Search

DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. Here, in contrast to other cancer types3–5, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of β2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy.

Purpose To evaluate women’s choice in the method of labour induction between oral misoprostol, PGE2 pessary and the Foley catheter. To compare women’s satisfaction according to their choice and to identify factors associated with patient satisfaction. Methods We conducted a comparative, prospective cohort study of 520 women who chose their preferred method for labour induction, in a French tertiary hospital, from July 2019 to October 2020. Before and after the delivery, they were asked to argument their choice and to evaluate their satisfaction through the use of questionnaires. The primary outcome was global level of satisfaction. Results Of the 520 women included, 67,5% of women chose oral Misoprostol compared to 21% PGE2 pessary and 11.5% the Foley catheter. Regarding global satisfaction, we found no significant difference between the three groups: 78,4%, 68,8% and 71,2% (p = 0,091) for respectively oral misoprostol, PGE2 pessary and the Foley catheter. Factors that seem to improve women’s satisfaction were nulliparity (OR = 2.03, 95%CI [1.19–3.53]), delivery within 24 hours after the start of induction (OR = 3.46, 95%CI. [2.02–6.14]) and adequate information (OR = 4.21,95%CI [1.86–9.64]). Factors associated with lower satisfaction rates were postpartum hemorrhage (OR = 0.51, 95%CI [0.30–0.88]) and caesarean section (OR = 0.31, 95%CI [0.17–0.54]). Conclusion Women satisfaction rates were not different between the three methods, when chosen by the patients themselves. These finding should encourage caregivers to promote shared decision making when possible.

Objective Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. Design This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. Methods Data were collected from 461 patients aged 0–18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. Results The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0–14.5) mg/m2/day at age 1–8 years and the highest dose of 14.0 (11.6–17.4) mg/m2/day at age 12–18 years. Glucocorticoid doses decreased after 2010 in patients 0–8 years (P < 0.001) and remained unchanged in patients aged 8–18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. Conclusions Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

In Africa, bat‐borne zoonoses emerged in the past few decades resulting in large outbreaks or just sporadic spillovers. In addition, hundreds of more viruses are described without any information on zoonotic potential. We discuss important characteristics of bats including bat biology, evolution, distribution and ecology that not only make them unique among most mammals but also contribute to their potential as viral reservoirs. The detection of a virus in bats does not imply that spillover will occur and several biological, ecological and anthropogenic factors play a role in such an event. We summarize and critically analyse the current knowledge on African bats as reservoirs for corona‐, filo‐, paramyxo‐ and lyssaviruses. We highlight that important information on epidemiology, bat biology and ecology is often not available to make informed decisions on zoonotic spillover potential. Even if knowledge gaps exist, it is still important to recognize the role of bats in zoonotic disease outbreaks and implement mitigation strategies to prevent exposure to infectious agents including working safely with bats. Equally important is the crucial role of bats in various ecosystem services. This necessitates a multidisciplinary One Health approach to close knowledge gaps and ensure the development of responsible mitigation strategies to not only minimize risk of infection but also ensure conservation of the species., Hundreds of viruses have been described from bats in Africa, some with proven spillover and causing human deaths, however for the majority there is no information on spillover potential. We summarize and critically analyze the current knowledge on African bats as reservoirs for corona, filo, paramyxo and lyssaviruses, including important characteristics of bats like biology, evolution, distribution and ecology that not only make them unique amongst most mammals but also contribute to their potential as viral reservoirs. We highlight the gaps in knowledge that is often not available to make informed decisions on zoonotic spillover potential. Despite this it is still important to recognize the role of bats in zoonotic disease outbreaks and implement mitigation strategies to prevent exposure to infectious agents, including working safely with bats. Equally important is the crucial role of bats in various ecosystem services.

Variants of the C19ORF12-gene have been described in patients with spastic paraplegia type 43 and in patients with mitochondrial membrane protein-associated neurodegeneration (MPAN), a subtype of neurodegeneration associated with brain iron accumulation (NBIA). In both subtypes optic atrophy and neuropathy have been frequently described. This case report describes a patient with bilateral optic atrophy and severe distal muscle weakness based on motor neuropathy without involvement of the central nervous system. Exome sequencing revealed a homozygous pathogenic missense variant (c.187G>C;p.Ala63Pro) of the C19ORF12-gene while iron deposits were absent on repeat MR-imaging of the brain, thus showing that peripheral neuropathy and optic neuropathy can be the sole manifestations of the C19ORF12-related disease spectrum whereby iron accumulation in the brain may be absent.

