Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Unilateral versus bilateral correction of unicoronal synostosis:An analysis of long-term results

<p>Introduction: Hollowing of the temporal region is a common problem after cranioplasty for unicoronal synostosis. In this study, first, the development of temporal hollowing pre- and postoperatively is evaluated. Second, the origin of temporal hollowing is investigated by comparing two operative techniques. Ultimately, the relation between timing of surgery and the development of hollowing is investigated.</p><p>Methods: From 1979 to 2010, 194 patients with unicoronal synostosis were operated at our center. Patients were treated with a unilateral or bilateral correction of the supraorbital rim. A total of 48 patients qualified for the present study. Mean age at follow-up was 7.5 years. Cephalic landmarks were identified on radiographs prior to and after surgery to determine the growth of the forehead. For visual analysis, two independent observers evaluated normal photographs for the presence and severity of temporal hollowing.</p><p>Results: Preoperative osseous asymmetry improved significantly after surgery. A total of 21 patients show an increase of temporal hollowing on photographs after surgery (46%). In 35 out of 48 patients, postoperative temporal hollowing was noted (73%). Bilaterally treated patients showed more severe temporal hollowing compared to unilaterally treated patients, though not significantly (23% vs. 6%, p = 0.229). Timing of surgery (before or after the age of 1 year) did not influence the occurrence of severe temporal hollowing.</p><p>Conclusions: Fronto-supraorbital advancement was unable to achieve normal growth in the temporal region in a large proportion of patients, although more symmetrywas achieved. The operative technique itself did not seem to influence the occurrence of temporal hollowing, nor did the timing of surgery. (C) 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.</p>

Rotational Advancement in Cleft Nose Rhinoplasty – Buccal Mucosal Grafts Serve as a Powerful Tool

Objective: Our aim was to analyze our technique of a modified rotational advancement in conjunction with buccal mucosal grafts (BMGs) in a subgroup of severe cleft cases. Design: A retrospective clinical and photographic evaluation was conducted. Columella angle (CA) and tip projection (TPR) served as instruments in a photometric analysis. Setting: Academic university hospital and specialized craniofacial cleft center. Patients: At the time of the secondary rhinoplasty, 61 cleft patients were included, all 17 years or older. Interventions: Rotational advancement with usage of BMGs was performed in selected cases by a single surgeon. Main Outcome Measures: Nasal symmetry and aesthetic appearance. Results: From 2003 to 2011, 29 unilateral severe cleft cases (group I) underwent a modified alar rotational advancement with BMGs. Group II, with 32 cases, represented patients without BMGs. Technique and management of BMGs were described in detail. The complication rate of donor and recipient site presented as very low. The CA was improved significantly in both groups. Also, TPR improved (not significantly) in group I. Using our technique, we considerably enhanced the aesthetic results and symmetry in secondary cleft rhinoplast. Conclusions: Rotating the vestibular skin makes it possible to eliminate the traction of this skin on the repositioned alar cartilage, therefore achieving a more pleasing and stable nasal symmetry in secondary cleft rhinoplasty. Versatile BMGs close this gap, thus making them a powerful tool in the arsenal of the reconstructive cleft surgeon

An Analysis of Aesthetic Refinements in 120 Secondary Cleft Rhinoplasties

Background Secondary cleft nose rhinoplasty remains a challenging procedure. Cartilage memory and scar contraction are problematic factors. The need for more detailed procedures for secondary reconstruction in this patient population has arisen. Contemporary refinements demonstrate a highly structured approach. We conducted a retrospective study evaluating the aesthetic results of cleft patients who underwent secondary rhinoplasty. Methods In a retrospective study, a photometric analysis of cleft patients operated in the period 2003-2011 was conducted. Reconstructive methods were documented. Pre- and postoperative photographs of cleft rhinoplasty patients were evaluated using a standardized protocol. Nostril width ratio, columellar angle, tip projection ratio, and nasolabial angle served as objective instruments. The Unilateral Cleft Lip Surgical Outcomes Evaluation score was chosen for external photometric rating and rated blindly by 2 external individual plastic surgeons as independent nonbiased reviewers. The interrater and intrarater reliabilities were calculated using the Cohen kappa coefficient (kappa). Results A total of 120 secondary rhinoplasties in 85 uni- and bilateral cleft patients could be included. Mean follow-up was 20 months. A total of 60 (71%) patients needed additional bone grafting (chin/pelvis), and 23 (27%) patients a LeFort I osteotomy. In one third of the secondary rhinoplasties, a medial and/or lateral osteotomy was performed (34%). In one fourth (24%), an external septoplasty was considered necessary. In 55% (47 patients) of the cases, a columellar strut was used. Excluding bone grafts, a total of 173 other grafts (mean of 2 grafts/patient) were applied. Postoperative measurements for nostril width ratio and columellar angle were statistically significant. A structured approach with contemporary refinements is described in detail. Intra- and interrater reliabilities for photometric assessment according to the Unilateral Cleft Lip Surgical Outcomes Evaluation score are shown. Conclusions A structured approach for secondary cleft rhinoplasty yields satisfying, reproducible, and stable results

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence

Human immunodeficiency virus continuum of care in 11 european union countries at the end of 2016 overall and by key population: Have we made progress?

Background. High uptake of antiretroviral treatment (ART) is essential to reduce human immunodeficiency virus (HIV) transmission and related mortality; however, gaps in care exist. We aimed to construct the continuum of HIV care (CoC) in 2016 in 11 European Union (EU) countries, overall and by key population and sex. To estimate progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, we compared 2016 to 2013 estimates for the same countries, representing 73% of the population in the region. Methods. A CoC with the following 4 stages was constructed: number of people living with HIV (PLHIV); proportion of PLHIV diagnosed; proportion of those diagnosed who ever initiated ART; and proportion of those ever treated who achieved viral suppression at their last visit. Results. We estimated that 87% of PLHIV were diagnosed; 92% of those diagnosed had ever initiated ART; and 91% of those ever on ART, or 73% of all PLHIV, were virally suppressed. Corresponding figures for men having sex with men were: 86%, 93%, 93%, 74%; for people who inject drugs: 94%, 88%, 85%, 70%; and for heterosexuals: 86%, 92%, 91%, 72%. The proportion suppressed of all PLHIV ranged from 59% to 86% across countries. Conclusions. The EU is close to the 90-90-90 target and achieved the UNAIDS target of 73% of all PLHIV virally suppressed, significant progress since 2013 when 60% of all PLHIV were virally suppressed. Strengthening of testing programs and treatment support, along with prevention interventions, are needed to achieve HIV epidemic control