DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8+ T Cell Responses, Enabling Faster Resolution of Influenza Disease

Current influenza vaccines are effective but imperfect, failing to cover against emerging strains of virus and requiring seasonal administration to protect against new strains. A key step to improving influenza vaccines is to improve our understanding of vaccine induced protection. Whilst it is clear that antibodies play a protective role, vaccine induced CD8+ T cells can improve protection. To further explore the role of CD8+ T cells we used a DNA vaccine that encodes antigen dimerised to an immune cell targeting module. Immunising CB6F1 mice with the DNA vaccine in a heterologous prime boost regime with the seasonal protein vaccine improved the resolution of influenza disease compared to protein alone. This improved disease resolution was dependent on CD8+ T cells. However, DNA vaccine regimes that induced CD8+ T cells alone were not protective and did not boost the protection provided by protein. The MHC targeting module used was an anti-I-Ed single chain antibody specific to the BALB/c strain of mice. To test the role of MHC targeting we compared the response between BALB/c, C57BL/6 mice and an F1 cross of the two strains (CB6F1). BALB/c mice were protected, C57BL/6 were not and the F1 had an intermediate phenotype; showing that the targeting of antigen is important in the response. Based on these findings, and in agreement with other studies using different vaccines, we conclude that in addition to antibody, inducing a protective CD8 response is important in future influenza vaccines

The Global Health interactive Curricula Experience (iCE) Platform & App : Technology that Enables Inter-professional Innovation

Global Health Initiatives Committee (GHIC) Serves the Jefferson community as the premier point of engagement for students & faculty interested in medical and public health issues that transcend national boundaries Creates an institutional focus on preparing students for public service careers in population health and public policy at local, national, and global levels To enable all TJU faculty to: - Deliver global health education, in a friendly, interactive format - Does not require an expert to deliver - Can be used in very small or large pieces depending on your need

Building Interprofessional Global Health Infrastructure at a University and Health System: Navigating Challenges and Scaling Successes

Mission: Global Jefferson will create sustainable programs of global distinction through collaboration that position Jefferson as a local and international destination and resource for education, research, and clinical activities. Global Jefferson is supported by the Associate Provost for Global Affairs, part of the Office of the Provost. Global activity at Jefferson includes: Global Health Initiatives Committee (GHIC) Service Learning Global Research & Exchange between institutions Pre-clinical, translational, clinical, and applied research Poster presented at: 8th Annual Global Health Conference of the Consortium of Universities for Global Health (CUGH)https://jdc.jefferson.edu/globalhealthposters/1000/thumbnail.jp

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM

An early myeloma bone disease model in skeletally mature mice as a platform for biomaterial characterization of the extracellular matrix

Multiple myeloma (MM) bone disease is characterized by osteolytic bone tissue destruction resulting in bone pain, fractures, vertebral collapse, and spinal cord compression in patients. Upon initial diagnosis of MM, almost 80% of patients suffer from bone disease. Earlier diagnosis and intervention in MM bone disease would potentially improve treatment outcome and patient survival. New preclinical models are needed for developing novel diagnostic markers of bone structural changes as early as possible in the disease course. Here, we report a proof-of-concept, syngeneic, intrafemoral MOPC315.BM MM murine model in skeletally mature BALB/c mice for detection and characterization of very early changes in the extracellular matrix (ECM) of MM-injected animals. Bioluminescence imaging (BLI) in vivo confirmed myeloma engraftment in 100% of the animals with high osteoclast activity within 21 days after tumor cell inoculation. Early signs of aggressive bone turnover were observed on the outer bone surfaces by high-resolution microcomputed tomography (microCT). Synchrotron phase contrast-enhanced microcomputer tomography (PCE-CT) revealed very local microarchitecture differences highlighting numerous active sites of erosion and new bone at the micrometer scale. Correlative backscattered electron imaging (BSE) and confocal laser scanning microscopy allowed direct comparison of mineralized and nonmineralized matrix changes in the cortical bone. The osteocyte lacunar-canalicular network (OLCN) architecture was disorganized, and irregular-shaped osteocyte lacunae were observed in MM-injected bones after 21 days. Our model provides a potential platform to further evaluate pathological MM bone lesion development at the micro- and ultrastructural levels. These promising results make it possible to combine material science and pharmacological investigations that may improve early detection and treatment of MM bone disease

T Cell Recognition of the Dominant I-Ak–Restricted Hen Egg Lysozyme Epitope: Critical Role for Asparagine Deamidation

