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Summary: Background: No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods: 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings: 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4–25.5] and 45.9 [IQR:37.9–53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p ≤ 0.0001. The risk of VF was particularly high among the youngest children (2–5 years), adolescents (13–17 years) and young adults (18–24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6–12 and 13–17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation: P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding: Inserm - ANRS MIE.

OBJECTIVE:: To analyze the utility of quick intraoperative parathyroid hormone (PTH) measurement in the surgical management of primary hyperparathyroidism.BACKGROUND DATA:: The use of intraoperative PTH monitoring is well established in the surgery of primary hyperparathyroidism. However, some false-negative predictions lead to unnecessary explorations; furthermore, surgeons are becoming increasingly dependent on hormone measurement for intraoperative decisions, which raises concerns about the cost-effectiveness of the method.METHODS:: A retrospective analysis of 268 neck explorations performed for primary hyperparathyroidism using intraoperative PTH monitoring from April 2001 to February 2003 was done. We used the criterion of “biologic recovery” of hyperfunctioning tissue, defined as a more than 50% decrease in PTH level from baseline value at 5 minutes after excision to predict the outcome of successful parathyroidectomy documented by normal postoperative serum calcium level. Additionally, we also sampled PTH at 10 minutes, 30 minutes, and the morning after surgery to compare the predictive value of delayed sampling. Patients were classified according to the prediction being concordant or discordant with the outcome. The data were analyzed using a 2 × 2 table construct for each of the sampling times, therefore providing sequential sensitivity, specificity, positive and negative predictive values, and overall accuracy of the predictions.RESULTS:: Concordance or overall accuracy of prediction (true positives and negatives) was obtained in 229 cases (85.4%), and discordance or failure of prediction (false positives and negatives) was obtained in 34 cases (12.7%) at T5. On analyzing the iPTH prediction at T10, T30, and D1 among the group of 33 false negatives, we found that 28 (10.4%) patients reached the concordance at 30 minutes, while by the first day 32 patients (12.3%) had achieved concordance. Thus, there was a progressive increase in sensitivity and overall accuracy, but more importantly, in the negative predictive value reaching 88.9% on the day after surgery.CONCLUSIONS:: The method of sampling PTH intraoperatively at 5 minutes has a high positive predictive value (99.5%) but a low negative predictive value (19.5%), which can lead to unnecessary explorations and a delay in the operative procedure. The negative predictive value increases substantially at 30 minutes and is best on the day after surgery. We suggest giving up the intraoperative measurement of PTH to adopt the first day postoperative measurement of PTH as a predictor of successful parathyroidectomy. [ABSTRACT FROM AUTHOR]

Despite major instrumental developments over the last decade, endodontic files are still not infallible. It is well known that NiTi rotary files can break without any visible sign of deformation. Instrument breakage under combined flexion-torsion loading is still common in clinical practice. Unfortunately, breakage of this type of instrument mainly occurs in narrow canals, through pinching in the apical region. When such an incident occurs, the endodontist must adopt a debris retrieval strategy that is both stressful and not guaranteed success. This study proposes a new method for experimental damage detection leading to the fracture of Ni-Ti shape memory alloy endodontic files. It is based on the acoustic emission (AE) technique and mechanical parameters measured in real-time and image analysis. It has been shown that the AE results correlate with the damage observations and torque and force measurements recorded during the tests. Having carried out numerous root canal treatment on resin blocks, it appears that this new detection and analysis technique can be used to analyze and anticipate the first signs of damage leading to endodontic file failure. The technological development of such a method, at the level of the engine itself, associated with the act in service procedure, would constitute a revolution in the field of endodontics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeanne Davril reports equipment, drugs, or supplies was provided by Micro-Mega SA. Marin Vincent has patent #FR3127686 issued to Marin Vincent. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The objective of our article is to review the literature and collect the advice of specialists for the evaluation of the reliabilityand appropriate indications of the use of pH paper in oral medicine practice. The literature pertaining to the use of pH paper in oral medicine practice was reviewed, and appropriate indications were suggested by a French multidisciplinary working group of specialists and validated by a lecture committee. By screening PubMed/MEDLINE from 1911 to March 2024, we found 621 articles. All abstracts were read, 22 articles were selected for full-text reading, and 12 were ultimately included in the review. Three more articles from other sources were included. Thus, 15 articles constituted the literature review; seven papers from PubMed/MEDLINE focusing on how to restore the salivary pH balance in cases of periodontitis and early childhood caries (ECC) completed the review. It is concluded that the lack of sensitivity of pH paper must be underlined. A low pH is a cofactor leading to oral pathologies, and the use of pH paper constitutes an easy diagnostic instrument in patients with pH variations correlated to leukemia, diabetic mellitus, or orofacial radiotherapy. The evaluation of salivary pH using pH paper may be used as a quick chairside test, specifically in cases of ECC and uncontrolled severe periodontitis. Early diagnosis of salivary low pH range in children as well as periodontitis with deep pocket associated with a low pH range in adults should lead to the supply of fluoride and prescript sodium bicarbonate-containing dentifrices, respectively. In children, the use of a chewable toothbrush may help reduce plaque and elevate salivary pH., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shamsi-Basha et al.)

