Disentangling Acid-Base Chemistry through Blue Shifting Hydrogen Bond Contributions.

The blue shifting of vibrational frequencies in hydrogen bonded molecules, as observed in aqueous environments, has been attributed to local partial charge transfer from solvation. Here, we extrapolate the blue shift model to the stronger ionic interactions between hydrogen bond acceptors associated with protonation through augmented pH levels and competitive interactions with counter ion pairing. The chemical model we utilize in this work is the aqueous pyridine-pyridinium equilibrium to characterize the blue shifts observed in the pyridinium chloride ionic system. The observed agreement between observed experimental and calculated spectral shifts shows that the blue shifting model can be extrapolated to stronger interactions and accurately describe the nature of the hydrogen bond.

Cutting Edge: Bispecific γδ T Cell Engager Containing Heterodimeric BTN2A1 and BTN3A1 Promotes Targeted Activation of Vγ9Vδ2+ T Cells in the Presence of Costimulation by CD28 or NKG2D.

Vγ9Vδ2+ T cell-targeted immunotherapy is of interest to harness its MHC-independent cytotoxic potential against a variety of cancers. Recent studies have identified heterodimeric butyrophilin (BTN) 2A1 and BTN3A1 as the molecular entity providing "signal 1" to the Vγ9Vδ2 TCR, but "signal 2" costimulatory requirements remain unclear. Using a tumor cell-free assay, we demonstrated that a BTN2A1/3A1 heterodimeric fusion protein activated human Vγ9Vδ2+ T cells, but only in the presence of costimulatory signal via CD28 or NK group 2 member D. Nonetheless, addition of a bispecific γδ T cell engager BTN2A1/3A1-Fc-CD19scFv alone enhanced granzyme B-mediated killing of human CD19+ lymphoma cells when cocultured with Vγ9Vδ2+ T cells, suggesting expression of costimulatory ligand(s) on tumor cells is sufficient to satisfy the "signal 2" requirement. These results highlight the parallels of signal 1 and signal 2 requirements in αß and γδ T cell activation and demonstrate the utility of heterodimeric BTNs to promote targeted activation of γδ T cells.

LIGHT (TNFSF14) Costimulation Enhances Myeloid Cell Activation and Antitumor Immunity in the Setting of PD-1/PD-L1 and TIGIT Checkpoint Blockade.

Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non-small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition-resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition-resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTßR (lymphotoxin ß receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

The Interplay of Biomechanical and Biological Changes Following Meniscus Injury.

PURPOSE OF REVIEW: Meniscus injury often leads to joint degeneration and post-traumatic osteoarthritis (PTOA) development. Therefore, the purpose of this review is to outline the current understanding of biomechanical and biological repercussions following meniscus injury and how these changes impact meniscus repair and PTOA development. Moreover, we identify key gaps in knowledge that must be further investigated to improve meniscus healing and prevent PTOA. RECENT FINDINGS: Following meniscus injury, both biomechanical and biological alterations frequently occur in multiple tissues in the joint. Biomechanically, meniscus tears compromise the ability of the meniscus to transfer load in the joint, making the cartilage more vulnerable to increased strain. Biologically, the post-injury environment is often characterized by an increase in pro-inflammatory cytokines, catabolic enzymes, and immune cells. These multi-faceted changes have a significant interplay and result in an environment that opposes tissue repair and contributes to PTOA development. Additionally, degenerative changes associated with OA may cause a feedback cycle, negatively impacting the healing capacity of the meniscus. Strides have been made towards understanding post-injury biological and biomechanical changes in the joint, their interplay, and how they affect healing and PTOA development. However, in order to improve clinical treatments to promote meniscus healing and prevent PTOA development, there is an urgent need to understand the physiologic changes in the joint following injury. In particular, work is needed on the in vivo characterization of the temporal biomechanical and biological changes that occur in patients following meniscus injury and how these changes contribute to PTOA development.

Non-local dielectric effects in nanoscience.

The physical properties of charges and excitations in nanoscale materials are influenced both by the dielectric properties of the material itself and the surrounding environment. This non-local dielectric effect was first discussed in the context of molecules in solvents over a century ago. In this perspective, we discuss non-local dielectric effects in zero-dimensional, one-dimensional, and two-dimensional nanoscale systems.