Background The efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers. Methods Whole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material. Results Neoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome. Conclusions We have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.

SARS-CoV-2 has rapidly spread worldwide since December 2019. Obviously, pregnant and lactating women will also be infected with SARS-CoV-2. Pregnant women, however, are a risk population for developing severe respiratory infections. Currently, the knowledge on potential risks and consequences of COVID-19 during pregnancy and lactation is limited. Available data show that pregnant women suffer from similar symptoms compared to non-pregnant patients. There is no evidence as yet that COVID-19 has a more serious course during pregnancy. Although pregnant women might suffer from a wide variety of symptoms, most of them are asymptomatic. Maternal SARS-CoV-2 infection might lead to adverse neonatal outcomes, such as prematurity or respiratory symptoms. There is currently no conclusive evidence of absence of intrauterine transmission of the virus; the virus has not been detected in breastmilk in most studies, although passage into breastmilk cannot be completely excluded.

The macrophage-associated molecule CD163 has been reported as a prognostic biomarker in different cancer types, but its role in colorectal cancer (CRC) is unclear. We studied CD163 in the tumor microenvironment and circulation of patients with CRC in relation to clinicopathological parameters. An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum sCD163 levels and multiparameter flow cytometry was used to study the peripheral blood monocytes and their CD163 expression in CRC patients (N = 78) and healthy donors (N = 50). The distribution of tumor-associated macrophages (TAMs) was studied in primary colorectal tumors with multiplex immunofluorescence. We showed that CRC patients with above-median sCD163 level had a shorter overall survival (OS, p = 0.035) as well as disease-free survival (DFS, p = 0.005). The above-median sCD163 remained significantly associated with a shorter DFS in the multivariate analysis (p = 0.049). Moreover, a shorter OS was observed in CRC patients with an above-median total monocyte percentage (p = 0.007). The number and phenotype of the stromal and intraepithelial TAMs in colorectal tumors were not associated with clinical outcome. In conclusion, sCD163 and monocytes in the circulation may be potential prognostic biomarkers in CRC patients, whereas TAMs in the tumor showed no association with clinical outcome. Thus, our results emphasize the importance of the innate systemic immune response in CRC disease progression.

Objective The subset distribution and immunophenotype of circulating immune cells (“peripheral blood immune cell profile”) may reflect tumor development and response to cancer treatment. In order to use the peripheral blood immune cell profile as biomarker to monitor patients over time, it is crucial to know how immune cell subsets respond to therapeutic interventions. In this study, we investigated the effects of tumor resection and adjuvant therapy on the peripheral blood immune cell profile in patients with colon carcinoma (CC). Methods The subset distribution and immunophenotype of T cells (CD3+CD56−), CD56dim NK cells (CD3−CD56dim), CD56bright NK cells (CD3−CD56bright) and NKT-like cells (CD3+CD56+) were studied in preoperative and postoperative peripheral blood mononuclear cell (PBMC) samples of 24 patients with CC by multiparameter flow cytometry. Changes in immunophenotype of circulating immune cells after tumor resection were studied in patients treated with and without (capecitabine-based) adjuvant therapy. Results The NKT-like cell (% of total PBMCs) and CD8+ T cell (% of total T cells) populations expanded in the peripheral blood of non-adjuvant-treated CC patients after surgery. NK- and NKT-like cells showed upregulation of activating receptors and downregulation of inhibitory receptors in non-adjuvant-treated CC patients after surgery. These changes were not observed in the peripheral blood of adjuvant-treated CC patients. Conclusions Our results suggest tumor-induced suppression of NK- and NKT-like cells in CC patients, an effect that could not be detected after tumor resection. In contrast, adjuvant therapy maintained tumor-induced immunosuppression of NK- and NKT-like cells in CC patients.