Part of the broader glycosphingolipid family, gangliosides are composed of a ceramide bound to a sialic acid-containing glycan chain, and locate at the plasma membrane. Gangliosides are produced through sequential steps of glycosylation and sialylation. This diversity of composition is reflected in differences in expression patterns and functions of the various gangliosides. Ganglioside GD2 designates different subspecies following a basic structure containing three carbohydrate residues and two sialic acids. GD2 expression, usually restrained to limited tissues, is frequently altered in various neuroectoderm-derived cancers. While GD2 is of evident interest, its glycolipid nature has rendered research challenging. Physiological GD2 expression has been linked to developmental processes. Passing this stage, varying levels of GD2, physiologically expressed mainly in the central nervous system, affect composition and formation of membrane microdomains involved in surface receptor signaling. Overexpressed in cancer, GD2 has been shown to enhance cell survival and invasion. Furthermore, binding of antibodies leads to immune-independent cell death mechanisms. In addition, GD2 contributes to T-cell dysfunction, and functions as an immune checkpoint. Given the cancer-associated functions, GD2 has been a source of interest for immunotherapy. As a potential biomarker, methods are being developed to quantify GD2 from patients' samples. In addition, various therapeutic strategies are tested. Based on initial success with antibodies, derivates such as bispecific antibodies and immunocytokines have been developed, engaging patient immune system. Cytotoxic effectors or payloads may be redirected based on anti-GD2 antibodies. Finally, vaccines can be used to mount an immune response in patients. We review here the pertinent biological information on GD2 which may be of use for optimizing current immunotherapeutic strategies., Competing Interests: SB is inventor of patents covering the therapeutic use of anti-OAcGD2 immunotherapies. The remaining 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 © 2023 Machy, Mortier and Birklé.)

Under agroforestry practices, inter-specific facilitation between tree rows and cultivated alleys occurs when plants increase the growth of their neighbors especially under nutrient limitation. Owing to a coarse root architecture limiting soil inorganic phosphate (Pi) uptake, walnut trees ( Juglans spp.) exhibit dependency on soil-borne symbiotic arbuscular mycorrhizal fungi that extend extra-radical hyphae beyond the root Pi depletion zone. To investigate the benefits of mycorrhizal walnuts in alley cropping, we experimentally simulated an agroforestry system in which walnut rootstocks RX1 ( J. regia x J. microcarpa ) were connected or not by a common mycelial network (CMN) to maize plants grown under two contrasting Pi levels. Mycorrhizal colonization parameters showed that the inoculum reservoir formed by inoculated walnut donor saplings allowed the mycorrhization of maize recipient roots. Relative to non-mycorrhizal plants and whatever the Pi supply, CMN enabled walnut saplings to access maize Pi fertilization residues according to significant increases in biomass, stem diameter, and expression of JrPHT1;1 and JrPHT1;2 , two mycorrhiza-inducible phosphate transporter candidates here identified by phylogenic inference of orthologs. In the lowest Pi supply, stem height, leaf Pi concentration, and biomass of RX1 were significantly higher than in non-mycorrhizal controls, showing that mycorrhizal connections between walnut and maize roots alleviated Pi deficiency in the mycorrhizal RX1 donor plant. Under Pi limitation, maize recipient plants also benefited from mycorrhization relative to controls, as inferred from larger stem diameter and height, biomass, leaf number, N content, and Pi concentration. Mycorrhization-induced Pi uptake generated a higher carbon cost for donor walnut plants than for maize plants by increasing walnut plant photosynthesis to provide the AM fungus with carbon assimilate. Here, we show that CMN alleviates Pi deficiency in co-cultivated walnut and maize plants, and may therefore contribute to limit the use of chemical P fertilizers in agroforestry systems., 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 © 2023 Mortier, Mounier, Kreplak, Martin-Laurent, Recorbet and Lamotte.)