2001: An artificial heart odyssey.

The quest to replace the natural heart with an artificial one as a permanent system is among the remaining holy grails in medicine and surgery. Beginning in 1969, when the first total artificial heart (TAH) was implanted into a human, to the present, several types have been developed-the AbioCor was among them. On November 5th, 2001, our team at Hahnemann University Hospital in Philadelphia, Pennsylvania placed the world's fifth AbioCor. Excerpts of that moment in time were recorded and serve as a memorial to the past and a testimony to the present and future quest of this elusive holy grail.

Lumbar intervertebral disc diurnal deformations and T2 and T1rho relaxation times vary by spinal level and disc region.

PURPOSE: Magnetic resonance imaging (MRI) is routinely used to evaluate spine pathology; however, standard imaging findings weakly correlate to low back pain. Abnormal disc mechanical function is implicated as a cause of back pain but is not assessed using standard clinical MRI. Our objective was to utilize our established MRI protocol for measuring disc function to quantify disc mechanical function in a healthy cohort. METHODS: We recruited young, asymptomatic volunteers (6 male/6 female; age 18-30 years; BMI < 30) and used MRI to determine how diurnal deformations in disc height, volume, and perimeter were affected by spinal level, disc region, MRI biomarkers of disc health (T2, T1rho), and Pfirrmann grade. RESULTS: Lumbar discs deformed by a mean of -6.1% (95% CI: -7.6%, -4.7%) to -8.0% (CI: -10.6%, -5.4%) in height and -5.4% (CI: -7.6%, -3.3%) to -8.5% (CI: -11.0%, -6.0%) in volume from AM to PM across spinal levels. Regional deformations were more uniform in cranial lumbar levels and concentrated posteriorly in the caudal levels, reaching a maximum of 13.1% at L5-S1 (CI:-16.1%, -10.2%). T2 and T1rho relaxation times were greatest in the nucleus and varied circumferentially within the annulus. T2 relaxation times were greatest at the most cranial spinal levels and decreased caudally. In this young healthy cohort, we identified a weak association between nucleus T2 and the diurnal change in the perimeter. CONCLUSIONS: Spinal level is a key factor in determining regional disc deformations. Interestingly, deformations were concentrated in the posterior regions of caudal discs where disc herniation is most prevalent.

Brain microstructural changes and cognitive function in non-demented essential tremor patients: a diffusion tensor imaging study.

BACKGROUND: Essential tremor (ET) is disease with both motor and non-motor features. Notable among the non-motor features is cognitive impairment. While this impairment has been attributed to cortico-thalamo-cerebellar pathway pathology, it is likely that a more complicated involvement of brain structures underlies cognitive function in ET. OBJECTIVE: To evaluate the brain microstructural changes of both white matter and grey matter in ET using region of interest based diffusion tensor imaging (DTI), and to correlate these changes with cognitive function assessed during detailed neuropsychological testing. METHOD: Thirty-five non-demented ET patients with a range of cognitive function (Clinical Dementia Rating = 0-0.5, mean age = 57.5 ± 16.7 years, age range = 23-76 years) underwent a comprehensive neuropsychological evaluation and brain magnetic resonance imaging, including DTI. DTI findings were reported as fractional anisotropy, average diffusion coefficient, these values were evaluated for 32 ROIs. Cognitive domains included attention, visuospatial functions, executive function, verbal memory, visual memory, and language. Domain Z-scores were calculated each cognitive domain and compared for each brain region. RESULTS: Microstructural changes in prefrontal cortical areas (dorsolateral, ventrolateral), paralimbic and limbic structures (posterior cingulate cortex, precuneus, hippocampus), basal ganglia (substantia nigra, putamen, caudate nucleus) and white matter bundles (corpus callosum, anterior thalamic radiation, longitudinal fasciculus, frontooccipital fasciculus, etc.) correlated with specific domains of cognitive function in ET patients. CONCLUSION: These data suggest that not only the cerebello thalamocortical pathway, but numerous other brain structures are related to level of cognitive performance and possibly underlie cognitive dysfunction in ET.

[Advances in the management of inflammatory bowel diseases]. / Nouveautés dans la prise en charge des maladies inflammatoires chroniques intestinales.

