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Chikungunya virus (CHIKV) is an emerging arthropod-borne virus that has spread globally during the last two decades. The virus is mainly transmitted by Aedes aegypti and Aedes albopictus mosquitos and is thus capable of replicating in both human and mosquito cells. CHIKV has a broad tropism in vivo, capable of replicating in various tissues and cell types but largely excluding blood cells. This was reflected in vitro by a broad array of adherent cell lines supporting CHIKV infection. One marked exception to this general rule is the resistance of the lung cancer-derived A549 cell line to CHIKV infection. We verified that A549 cells were restrictive to infection by multiple alphaviruses while being completely permissive to flavivirus infection. The adaptive growth of a primary CHIKV strain through multiple passages allowed the emergence of a CHIKV strain that productively infected A549 cells while causing overt cytopathic effects and without a fitness cost for replication in otherwise CHIKV-susceptible cells. Whole genome sequencing of polyclonal and monoclonal preparations of the adapted virus showed that a limited number of mutations consistently emerged in both structural (2 mutations in E2) and non-structural proteins (1 mutation in nsP1 and 1 mutation in nsP2). The introduction of the adaptive mutations, individually or in combinations, into a wild-type molecular clone of CHIKV allowed us to determine the relative contributions of the mutations to the new phenotype. We found that the mutations in the E2 envelope protein and non-structural proteins contributed significantly to the acquired phenotype. The nsP mutations were introduced in a split-genome trans-replicase assay to monitor their effect on viral genome replication efficiency. Interestingly, neither mutation supported increased viral genomic replication in either Vero or A549 cells.

Background: Patients recently diagnosed with rheumatoid arthritis (RA) have specific educational and supportive needs. These could partly be addressed with mentoring by other patients living with RA. This qualitative study explores stakeholder perceptions towards peer mentoring in early RA care., Methods: Two focus groups with patients with early RA (n=10), one with patient organisation representatives (n=5), one with rheumatologists (n=8) and one with rheumatology nurses (n=5) were held. Two patient research partners supported analysis and interpretation., Results: Four overarching themes were found: added value, experience with peer mentoring, concerns and need in daily care. Patients and patient organisation representatives confirmed the potential of peer mentoring especially regarding sensitive topics not easily discussed with professionals. Patients felt it could provide additional understanding and recognition. Nurses and rheumatologists were less convinced of the added value of peer mentoring because patients never mentioned it and they were concerned about the loss of control over correct information provision. The need for peer mentoring was perceived as person and disease phase-dependent and should therefore be optional, rather than a care standard. The requirements for a peer mentorship programme remained challenging to define for stakeholders. However, all expressed the need for supervision by healthcare professionals and that peer mentors should be carefully selected, educated and matched to newly diagnosed patients., Conclusion: Peer mentoring and its implementation remain vague concepts, especially for healthcare providers. However, patients are interested in mentoring by peers, and the current results may support in effectively implementing such programmes early in the disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chikungunya virus (CHIKV) is an arthropod-borne virus that has re-emerged recently and has spread to previously unaffected regions, resulting in millions of infections worldwide. The genus Alphavirus, in the family Togaviridae, contains several members with a similar potential for epidemic emergence. In order for CHIKV to replicate in targeted cell types it is essential for the virus to enter these cells. In this review, we summarize our current understanding of the versatile and promiscuous steps in CHIKV binding and entry into human and mosquito host cells. We describe the different entry pathways, receptors, and attachment factors so far described for CHIKV and other mosquito-borne alphaviruses and discuss them in the context of tissue tropism and potential therapeutic targeting., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chikungunya virus (CHIKV) is an arbovirus with a global spread and significant public health impact. It is a positive stranded RNA alphavirus belonging to the Togaviridae family. However, many questions about the replication cycle of CHIKV remain unanswered. The entry process of CHIKV is not completely understood nor are the associated virus-receptor interactions fully identified. Here, we designed an affinity purification mass spectrometry coupled approach that allowed the identification of factors that facilitate entry of CHIKV in human cells. The identified entry factors were further validated using CRISPR/Cas9. In HEK293T cells we identified the CD147 protein complex as an entry factor for CHIKV. We further showed the involvement of the CD147 protein complex in the replication cycle of related alphaviruses. Interestingly, CD147 contains similar protein domains as the previously identified alphavirus entry factor MXRA8., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Caluwé, Coppens, Vereecken, Daled, Dhaenens, Van Ostade, Deforce, Ariën and Bartholomeeusen.)