Background: Melanoma is a lethal skin cancer, and the risk of developing it is increased by exposure to ultraviolet (UV) radiation. The production of cytokines such as interleukin-15 (IL-15), induced by the exposure of skin cells to UV rays, could also promote melanoma development. The aim of this study is to investigate the possible role of Interleukin-15/Interleukin-15 Receptor α (IL-15/IL-15Rα) complexes in melanoma development., Methods: The expression of IL-15/IL-15Rα complexes by melanoma cells was evaluated both ex vivo and in vitro by tissue microarray, PCR, and flow cytometry. The presence of the soluble complex (sIL-15/IL-15Rα) in the plasma of metastatic melanoma patients was detected using an ELISA assay. Subsequently, we investigated the impact of natural killer (NK) cell activation after rIL-2 starvation followed by exposure to the sIL-15/IL-15Rα complex. Finally, by analyzing public datasets, we studied the correlation between IL-15 and IL-15Rα expressions and melanoma stage, NK and T-cell markers, and overall survival (OS)., Results: Analysis of a melanoma tissue microarray shows a significant increase in the number of IL-15 + tumor cells from the benign nevi to metastatic melanoma stages. Metastatic melanoma cell lines express a phorbol-12-myristate-13-acetate (PMA)-cleavable membrane-bound IL-15 (mbIL-15), whereas cultures from primary melanomas express a PMA-resistant isoform. Further analysis revealed that 26% of metastatic patients present with consistently high plasmatic levels of sIL-15/IL-15Rα. When the recombinant soluble human IL-15/IL-15Rα complex is added to briefly starved rIL-2-expanded NK cells, these cells exhibit strongly reduced proliferation and levels of cytotoxic activity against K-562 and NALM-18 target cells. The analysis of public gene expression datasets revealed that high IL-15 and IL-15Rα intra-tumoral production correlates with the high levels of expression of CD5 + and NKp46 + (T and NK markers) and significantly correlates with a better OS in stages II and III, but not in stage IV., Conclusions: Membrane-bound and secreted IL-15/IL-15Rα complexes are continuously present during progression in melanoma. It is notable that, although IL-15/IL-15Rα initially promoted the production of cytotoxic T and NK cells, at stage IV promotion of the development of anergic and dysfunctional cytotoxic NK cells was observed. In a subgroup of melanoma metastatic patients, the continuous secretion of high amounts of the soluble complex could represent a novel NK cell immune escape mechanism., 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 © 2023 Di Matteo, Munari, Fiore, Santopolo, Sampaoli, Pelosi, Chouaib, Tumino, Vacca, Mariotti, Ebert, Machwirth, Haas, Pezzullo, Pietra, Grottoli, Buart, Mortier, Maggi, Moretta, Caruana and Azzarone.)

Introduction: Obesity is associated with a number of chronic diseases such as cardiovascular diseases and cancers. The association of obesity with occupational accidents has been suggested although the evidence is less convincing. The objective of the study is to analyse the relationship between BMI values and ergonomic accidents in a large University Hospital., Methods: The relationship between body mass index (BMI) and the incidence of ergonomic occupational accidents over a period of 8 years was investigated in a cohort of employees of a large University Hospital, covering almost 27,000 person-years of observation. This relationship was stratified according to the variables age, gender, functional status within the organization and work schedule (part-time or full time). Height and weight were objectively measured, demographic data were obtained from the human resource department and the registration of ergonomic accidents was carried out by the safety and prevention department of the hospital., Results: The number of ergonomic accidents, expressed as number/1000 person-years was higher for female employees compared to male employees, increased with age and markedly increased from functional class A (leading or expert function and higher educational level) to D (executive function in patient care and technical department). However, the incidence of ergonomic accidents accompanied by loss of working time was not significantly associated with BMI, independently of age and gender. In addition, the type of accident and the severity of the accidents expressed as the number of days absent from work were unrelated to BMI., Conclusion: No independent relationship between BMI and the incidence of ergonomic accidents could be identified in our cohort. Tailoring working conditions to individual BMI levels is not recommended.

Interleukin (IL)-15 belongs to the common gamma-dependent cytokine family, along with IL-2, IL-4, IL-7, IL-9, and IL-21. IL-15 is crucial for the homeostasis of Natural Killer (NK) and memory CD8 T cells, and to fight against cancer progression. However, dysregulations of IL-15 expression could occur and participate in the emergence of autoimmune inflammatory diseases as well as hematological malignancies. It is therefore important to understand the different modes of action of IL-15 to decrease its harmful action in pathology without affecting its beneficial effects in the immune system. In this review, we present the different approaches used by researchers to inhibit the action of IL-15, from most broad to the most selective. Indeed, it appears that it is important to selectively target the mode of action of the cytokine rather than the cytokine itself as they are involved in numerous biological processes.