New therapeutic strategies and new molecules have been recently developed for the management of inflammatory bowel diseases. The treat-to-target strategy aims to define specific objectives based on the patient and the disease characteristics. A regular monitoring using biomarkers and imaging is required to assess the objectives' achievement. Better outcomes have been demonstrated with this approach compared to the standard of care guided by symptoms only. On top of anti-TNF, new biologics have been available for the last few years. Vedolizumab, an anti-integrine, and ustekinumab, an interleukine 12/23 inhibitor, have demonstrated their efficacy in ulcerative colitis and Crohn's disease with an excellent safety profile and a sustained efficacy over time. Small molecules like tofacitinib are available in ulcerative colitis. The delay of action of these oral molecules is short. The risk of infection is similar compared to anti-TNF. Thromboembolic events have been reported with a prolonged double dose in predisposed patients. Preferential JAK inhibitors will be shortly available with an expected better safety profile. The growing number of available molecules allows a more effective management of inflammatory bowel diseases by choosing the right treatment for the right patient.

: De nouvelles stratégies sont disponibles pour la prise en charge des maladies inflammatoires chroniques intestinales. Elles ont pour but de fixer des objectifs précis, parfois très ambitieux dans les cas les plus sévères, tout en surveillant de façon étroite les patients à l'aide de biomarqueurs ou d'imagerie. Cette stratégie a démontré une meilleure efficacité sur le moyen et le long terme qu'un traitement standard basé sur les symptômes. à côté des anti-TNF, de nouveaux biologiques comme le védolizumab, un anti-intégrine, ou l'ustékinumab, un inhibiteur des interleukines 12 et 23, sont disponibles, tous deux présentant un excellent profil de sécurité et une efficacité soutenue au fil du temps. Des petites molécules anti-JAK (Janus Kinase) comme le tofacitinib sont accessibles pour le traitement de la rectocolite ulcéro-hémorragique (RCUH). Il s'agit de traitements oraux présentant une efficacité rapide. Le risque infectieux est similaire à celui des anti-TNF. Des inhibiteurs préférentiels des JAK seront bientôt disponibles pour le traitement de la maladie de Crohn et de la RCUH, avec un meilleur profil de sécurité potentiel. Le choix thérapeutique devient de plus en plus large, mais aussi de plus en plus complexe. Il doit se baser sur le profil du patient et de la maladie et doit nécessiter un avis spécialisé dans les situations difficiles.

[Clinical impact of small bowell capsule endoscopy in obscure gastrointestinal bleeding : retrospective single-center study]. / Impact clinique de la vidéocapsule endoscopique du grêle dans les saignements digestifs inexpliqués. Etude rétrospective monocentrique.

INTRODUCTION: The small-bowel capsule endoscopy (VCE) has been validated in the investigation of obscure gastrointestinal bleeding (OGIB). The aim of this study was to evaluate the clinical impact of VCE for OGIB in routine practice, in terms of subsequent management and the risk of rebleeding. METHODS: Our retrospective study analyzed the VCE at the CHU of Liège from March 2016 to December 2019 (cohort of 110 patients with OGIB). RESULTS: We found a diagnostic yield of 58 %, a change in therapeutic attitude in 39 % of patients and a recurrence rate of 22.5 % (out of 102 patients followed at 2 years). The rate of rebleeding was particularly low in patients with normal VCE and in those for whom a therapeutic modification was made. Finally, about 45 % of patients did not have any change in therapeutic attitude nor recurrence. CONCLUSION: VCE leads to a therapeutic modification in about 40 % of patients with a low risk of relapse. However, VCE could be avoided in some patients as evidenced by a subgroup representing 45 % of patients for whom there was no therapeutic modification nor recurrence.