Cancers are characterized by extensive heterogeneity that occurs intratumorally, between lesions, and across patients. To study cancer as a complex biological system, multidimensional analyses of the tumor microenvironment are paramount. Single-cell technologies such as flow cytometry, mass cytometry, or single-cell RNA-sequencing have revolutionized our ability to characterize individual cells in great detail and, with that, shed light on the complexity of cancer microenvironments. However, a key limitation of these single-cell technologies is the lack of information on spatial context and multicellular interactions. Investigating spatial contexts of cells requires the incorporation of tissue-based techniques such as multiparameter immunofluorescence, imaging mass cytometry, or in situ detection of transcripts. In this Review, we describe the rise of multidimensional single-cell technologies and provide an overview of their strengths and weaknesses. In addition, we discuss the integration of transcriptomic, genomic, epigenomic, proteomic, and spatially-resolved data in the context of human cancers. Lastly, we will deliberate on how the integration of multi-omics data will help to shed light on the complex role of cell types present within the human tumor microenvironment, and how such system-wide approaches may pave the way toward more effective therapies for the treatment of cancer.

Meteorites contain minerals from Solar System asteroids with differentproperties (like size, presence of water, core formation). We providenew mid-IR transmission spectra of powdered meteorites to obtaintemplates of how mid-IR spectra of asteroidal debris would look like.This is essential for interpreting mid-IR spectra of past and futurespace observatories, like the James Webb Space Telescope. First wepresent new transmission spectra of powdered ordinary chondrite,pallasite and HED meteorites and then we combine them with alreadyavailable transmission spectra of chondrites in the literature, giving atotal set of 64 transmission spectra. In detail we study the spectralfeatures of minerals in these spectra to obtain measurables used tospectroscopically distinguish between meteorite groups. Being able todifferentiate between dust from different meteorite types means we canprobe properties of parent bodies, like their size, if they were wet ordry and if they are differentiated (core formation) or not.We show that the transmission spectra of wet and dry chondrites,carbonaceous and ordinary chondrites and achondrite and chondritemeteorites are distinctly different in a way one can distinguish inastronomical mid-IR spectra. Carbonaceous chondrites type

Mutation in the insulin-like growth factor-1 receptor (IGF1R) gene is a rare cause for intrauterine and postnatal growth disorders. Patients identified with IGF1R mutations present with either normal or impaired glucose tolerance. None of the cases described so far showed hypoglycemia. We aimed to identify the genetic basis for small for gestational age, short stature and hypoglycemia over three generations in one family. The proband, a 9-year-old male, presented in infancy with recurrent hypoglycemic episodes, symmetric intrauterine growth retardation and postnatal growth retardation. Blood DNA samples from the patient, his parents, a maternal sister and maternal grandmother underwent Sanger sequencing of the IGF1R gene. Primary skin fibroblast cultures of the patient, his mother and age- and sex-matched control donors were used for gene expression and receptor functional analyses. We found a novel heterozygous mutation (c.94 + 1g > a, D1105E) affecting the splicing site of the IGF1R mRNA in the patient, his mother and his grandmother. Primary fibroblast cultures derived from the patient and his mother showed reduced proliferation and impaired activation of the IGF1R, evident by reduced IGF1R and AKT phosphorylation upon ligand binding. In conclusion, the newly identified heterozygous missense mutation in exon 1 of IGF1R (D1105E) results in impaired IGF1R function and is associated with small for gestational age, microcephaly and abnormal glucose metabolism. Further studies are required to understand the mechanisms by which this mutation leads to hypoglycemia.

Objective As the development and progression of colorectal cancer (CRC) are known to be affected by the immune system, cell subsets such as T cells, natural killer (NK) cells, and natural killer T (NKT) cells are considered interesting targets for immunotherapy and clinical biomarker research. Until now, the role of systemic immune profiles in tumor progression remains unclear. In this study, we aimed to characterize the immunophenotype of circulating T cells, NK cells, and NKT-like cells in patients with CRC, and to subsequently correlate these immunophenotypes to clinical follow-up data. Methods Using multiparameter flow cytometry, the subset distribution and immunophenotype of T cells (CD3+CD56−), CD56dim NK cells (CD3−CD56dim), CD56bright NK cells (CD3−CD56bright), and NKT-like (CD3+CD56+) cells were investigated in peripheral blood mononuclear cell (PBMC) samples from 71 CRC patients and 19 healthy donors. Results CRC patients showed profound differences in immune cell subset distribution and their immunophenotype compared to healthy donors, as characterized by increased percentage of regulatory T cells, and reduced expression level of the natural cytotoxicity receptors NKp44 and NKp46 on both CD56dim NK cells and NKT-like cells. Finally, we showed in a multivariate analysis that above-median percentage of CD16+ NKT-like cells was independently associated with shorter disease-free survival in CRC patients. Conclusion The altered phenotype of circulating immune cell subsets in CRC and its association with clinical outcome highlight the potential use of PBMC subsets as prognostic biomarkers in CRC, thereby contributing to better insight into the role of systemic immune profiles in tumor progression. Electronic supplementary material The online version of this article (10.1007/s00262-019-02343-7) contains supplementary material, which is available to authorized users.

