongly affected by dental esthetics, and these effects were more dramatic and consistent for male faces.

The human immune system is comprised of a complex network of immune checkpoint receptors that are promising new immunotherapy targets for the treatment of a variety of cancers and autoimmune disorders. The Nobel prize for Medicine in 2018 was awarded for seminal studies on the role of immune checkpoint targets in T cell activation and furthermore, combining different strategies to release the brakes on the immune system with the aim of eliminating tumor cells even more efficiently. Immunotherapies designed to block co-inhibitory receptors (e.g. PD-1, CTLA-4, TIGIT) are showing unprecedented efficacy in the treatment of cancer. However, not all patients and tumor types respond to this approach. This has resulted in broadening of immunotherapy research programs to target additional co-inhibitory (e.g. LAG-3, TIM-3) and co-stimulatory (e.g. 4-1BB, GITR, OX40, ICOS) receptors individually and in combination. A major challenge in the development of antibody-based biologics is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable and fail to yield data required for drug development in a quality-controlled environment. To address this need, we have developed a suite of cell-based functional bioassays to interrogate modulation of immune checkpoint receptors individually (e.g. PD-1, LAG-3, TIM-3, GITR, 4-1BB) and in combination (e.g. PD-1+CTLA-4, PD-1+LAG-3). These assays consist of stable cell lines that express luciferase reporters driven by response elements under the precise control of mechanistically relevant intracellular signals. Thus, the bioassays reflect mechanisms of action for the drug candidates designed for each immune checkpoint receptor and demonstrate high specificity, sensitivity and reproducibility. Here we describe the application of MoA-based immune checkpoint receptor bioassays as tools for biologics drug discovery, development, potency and stability studies. Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays to advance immunotherapy programs targeting immune checkpoint receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4113.