introduction et but : La vidéocapsule endoscopique grêle (VCE) est validée dans l'exploration des saignements digestifs inexpliqués (OGIB). Le but de notre travail a été d'évaluer l'impact clinique de la réalisation d'une VCE pour OGIB en pratique courante, en termes de prise en charge ultérieure et de risque de récidive du saignement. Méthodes : Notre étude rétrospective a analysé les VCE réalisées au CHU de Liège de mars 2016 à décembre 2019. Résultats : Les VCE de 110 patients ont été rétrospectivement analysées. Nous avons observé un pouvoir diagnostique de 58 % et une modification d'attitude thérapeutique chez 39 % des patients. Le taux de récidive (pour les 102 patients dont le suivi était disponible à maximum 2 ans) était de 22,5 %. Le taux de récidive de saignement était particulièrement faible chez les patients avec VCE normale et chez ceux pour lesquels une modification thérapeutique a été faite. Enfin, environ 45 % des patients n'ont pas eu de modification de l'attitude thérapeutique ni de récidive. Conclusions : La VCE débouche sur une modification thérapeutique chez environ 40 % des patients avec, dans la foulée, un faible risque de récidive. Par contre, la VCE pourrait être évitée chez certains patients comme en témoigne un sous-groupe représentant 45 % des patients pour lesquels il n'y a eu ni modification thérapeutique ni rechute.

[Cellular immunotherapy at the University Hospital of Liege : advances, challenges and prospects]. / Immunothérapie cellulaire au CHU de Liège : avancées, défis et perspectives.

Cellular immunotherapy consists in using the cells of the immune system as a therapeutic weapon. In this constantly evolving field, the therapeutic strategies developed at the University Hospital of Liege are hematopoietic stem cell transplantation, mesenchymal stromal cells and targeted therapy with CAR-T cells (Chimeric Antigen Receptor T cells). The first two modalities represent a form of non-targeted cell therapy that has been developed over the past decades. While hematopoietic stem cell transplantation is established as the reference treatment for many hematological diseases, mesenchymal stromal cells are still under investigation in various pathologies (notably Crohn's disease, organ transplantation, COVID-19 and pulmonary fibrosis). By contrast, CAR-T cells represent a recently developed and extremely promising targeted immunotherapy. This therapeutic approach has already revolutionized the treatment of B-cell lymphopathies, and has the potential to do the same for many other diseases in the near future.

L'immunothérapie cellulaire consiste en l'utilisation de cellules du système immunitaire comme arme thérapeutique. Dans ce domaine en évolution constante, les stratégies thérapeutiques développées au CHU de Liège sont la greffe de cellules souches hématopoïétiques, les cellules stromales mésenchymateuses et la thérapie ciblée par cellules CAR-T («Chimeric Antigen Receptor T cells¼). Les deux premières approches représentent une forme de thérapie cellulaire non ciblée, développées depuis de nombreuses années. Si la greffe de cellules souches hématopoïétiques est établie comme le traitement de référence de nombreuses hémopathies, les cellules stromales mésenchymateuses sont, quant à elles, toujours à l'étude dans diverses pathologies (notamment maladie de Crohn, transplantation d'organes, COVID-19 et fibrose pulmonaire). À l'opposé, les cellules CAR-T représentent une immunothérapie ciblée, développée récemment et extrêmement prometteuse. Cette modalité thérapeutique a déjà révolutionné le traitement des lymphopathies B, et elle possède le potentiel d'en faire de même pour de nombreuses autres pathologies dans un avenir proche.

Immunogenicity of a Live-Attenuated Dengue Vaccine Using a Heterologous Prime-Boost Strategy in a Phase 1 Randomized Clinical Trial.

BACKGROUND: Dengue is a global health problem and the development of a tetravalent dengue vaccine with durable protection is a high priority. A heterologous prime-boost strategy has the advantage of eliciting immune responses through different mechanisms and therefore may be superior to homologous prime-boost strategies for generating durable tetravalent immunity. METHODS: In this phase 1 first-in-human heterologous prime-boost study, 80 volunteers were assigned to 4 groups and received a tetravalent dengue virus (DENV-1-4) purified inactivated vaccine (TDENV-PIV) with alum adjuvant and a tetravalent dengue virus (DENV-1-4) live attenuated vaccine (TDENV-LAV) in different orders and dosing schedules (28 or 180 days apart). RESULTS: All vaccination regimens had acceptable safety profiles and there were no vaccine-related serious adverse events. TDEN-PIV followed by TDEN-LAV induced higher neutralizing antibody titers and a higher rate of tetravalent seroconversions compared to TDEN-LAV followed by TDEN-PIV. Both TDEN-PIV followed by TDEN-LAV groups demonstrated 100% tetravalent seroconversion 28 days following the booster dose, which was maintained for most of these subjects through the day 180 measurement. CONCLUSIONS: A heterologous prime-boost vaccination strategy for dengue merits additional evaluation for safety, immunogenicity, and potential for clinical benefit. CLINICAL TRIALS REGISTRATION: NCT02239614.