We address the problem of detecting highly raised crowd density in situations such as indoor dance events.We propose a new method for estimating crowd density by anonymous, non-participatory, indoor Wi-Fi localization of smart phones. Using a probabilistic model inspired by statistical mechanics, and relying only on big data analytics, we tackle three challenges: (1) the ambiguity of Wi-Fi based indoor positioning, which appears regardless of whether the latter is performed with machine learning or with optimization, (2) the MAC address randomization when a device is not connected, and (3) the volatility of packet interarrival times. The main result is that our estimation becomes more -- rather than less -- accurate when the crowd size increases. This property is crucial for detection of dangerous crowd density.

ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.DesignThirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.ResultsWe discovered that a previously unappreciated innate lymphocyte population (Lin–CD7+CD127–CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.ConclusionThis work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.

International audience; BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus

Aanleiding tot de herziening van deze LESA was de aanpassing van de KNMG-meldcode en de uitbreiding hiervan met de kindcheck,1 alsmede de invoering van de nieuwe Jeugdwet waardoor de gemeenten sinds 1 januari 2015 verantwoordelijk zijn voor de Jeugdzorg.2

The lattice location of ion implanted radioactive 24Na (t1/2=14.96 h) in GaN and AlN was determined using the emission channeling technique at the ISOLDE/CERN facility. In the room temperature as-implanted state in both GaN and AlN, the majority of the sodium atoms are found on interstitial sites near the octahedral position, with a minority on cation Ga or Al substitutional sites. Following annealing at 800-900°C the interstitial fraction is reduced while the substitutional incorporation increases. Our results thus further establish the amphoteric character of Na in GaN and AlN, in analogy to the other light alkali Li, and alkaline earths Be and Mg. The site changes upon annealing are attributed to the onset of migration of interstitial Na, for which an activation energy of 2.2-3.4 eV is estimated in GaN and 2.0-3.1 eV in AlN, and its subsequent capture by cation vacancies resulting from the implan-tation. Comparison of the lattice site change behavior of Li, Be, Na and Mg shows that the onset of interstitial mi-gration correlates with the ionic radii of these elements.

Trophically transmitted parasites start their development in an intermediate host, before they finish the development in their definitive host when the definitive host preys on the intermediate host. In intermediate-definitive host systems, two strategies of host manipulation have been evolved: increasing the rate of transmission to the definitive host by increasing the chance that the definitive host will prey on the intermediate host, or increasing the lifespan of the parasite in the intermediate host by decreasing the predation chance when the intermediate host is not yet infectious. As the second strategy is less well studied than the first, it is unknown under what conditions each of these strategies is prevailed and evolved. We analysed the effect of both strategies on the presence of parasites in intermediate-definitive host systems with a structured population model. We show that the parasite can increase the parameter space where it can persist in the intermediate-definitive host system using one of these two strategies of host manipulation. We found that when the intermediate host or the definitive host has life-history traits that allow the definitive host to reach large population densities, that is high reproduction rate of the intermediate host or high conversion efficiency of the definitive host (efficiency at which the uninfected definitive host converts caught intermediate hosts into offspring), respectively, evolving manipulation to decrease the predation chance of the intermediate host will be more beneficial than manipulation to increase the predation chance to enhance transmission. Furthermore, manipulation to decrease the predation chance of the intermediate host results in higher population densities of infected intermediate hosts than manipulation that increases the predation chance to enhance transmission. Our study shows that host manipulation in early stages of the parasite development to decrease predation might be a more frequently evolved way of host manipulation than is currently assumed.