This cross-sectional study aims to determine the prevalence of metabolic syndrome (MetS) in patients with severe mental illness (SMI) on a Caribbean island, Curaçao, using the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Among 350 patients (240 men and 110 women) with a mean age of 51.9 years (S.D.=13.5) MetS prevalence was 37.4%, significantly higher in female patients (63.6%) compared to male patients (25.4%). Increased waist circumference was present in 51.1%, low HDL in 50.6%, hypertension in 49.4%, hyperglycemia in 28.6% and 25.7% had hypertriglyceridemia. Except for hypertriglyceridemia, all criteria were more prevalent in female patients. Binary logistic regression analysis indicated that female gender, outpatient treatment setting and the absence of substance use disorder were all significant predictors for MetS. Compared to data from the general population obtained by the 2013 National Health Survey Curaçao, this study showed significantly higher prevalence of diabetes and hypertension in patients with SMI. Moreover, female patients had the highest prevalence of diabetes (28.2%), obesity (50.0%) and increased waist circumference (88.2%). This study demonstrates that African-Caribbean patients with SMI are at high-risk for MetS, especially female patients. Our data suggest to focus on modifiable lifestyle risk factors, as promoting physical activity and healthy dietary habits., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Success of dendritic cell (DC) therapy in treating malignancies is depending on the DC capacity to attract immune effector cells, considering their reciprocal crosstalk is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC vaccination. In this paper we have made a head-to-head comparison of interleukin (IL)-15-cultured DCs and conventional IL-4-cultured DCs with regard to their proficiency in the recruitment of (innate) immune effector cells. Here, we demonstrate that IL-4 DCs are suboptimal in attracting effector lymphocytes, while IL15 DCs provide a favorable chemokine milieu for recruiting CD8+ T cells, natural killer (NK) cells and gamma delta (γδ) T cells. Gene expression analysis revealed that IL-15 DCs exhibit a high expression of chemokines involved in antitumor immune effector cell attraction, while IL-4 DCs display a more immunoregulatory profile characterized by the expression of Th2 and regulatory T cell-attracting chemokines. This is confirmed by functional data indicating an enhanced recruitment of granzyme B+ effector lymphocytes by IL-15 DCs, as compared to IL-4 DCs, and subsequent superior killing of tumor cells by the migrated lymphocytes. Elevated CCL4 gene expression in IL-15 DCs and lowered CCR5 expression on both migrated γδ T cells and NK cells, led to validation of increased CCL4 secretion by IL15 DCs. Moreover, neutralization of CCR5 prior to migration resulted in an important inhibition of γδ T cell and NK cell recruitment by IL-15 DCs. These findings further underscore the strong immunotherapeutic potential of IL-15 DCs.

Background: Preoperative radiotherapy (RT) decreases local recurrence rate and improves survival in stage II and III rectal cancer patients. The combination of chemotherapy with RT has a sound radiobiological rationale, and phase II trials of combined chemoradiation (CRT) have shown promising activity in rectal cancer., Objectives: To compare preoperative RT with preoperative CRT in patients with resectable stage II and III rectal cancer., Search Methods: We searched the Cochrane Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until June 2012. A manual search was performed of Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys and the proceedings of ASTRO, ECCO and ASCO from 1990 until June 2012., Selection Criteria: Relevant studies randomized resectable stage II or III rectal cancer patients to at least one arm of preoperative RT alone or at least one arm of preoperative CRT., Data Collection and Analysis: Primary outcome parameters included overall survival (OS) at 5 years and local recurrence (LR) rate at 5 years. Secondary outcome parameters included disease free survival (DFS) at 5 years, metastasis rate, pathological complete response rate, clinical response rate, sphincter preservation rate, acute toxicity, postoperative mortality and morbidity, and anastomotic leak rate. Outcome parameters were summarized using the Odds Ratio (OR) and associated 95% confidence interval (CI) using the fixed effects model., Main Results: Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years., Authors' Conclusions: Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials.

Background: Bariatric results expressed in the relative measure excess weight loss (%EWL) vary significantly by initial body mass index (BMI): the heavier the patient, the lower the %EWL. We examine if this variation is caused by using a wrong outcome measure and argue that no relative weight loss measure can express bariatric or metabolic goals unequivocally., Methods: Nadir weight loss results after laparoscopic gastric bypass in 168 women with initial BMI ≥35 to <60 kg/m2 are calculated for %EWL and 61 different relative measures using the formula 100% × (initial BMI - nadir BMI) / (initial BMI-a), with a ranging from -30 to +30. Standard deviations are compared mutually and with those reported in the literature. For each relative measure, the significance of any variation by initial BMI is determined with the Mann-Whitney U test., Results: Mean initial BMI was 44.9 ± 6.7 (35.0-59.7) kg/m2. Mean nadir BMI was 28.8 ± 5.8 (18.5-44.4) kg/m2. Mean nadir excess BMI loss (%EBL; a = 25) was 87.0 ± 28.0 (19.4-155.1)%. Mean nadir (total) weight loss (%TWL; a = 0) was 35.9 ± 8.5 (9.5-57.1)%. Mean nadir %EWL was 77.3 ± 22.8 (17.7-135.2)%. The smallest variation coefficient was 23.7% at a ranging from -1 to +3, including %TWL (a = 0). This is lower than variation coefficients of %EWL results in our series and in the literature. Variation by initial BMI is significant using relative measures with a ≥3, including %EBL and %EWL (both p < 0.0001) and not significant with a <3, including %TWL (p = 0.13)., Conclusions: In contrast to their widespread use, %EBL and %EWL are not suited for comparing different patients or nonrandomized groups. They cause variation by initial BMI, which disappears using %TWL. In general, absolute terms should be preferred for bariatric outcome and goals. The power of bariatric procedures is best represented by their mean %TWL value.