A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain.

BACKGROUND: Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. METHODS: A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. RESULTS: Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5-9 days) and mean time of viremia was 6.8 days (range 3-9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted. CONCLUSIONS: We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing. CLINICAL TRIALS REGISTRATION: NCT02372175.

Creatine Transporter, Reduced in Colon Tissues From Patients With Inflammatory Bowel Diseases, Regulates Energy Balance in Intestinal Epithelial Cells, Epithelial Integrity, and Barrier Function.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBDs) have intestinal barrier dysfunction. Creatine regulates energy distribution within cells and reduces the severity of colitis in mice. We studied the functions of the creatine transporter solute carrier family 6 member 8 (SLC6A8, also called CRT) in intestinal epithelial cells (IECs) and mice, and we measured levels in mucosal biopsies from patients with IBD. METHODS: Colon biopsy specimens from patients with IBD (30 with Crohn's disease and 27 with ulcerative colitis) and 30 patients without IBD (control individuals) and colon tissues from mice (with and without disruption of Crt) were analyzed by immunofluorescence, immunoblots, and/or quantitative reverse-transcription polymerase chain reaction (qRT-PCR). CRT was knocked down or overexpressed in T84 cells, which were analyzed by immunofluorescence, immunoblots, high-performance liquid chromatography (to measure creatine levels), qRT-PCR, transepithelial electrical resistance, barrier function, actin localization, wound healing, mitochondrial oxygen consumption, and glycolysis extracellular acidification rate assays. Organoids from colon cells of CRT-knockout mice and control mice were analyzed by qRT-PCR, immunoblot, and transepithelial electrical resistance. RESULTS: CRT localized around tight junctions (TJs) of T84 IECs. In analyses of IECs with CRT knockdown or overexpression, we found that CRT regulates intracellular creatine, barrier formation, and wound healing. CRT-knockout organoids also had diminished barrier formation. In the absence of adequate creatine, IECs transition toward a stressed, glycolysis-predominant form of metabolism; this resulted in leaky TJs and mislocalization of actin and TJ proteins. Colon tissues from patients with IBD had reduced levels of CRT messenger RNA compared with those from control individuals. CONCLUSIONS: In an analysis of IEC cell lines and colonoids derived from CRT-knockout mice, we found that CRT regulates energy balance in IECs and thereby epithelial integrity and barrier function. Mucosal biopsy specimens from patients with ulcerative colitis and inactive Crohn's disease have lower levels of CRT, which might contribute to the reduced barrier function observed in patients with IBD.

Driveline damage and repair in continuous-flow left ventricular assist devices: A systematic review.

With mounting time on continuous-flow left ventricular assist device (CF-LVAD) support, patients occasionally sustain damage to the device driveline. Outcomes associated with external and internal driveline damage and repair are currently not well documented. We sought to evaluate the outcomes of driveline damage and its repair. Electronic search was performed to identify all relevant studies published over the past 20 years. Fifteen studies were selected for analysis comprising of 55 patients with CF-LVAD dysfunction due to driveline damage. Demographic and perioperative variables along with outcomes including survival rates were extracted and pooled for the systematic review. Most patients (53/55) were supported on HeartMate II LVAD (Abbott Laboratories, Abbott Park, IL). Internal damage was more commonly reported than external damage [69.1% (38/55) vs. 30.9% (17/55), P = .01]. Median time to driveline damage was 1.9 years [IQR 1.0, 2.5]. Most patients presented with a CF-LVAD alarm [94.5% (52/55)] and patients with internal driveline damage had a significantly higher rate of alarm activation compared to that observed for those with external damage [38/38 (100%) vs. 14/17 (82.4%), P = .04]. Patients with internal driveline dysfunction were more likely to experience component wear compared to those with external driveline dysfunction [10/38 (26.3%) vs. 0/17 (0%), P = .05]; 14.5% of patients (8/55) underwent external repair of the driveline, 5.5% (3/55) were treated with rescue tape, and 5.5% (3/55) were placed on an ungrounded cable, indicating a short-to-shield event had occurred. A total of 49.1% of patients (27/55) underwent CF-LVAD exchange, 5.5% (3/55) were weaned off the CF-LVAD to explant, and 5.5% (3/55) underwent emergent heart transplantation. The median length of hospital stay was 12 days [IQR 7, 12] and 30-day mortality rate was 14.5% (8/55). Driveline damage was more commonly reported at an internal location and despite being a well-recognized complication, mortality still appears high.