Background Personal recovery is an individualized process through which people develop a positive identity and live a meaningful life, with symptoms of mental illness. Few studies have explored the role of recreation therapy in the recovery process from the perspectives of individuals with lived experience of mental illness. Objectives To understand how community-based recreation therapy can support mental health recovery, from the perspectives of people diagnosed with mental illness, and to guide the development, delivery and evaluation of recovery-oriented mental health services. Methods Guided by the principles of participatory action research (PAR) and photovoice, six participant researchers (PRs) generated arts-based media and narrative data in response to the research question: How can therapeutic recreation, in a community mental health center, support the recovery of individuals diagnosed with mental illness? The research group analyzed the qualitative data through a participatory data analysis process. Results The PRs produced and analyzed 24 pieces of arts-based media and 5 hours of transcribed narrative data describing their artworks' relationship to therapeutic recreation and recovery. The PRs identified seven salient themes through the participatory data analysis process: providing a safe place, promoting hope, finding balance, developing self-wisdom, increasing enjoyment, building confidence, and encouraging self-determination. Conclusions Service recipients' unique preferences and perspectives must be integral to service development to deliver therapeutic recreation interventions that are truly recovery-oriented. The research findings will be used to guide the delivery of innovative, collaborative, person-centered programming in community-based mental health settings.

The superwind is believed to be the tool with which stars with an intermediate main-sequence mass between 5 and 8 Me shed most of their stellar mantle to evolve from the asymptotic giant branch (AGB) into the post-AGB and planetary-nebulae stages. For this to work, the superwind duration must be on the order of at least ten thousand years given a mass-loss rate of 10(-4) M-circle dot per year. This contrasts heavily with recent, independent results indicating that the superwind duration may be shorter by an order of magnitude.

The etiology of the stiff knee after total knee arthroplasty (TKA) is largely unknown, although excessive scar tissue due to arthrofibrosis is an important reason for a limited range of motion (ROM) after this procedure. Persistent limited ROM after TKA results in poor patient-reported outcomes and is increasingly becoming a more prominent reason for TKA revision surgery. A narrative review of current literature on manipulation under anesthesia (MUA) after TKA analyzing etiology and risk factors for stiffness after TKA, effectiveness of MUA and what is known about rehabilitation after MUA. Literature describes numerous risk factors for insufficient knee ROM after TKA, but a comprehensive valid risk model is lacking. MUA is an effective treatment option with evidence suggesting better outcomes if performed within the first 3 months after TKA. The wide variety in both the indication and timing for MUA, and the lack of scientific evidence on how to rehabilitate patients after MUA, complicates the interpretation of available literature. This is even more so the case on the reporting of one versus two or more MUAs after TKA. Future comparative trials, preferably with a randomized study design, should be conducted to elude more clear indications for MUA, to give clinical guidance on correct timing for MUA and on how to rehabilitate patients afterward.

Item does not contain fulltext OBJECTIVE: To rescue chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in osteoarthritic conditions by inhibition of protein kinases. METHODS: hMSCs were cultured in pellets. During early chondrogenic differentiation, these were exposed to osteoarthritic synovium-conditioned medium (OAS-CM), combined with the Janus kinase (JAK)-inhibitor tofacitinib and/or the transforming growth factor beta-activated kinase 1 (TAK1)-inhibitor oxozeaenol. To evaluate effects on chondrogenesis, the glycosaminoglycan (GAG) content of the pellets was measured at the time that chondrogenesis was manifest in control cultures. Moreover, mRNA levels of matrix molecules and enzymes were measured during this process, using real-time polymerase chain reaction (RT-PCR). Initial experiments were performed with hMSCs from a fetal donor, and results of these studies were confirmed with hMSCs from adult donors. RESULTS: Exposure to OAS-CM resulted in pellets with a much lower GAG content, reflecting inhibited chondrogenic differentiation. This was accompanied by decreased mRNA levels of aggrecan, type II collagen, and Sox9, and increased levels of matrix metalloproteinase (MMP)1, MMP3, MMP13, ADAMTS4, and ADAMTS5. Both tofacitinib (JAK-inhibitor) and oxozeaenol (TAK1 inhibitor) significantly increased the GAG content of the pellets in osteoarthritis (OA)-like conditions. The combination of both protein kinase inhibitors showed an additive effect on GAG content. In agreement with this, in the presence of OAS-CM, both tofacitinib and oxozeaenol increased mRNA expression of sox9. The expression of aggrecan and type II collagen was also up-regulated, but this only reached significance for aggrecan after TAK1 inhibition. Both inhibitors decreased the mRNA levels of MMP1, 3, and 13 in the presence of OAS-CM. Moreover, oxozeaenol also significantly down-regulated the mRNA levels of aggrecanases ADAMTS4 and ADAMTS5. When combined, the inhibitors caused additive reduction of OA-induced MMP1 mRNA expression. Counteraction of OAS-CM-induced inhibition of chondrogenesis by these protein kinase inhibitors was confirmed with hMSCs of two different adult donors. Both tofacitinib and oxozeaenol significantly improved GAG content in cell pellets from these adult donors. CONCLUSIONS: Tofacitinib and oxozeaenol partially prevent the inhibition of chondrogenesis by factors secreted by OA synovium. Their effects are additive. This indicates that these protein kinase inhibitors can potentially be used to improve cartilage formation under the conditions occurring in osteoathritic, or otherwise inflamed, joints.