Type-B T cells raised against the immunodominant peptide in hen egg lysozyme (HEL48–62) do not respond to whole lysozyme, and this has been thought to indicate that peptide can bind to l-Ak in different conformations. Here we demonstrate that such T cells recognize a deamidated form of the HEL peptide and not the native peptide. The sequence of the HEL epitope facilitates rapid and spontaneous deamidation when present as a free peptide or within a flexible domain. However, this deamidated epitope is not created within intact lysozyme, most likely because it resides in a highly structured part of the protein. These findings argue against the existence of multiple conformations of the same peptide–MHC complex and have important implications for the design of peptide-based vaccines. Furthermore, as the type-B T cells are known to selectively evade induction of tolerance when HEL is expressed as a transgene, these results suggest that recognition of posttranslationally modified self-antigen may play a role in autoimmunity

Gefäßchirurgische Ausbildung in endovaskulärer Technik in Lausanne

Zusammenfassung: Zwischen 1995 und 2005 wuchs die Anzahl der jährlich von uns mit endovaskulären Techniken versorgten Aortenaneurysmen (EVAR) von 0 auf 50, und dies auf allen Stufen der Aorta. Zu unserer Organisation gehören ein breites Team von Chirurgen, ein Lager mit 3kompletten Familien von Endoprothesen (gerade Endoprothesen, konische Endoprothesen, und Bifurkationen), ein mobiler Wagen mit Zubehör (Einführungsbestecke, Führungsdrähte, Katheter, Ballone etc.) und ein Apparat auf Rädern für die intravaskuläre Ultraschalluntersuchung (IVUS). Letzterer erlaubt es zusammen mit einer mobilen Durchleuchtungsanlage (C-Bogen), in jedem Operationssaal unserer Institution endovaskulär Aneurysmen zu analysieren, und dies in der Regel ohne Angiographie bzw. Kontrastmittel. Deshalb sind wir nicht mehr auf eine ausgiebige bildgebende präoperative Abklärung potenzieller Kandidaten für eine endovaskuläre Sanierung von Aneurysmen angewiesen und können rupturierte Aneurysmen der Bauchaorta oder der thorakalen Aorta ohne Verzug behandeln. Bei der endovaskulären Sanierung von Aortenaneurysmen unterscheiden wir zwischen Prozessschritten (Indikationsstellung, Darstellung der Zugangsgefäße, Ausmessen mittels IVUS und Roadmapping mittels Durchleuchtung, Implantatwahl, Implantatinsertion, Positionierung, Implantatabwurf, Erfolgsbeurteilung, Rekonstruktion der Zugangsgefäße und Nachkontrolle) und Kompetenzstufen (Assistent, Oberarzt, Leitender Arzt). Unsere ultraschallgestützte Technik zur endovaskulären Sanierung von Aneurysmen wurde mittels IVUS-Transporter und Telementoring erfolgreich auch anderen Institutionen zur Verfügung gestell

“That little doorway where I could suddenly start shouting out”: barriers and enablers to the disclosure of distressing voices

Hearing distressing voices is a key feature of psychosis. The time between voice onset and disclosure may be crucial as voices can grow in complexity. This study investigated barriers and enablers to early voice disclosure. Interviews with 20 voice hearers underwent Thematic Analysis. Beliefs about the effect of disclosure on self and others acted as a barrier and enabler to voices being discussed. Voice hearing awareness should be increased amongst young people, the public and care services. To support earlier disclosure measures need to increase skill amongst those likely to be disclosed to

Study design and rationale for a randomized controlled trial to assess effectiveness of stochastic vibrotactile mattress stimulation versus standard non-oscillating crib mattress for treating hospitalized opioid-exposed newborns

The incidence of Neonatal Abstinence Syndrome (NAS) continues to rise and there remains a critical need to develop non-pharmacological interventions for managing opioid withdrawal in newborns. Objective physiologic markers of opioid withdrawal in the newborn remain elusive. Optimal treatment strategies for improving short-term clinical outcomes and promoting healthy neurobehavioral development have yet to be defined. This dual-site randomized controlled trial (NCT02801331) is designed to evaluate the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment, and length of hospitalization, and for improving developmental outcomes in opioid-exposed neonates. Hospitalized newborns (n = 230) receiving standard clinical care for prenatal opioid exposure will be randomly assigned within 48-hours of birth to a crib with either: 1) Intervention (SVS) mattress: specially-constructed SVS crib mattress that delivers gentle vibrations (30-60 Hz, ~12 mum RMS surface displacement) at 3-hr intervals; or 2) Control mattress (treatment as usual; TAU): non-oscillating hospital-crib mattress. Infants will be studied throughout their hospitalization and post discharge to 14-months of age. The study will compare clinical measures (i.e., withdrawal scores, cumulative dose and duration of medications, velocity of weight gain) and characteristic progression of physiologic activity (i.e., limb movement, cardio-respiratory, temperature, blood-oxygenation) throughout hospitalization between opioid-exposed infants who receive SVS and those who receive TAU. Developmental outcomes (i.e., physical, social, emotional and cognitive) within the first year of life will be evaluated between the two study groups. Findings from this randomized controlled trial will determine whether SVS reduces in-hospital severity of NAS, improves physiologic function, and promotes healthy development