[«Watch and Wait¼ strategy in the management of rectal adenocarcinoma]. / Stratégie «Watch and Wait¼ dans la prise en charge des adénocarcinomes du rectum.

Currently, the standard management of locally advanced adenocarcinoma of the middle and lower rectum consists in first intention of pre-operative radio-chemotherapy. This treatment is then usually followed by rectal surgery with removal of the mesorectum. The local recurrence rate is quite low, but at the cost of a non negligible morbidity (urinary, anal and sexual functional sequelae). This raises the question of a possible sparing of surgery and therefore organ preservation in well selected patients with a complete response after radio-chemotherapy. The Brazilians are pioneers in this field. Already in 2004, their publications suggested that the «Watch and Wait¼ strategy was safe and effective in patients with a complete clinical response. Other publications have followed and tend to confirm that there is no oncological risk in proposing a «watch and wait¼ strategy for these well selected patients in complete clinical, endoscopic and iconographic remission on the basis of magnetic resonance imaging (MRI). In these conditions, an attentive surveillance strategy allows to avoid operative morbi-mortality without oncological compromise. Monitoring is therefore multi-modal, clinical and endoscopic, but also based on MRI.

Actuellement, la prise en charge classique de l'adénocarcinome localement avancé du moyen et du bas rectum consiste d'abord en de la radio-chimiothérapie préopératoire. Ce traitement est ensuite habituellement suivi d'une chirurgie rectale avec exérèse du mésorectum. Le taux de récidive locale est assez bas, toutefois au prix d'une morbidité non négligeable (séquelles fonctionnelles urinaires, anales et sexuelles). Se pose alors la question d'une éventuelle épargne chirurgicale et donc d'une préservation d'organe chez des patients bien sélectionnés en réponse complète après radio-chimiothérapie. Les chercheurs brésiliens font office de pionniers dans le domaine. Déjà en 2004, leurs publications suggéraient que la stratégie de surveillance rapprochée («Watch and Wait¼) était sûre et efficace chez les patients en réponse clinique complète. D'autres publications ont suivi et tendent à confirmer qu'il n'y a pas de risque oncologique à proposer une surveillance attentive chez ces patients bien sélectionnés, en rémission complète clinique, endoscopique et iconographique sur base de la réalisation d'une imagerie par résonance magnétique (IRM). Dans ces conditions, une stratégie de surveillance attentive permet d'éviter la morbimortalité opératoire sans compromis oncologique. La surveillance est donc multi-modale: clinique et endoscopique, mais également basée sur l'IRM.

[Liver hydatidosis causing obstructive cholangitis : a case report]. / Cholangite obstructive chez un patient atteint d'une hydatidose.

The authors report the case of a 41-year-old patient originating from Algeria who developed obstructive cholangitis caused by the membrane of a ruptured hydatid cyst leading to the diagnosis of cystic echinococcosis. Cystic echinococcosis can be asymptomatic for several years until a complication occurs, such as in this case an obstruction of the common bile duct, or cholangio-hydatidosis. This cause of jaundice is uncommon in Western Europe whereas it is more frequent in endemic areas. Identification and treatment of ruptured cysts are mandatory because of the mortality rate of these complications if left untreated. In this particular case, the treatment by endoscopic retrograde cholangiopancreatography was successful.