Checkpoint blockade has revived the potential of immunotherapy for cancer treatment. For optimal application and development of cancer immunotherapies, a comprehensive understanding of the antitumor immune response is required. We unraveled local and systemic immune profiles of colorectal cancer by multidimensional mass cytometric analysis of 36 immune cell markers at the single-cell level in tumor tissues, tumor-associated lymph nodes, adjacent normal mucosa, and peripheral blood samples from CRC patients. We identified 218 phenotypically distinct immune cell clusters, including a previously neglected innate lymphoid cell (CD7+CD3-CD127-CD45RO+CD56+) population with cytotoxic potential. This subset demonstrated a tissue-resident (CD69+, CD103+) phenotype, and was most abundant in the immunogenic mismatch repair deficient (MMRd) cancers. Furthermore, tumor-resident immune cell populations were identified across the adaptive (CD4+ and CD8+) and innate (gammadelta) T-cell compartments showing a highly similar activated (HLA-DR+, CD38+, PD-1+) phenotype. PD-1 intermediate and PD-1 high CD8+ T-cell subsets represented distinct states of T-cell activation that further discriminated immunogenic from non-immunogenic colorectal cancers. Remarkably, activated gammadelta T-cells were specific for MMRd cancers, and their potential role in the response to PD-1 checkpoint blockade requires further clarification. The nonactivated counterparts of the tumor-resident CD103+PD-1+ cytotoxic and gammadelta T-cells were present in both tumor and healthy colorectal tissues. We did not detect any of the aforementioned tumor-resident immune cell populations in lymph node samples, with the exception of a tumor-positive lymph node. This indicates that the critical immune cell populations with antitumor activity reside in the colorectal mucosa, and that the role of lymph nodes in the antitumor immune response should be revisited. Finally, by applying imaging mass cytometry we demonstrated that the cytotoxic anti-tumor response in colorectal cancer is highly diverse and not restricted to cytotoxic T-cells, which opens new avenues for the management of this disease.The findings presented here advance the paradigm of antitumor immunity in colorectal cancer and provide a blueprint for the detailed characterization of the involved immune cell subsets. The coordinated action of innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumor properties in a therapeutic setting. Citation Format: Noel F. de Miranda, Natasja L. de Vries, Vincent van Unen, Tamim Abdelaal, Marieke E. Ijsselsteijn, Ruud van der Breggen, Arantza Farina-Sarasqueta, Koen C.M.J. Peeters, Thomas Höllt, Boudewijn P.F. Lelieveldt, Frits Koning. Multidimensional cytometric analysis of colorectal cancer reveals novel and diverse mediators of antitumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A063.