Les auteurs rapportent le cas d'un patient de 41 ans, originaire d'Algérie, chez qui un diagnostic d'échinococcose a été posé à la suite d'une cholangite obstructive sur rupture d'un kyste hydatique. L'échinococcose kystique peut être asymptomatique pendant plusieurs années jusqu'à ce qu'une complication ne survienne, comme une obstruction du canal cholédoque commun appelée également cholangio-hydatidose. Cette cause d'ictère est rare en Europe occidentale alors qu'elle est plus fréquente dans les zones endémiques. L'identification et le traitement des kystes rompus sont nécessaires en raison du taux de mortalité de ces complications lorsqu'elles ne sont pas traitées de manière adéquate. Dans ce cas particulier, le traitement par cholangio-pancréatographie rétrograde endoscopique s'est révélé efficace.

Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta.

Mural cells (vascular smooth muscle cells and pericytes) play an essential role in the development of the vasculature, promoting vascular quiescence and long-term vessel stabilization through their interactions with endothelial cells. However, the mechanistic details of how mural cells stabilize vessels are not fully understood. We have examined the emergence and functional role of mural cells investing the dorsal aorta during early development using the zebrafish. Consistent with previous literature, our data suggest that cells ensheathing the dorsal aorta emerge from a sub-population of cells in the adjacent sclerotome. Inhibition of mural cell recruitment to the dorsal aorta through disruption of pdgfr signaling leads to a reduced vascular basement membrane, which in turn results in enhanced dorsal aorta vessel elasticity and failure to restrict aortic diameter. Our results provide direct in vivo evidence for a functional role for mural cells in patterning and stabilization of the early vasculature through production and maintenance of the vascular basement membrane to prevent abnormal aortic expansion and elasticity.

Survival outcomes of stenting outflow graft stenosis in continuous-flow left ventricular assist devices: a systematic review.

Stenosis in the continuous-flow left ventricular assist device (CF-LVAD) outflow graft is caused by various factors. We discuss indications for percutaneous intervention of outflow graft complications and evaluate the use of this treatment in re-establishing adequate CF-LVAD flow. An electronic search was performed to identify all studies in the English literature reporting CF-LVAD outflow graft stenting. Twenty-one studies consisting of 26 patients were included. Patient-level data were extracted for statistical analysis. Median patient age was 59 years [45.8-67.0] and 65.4% (17/26) were male. 58.3% (14/24) of patients had HeartWare HVAD, 37.5% (9/24) had HeartMate II LVAD, and 4.2% (1/24) had HeartMate III LVAS. Median time from device placement to outflow graft stenting was 24.0 months [7.8-30.4]. 76.9% of patients (20/26) presented with heart failure. Complications of the CF-LVAD outflow graft included thrombosis in nine patients (34.6%), stenosis in nine patients (34.6%), kinking in three patients (11.5%), pseudoaneurysm in one patient (3.8%), external graft compression in one patient (3.8%), and bronchial-arterial fistula in one patient (3.6%). Immediate flow improvement occurred in 23/26 patients (88.5%), with the remaining 11.5% (3/26) requiring additional procedures. Pre- and post-intervention flows were 2.9 L/min [2.0-3.5] and 4.7 L/min [4.1-4.8] respectively (p = 0.01). Of patients, 96.2% (25/26) were discharged with a median time to discharge of 4 days [3.0-5.0]. The 30-day mortality was 6.7% (1/15). Overall mortality during the median follow-up of 90 days was 9.5% (2/21). Outflow graft stenting appears to effectively alleviate CF-LVAD outflow graft obstruction and is associated with low overall mortality.

Dark Matter Signals from Timing Spectra at Neutrino Experiments.

We propose a novel strategy to search for new physics in timing spectra at low-energy neutrino experiments using a pulsed beam, envisioning the situation in which a new particle comes from the decay of its heavier partner with a finite particle width. The timing distribution of events induced by the dark matter (DM) candidate particle scattering at the detector may populate in a relatively narrow range, forming a "resonancelike" shape. Because of this structural feature, the signal may be isolated from the backgrounds, in particular when the backgrounds are uniformly distributed in energy and time. For proof of the principle, we investigate the discovery potential for DM from the decay of a dark photon in the ongoing COHERENT experiment and show the exciting prospects for exploring the associated parameter space with this experiment. We analyze the existing CsI detector data with a timing cut and an energy cut, and we find, for the first time, an excess in the timing distribution that can be explained by such DM. We compare the sensitivity to the kinetic mixing parameter (ε) for current and future COHERENT experiments with the projected limits from LDMX and DUNE.