The aim of this study is to assess the impact of the internet-based upload blood glucose monitoring and therapy management system (Carelink(®)) in patients with type 1 diabetes. Diabetic patients treated with pump infusion for ≥3 months were prospectively randomized to use the CareLink(®) with (4 months) and without (4 months) diabetes-team initiated contact (n = 36, intervention group) or to continue standard care for 4 months and then transfer to the CareLink(®) without diabetes-team initiated contact (n = 34, control group). In the first 4 months, treatment was adjusted monthly by the same team in both groups. Main outcome measures were HbA1c level and scores on the Diabetes Treatment Satisfaction and Diabetes Quality of Life Questionnaires. Patients who submitted3 times during each 4-month segment were considered noncompliant. Mean patient age was 14.02 ± 5.33 years; mean diabetes duration, 6.4 ± 4.7 years; median duration of pump treatment, 2.5 years. After 4 months, mean HbA1c level decreased from 8.75 ± 0.84 to 8.45 ± 0.90% in the intervention group (p = 0.013) and from 8.65 ± 0.57 to 8.37 ± 0.73% in the control group (p = 0.054). Within the intervention group, the difference in the change in HbA1c levels between compliant and noncompliant patients was significant (8.17 ± 0.81 vs. 8.99 ± 0.85%, p = 0.017). Only in the compliant subgroup was the decrease from baseline significant (p = 0.006). Similar findings were noted in the control group at 8 months (p0.05 and p = 0.018, respectively). There were no significant changes in questionnaire scores at 4 or 8 months in either group. Use of the CareLink(®) system is associated with significantly improved glycemic control in compliant patients, with no apparent effect on patient satisfaction or quality of life.

Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor.

Diabet. Med. 29, e170–e175 (2012) Abstract Aims To determine whether the frequency and severity of diabetic ketoacidosis and the clinical characteristics of children at diagnosis of Type 1 diabetes mellitus have changed over the past decades among patients under surveillance of a tertiary paediatric centre. Methods In three time-periods, 75 (1986–1987), 86 (1996–1997) and 245 (2006–2007) patients at mean age 10.1 ± 4.7 years (0.6–20.0) were diagnosed with new-onset Type 1 diabetes. Data on clinical characteristics and laboratory evaluation at diagnosis retrieved from the patients’ files . Comparative analysis was performed between the three time periods. Results The frequency of diabetic ketoacidosis at diagnosis was 40% in 1986–1987, 41.8% in 1996–1997 and 29.4% in 2006–2007; the last rate was significantly lower (P = 0.04). No significant differences in the proportions of patients with severe or moderate diabetic ketoacidosis were found over time. Mean weight standard deviation score significantly increased from −0.72 ± 1.8 in 1986–1987 to −0.27 ± 1.2 in 2006–2007 (P

Although several treatments for cartilage repair have been developed and used in clinical practice the last 20 years, little is known about the mechanisms that are involved in the formation of repair tissue after these treatments. Often, these treatments result in the formation of fibrocartilaginous tissue rather than normal articular cartilage. Because the repair tissue is inferior to articular cartilage in terms of mechanical properties and zonal organization of the extracellular matrix, complaints of the patient may return. The biological and functional outcome of these treatments should thus be improved. For this purpose, an in vitro model allowing investigation of the involved repair mechanisms can be of great value. We present the development of such a model. We used bovine osteochondral biopsies and created a system in which cartilage defects of different depths can be studied. First, our biopsy model was characterized extensively: we studied the viability by means of lactate dehydrogenase (LDH) excretion over time and we investigated expression of cartilage-related genes in osteochondral biopsies and compared it with conventional cartilage-only explants. After 28 days of culture, LDH was detected at low levels and mRNA could be retrieved. The expression of cartilage-related genes decreased over time. This was more evident in cartilage-only explants, indicating that the biopsy model provided a more stable environment. We also characterized the subchondral bone: osteoclasts and osteoblasts were active after 28 days of culture, which was indicated by tartrate acid phosphatase staining and alkaline phosphatase measurements, respectively, and matrix deposition during culture was visualized using calcein labeling. Second, the applicability of the model was further studied by testing two distinct settings: (1) implantation of chondrocytes in defects of different depths; (2) two different seeding strategies of chondrocytes. Differences were observed in terms of volume and integration of newly formed tissue in both settings, suggesting that our model can be used to model distinct conditions or even to mimic clinical treatments. After extensive characterization and testing of our model, we present a representative and reproducible in vitro model that can be used to evaluate new cartilage repair treatments and study mechanisms in a controlled and standardized environment.

Solid state spectroscopy continues to be an important source of information on the mineralogical composition and physical properties of dust grains both in space and on planetary surfaces. With only a few exceptions, artificially produced or natural terrestrial analog materials, rather than 'real' cosmic dust grains, are the subject of solid state astrophysics. The Jena laboratory has provided a large number of data sets characterizing the UV, optical and infrared properties of such cosmic dust analogs. The present paper highlights recent developments and results achieved in this context, focussing on 'non-standard conditions' such as very low temperatures, very high temperatures and very long wavelengths., 15 pages, 10 figures. Contribution to an IAU Conference "The Molecular Universe" held in Toledo in June 2011

Pelvic ultrasound evaluation of girls presenting with secondary sex characteristics before the age of 8 years may help to differentiate precocious puberty from premature thelarche, functioning ovarian cyst, and obesity. However, although uterine and ovarian measurements are significantly higher in girls with true precocious puberty than controls, there is a significant overlap of normal prepubertal and early pubertal values. In girls with precocious puberty treated with gonadotropin-releasing hormone analogue, ultrasound is a valid tool for monitoring ovarian suppression.

The debris disk around $\beta$~Pictoris is known to contain gas. Previous ALMA observations revealed a CO belt at $\sim$85 au with a distinct clump, interpreted as a location of enhanced gas production. Photodissociation converts CO into C and O within $\sim$50 years. We resolve CI emission at 492 GHz using ALMA and study its spatial distribution. CI shows the same clump as seen for CO. This is surprising, as C is expected to quickly spread in azimuth. We derive a low C mass (between $5\times10^{-4}$ and $3.1\times10^{-3}$ M$_\oplus$), indicating that gas production started only recently (within $\sim$5000 years). No evidence is seen for an atomic accretion disk inwards of the CO belt, perhaps because the gas did not yet have time to spread radially. The fact that C and CO share the same asymmetry argues against a previously proposed scenario where the clump is due to an outward migrating planet trapping planetesimals in an resonance; nor can the observations be explained by an eccentric planetesimal belt secularly forced by a planet. Instead, we suggest that the dust and gas disks should be eccentric. Such a configuration, we further speculate, might be produced by a recent tidal disruption event. Assuming that the disrupted body has had a CO mass fraction of 10%, its total mass would be $\gtrsim$3 $M_\mathrm{Moon}$., Comment: 30 pages, 15 figures, accepted by ApJ

Noninvasive imaging of the heart using computed tomography (CT) is an increasingly important diagnostic approach for patients with known or suspected coronary artery disease. Coronary CT angiography has recently received great attention because it provides imaging of the coronary arteries and quantification of the coronary plaque burden with a spatial and temporal resolution not available with any other noninvasive imaging test. In this moderated scientific debate we discuss the advantages and disadvantages of different technical solutions to CT imaging of the fast moving heart including its small and tortuous coronary arteries. Our discussion goes into the details of developments regarding larger Z-axis coverage (320-row volume CT, high pitch spiral acquisition), improved temporal resolution (dual-source CT, adaptive multi-segment reconstruction, and shorter gantry rotation times with air-bearing gantries), improved spatial resolution (high-definition detectors), and improved reconstruction algorithms (iterative reconstruction, cone beam reconstruction). The discussion also touches on the future technological developments that will be necessary to further improve the acceptance and widespread clinical use of cardiac CT, focusing on radiation exposure reduction and independence from heart rate. Finally, the representatives of the four main vendors explain the most important research projects regarding cardiac CT that they plan to pursue in the near future.

Diabet. Med. 27, 339–347 (2010) Abstract Aims To identify variables that predict glycaemic control in Type 1 diabetic patients switched to a continuous subcutaneous insulin infusion (CSII) regimen, in order to improve patient selection for this treatment. Methods The notes of 421 Type 1 diabetic patients aged 2.6–39.8 years (median 19.4) who initiated CSII treatment in 1998–2007 and used it for ≥ 1 year were reviewed. Details about their background and disease-related and treatment-related variables were recorded. At pump initiation, the mean age was 15.9 ± 7.2 years, mean diabetes duration 6.4 ± 5.8 years. Mean time of CSII use was 4.1 ± 2.1 years. Good glycaemic control was defined by glycated haemoglobin (HbA1c) stratified by age (American Diabetes Association target levels). Improvement in glycaemic control was defined as a reduction of ≥ 0.5% in HbA1c from baseline. The change in the rate of severe hypoglycaemic or diabetic ketoacidosis events was also determined. Results There was a significant sustained decrease in HbA1c with CSII for an average of 6 years, without increased rates of hypoglycaemia. Achievement of target HbA1c was significantly associated with the following parameters at pump initiation: lower HbA1c (P