Introduction: Health-care organizations are facing a high burden of ergonomic occupational accidents, and prevention is a continuous point of interest. In this manuscript, we describe the characteristics of ergonomic accidents in a large Belgian university hospital and discuss the value of near misses., Methods: Combining databases, we identified the frequency [number of accidents × 10 6 hours worked per year], severity (number of days off work × 10 3 hours worked per year), and profile of the victims of occupational ergonomic accidents (with absence from work) or incidents or near-misses (without absence from work). Ergonomic accidents and incidents include slips, trips, falls, injurious body movements, overexertion, and handling heavy weights., Results: In a period of 23 years, we noticed a significant decrease in the frequency of ergonomic accidents (from about 7 to about 4 standard units), without changes in the severity. The decrease in the frequency of accidents is mirrored by an increase in the frequency of incidents (from about 4 to about 6 standard units). Female and older employees are more vulnerable to accidents, and the frequency was between two and four times higher for employees mostly involved in manual tasks compared to employees mostly involved in managerial tasks. The profile of the victims and the causes of accidents and incidents were identical., Conclusion: Although it is premature to assume a cause-consequence relationship between incidents and accidents, it is tempting to speculate that the increased ratio of the frequencies of incidents over accidents might be one of the variables reflecting the adequacy of preventive measures and the growth of safety behavior.

Objectives: More than 1 year after the start of the Covid-19 pandemic it is becoming increasingly clear that vaccines will prove to be essential in combating this global pandemic. The demand for such vaccines is great (since nearly everyone is a candidate for vaccination) yet supplies are currently limited. This raises clear ethical questions regarding the current and future Covid-19 vaccines., Methods: In this paper we highlight the several ethical questions that are raised using a three-fold categorization. We will discuss questions concerning: (1) the design and testing of vaccines; (2) who gets the vaccines; and (3) the tensions between public health and individual interest/autonomy. Each of these three more broad categories encompasses many different and concrete ethical questions., Results: We argue that different ethical frameworks apply both across these three categories, but also within these categories., Conclusion: Despite the fact that ethical conflict might not completely disappear, we argue that distinguishing and discussing separate questions from an ethical perspective can help create the necessary clarity and provide an ethical justification in favour of particular vaccination issues.

Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Rα/IL-2Rβ/γc receptor while leaving IL-15 signaling through the dimeric IL-2Rβ/γc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Rα/IL-2Rβ/γc receptor, highlighting the interest of selectively targeting this receptor., 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 © 2022 Meghnem, Maillasson, Barbieux, Morisseau, Keita, Jacques, Quéméner and Mortier.)

Background: In foreign language syndrome, patients switch from their native language and fixate for a period of time on a second language. There have been few reported cases. The language switch typically occurs postoperatively and spontaneously resolves after a short period of time. The primary cause of this switching remains unclear. There is speculation about the involvement of anesthesia, but its specific influence remains unclear., Case Presentation: A 17-year-old Dutch Caucasian male lost the ability to understand and speak Dutch for 24 hours after an orthopedic surgery, combined with a brief confused state including disorientation of place and the inability to recognize his parents. During the period, he communicated in English, which he had learned during school classes but had never spoken outside of school. Further follow-up, including neuropsychological examination, revealed no indication of cognitive impairment., Conclusions: The exact pathophysiology of foreign language syndrome remains unclear, most specifically whether it is a syndrome of its own or a phenotype of emergence delirium. There is still much to be learned, and further research is needed., (© 2022. The Author(s).)

Introduction: During the first wave of the coronavirus-disease 2019 (covid-19) pandemic in early 2020, hydroxychloroquine (HCQ) was widely prescribed in light of in vitro activity against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Our objective was to evaluate in early 2020 the rate of French hospitalists declaring having prescribed HCQ to treat covid-19 patients outside any therapeutic trial, compare the reasons and the determinants for having prescribed HCQ or not., Material and Methods: A national inquiry submitted by email from May 7 to 25, 2020, to a sample of French hospitalists: doctors managing patients hospitalized for covid-19 in a French department of internal medicine or infectious diseases and identified in the directories of French hospitals or as a member of the French Infectious Diseases Society (SPILF). Primary outcome was the percentage of hospitalists declaring having prescribed HCQ to covid-19 patients. Secondary outcomes were reasons and determinants of HCQ prescription., Results: Among 400 (22.8%) responding hospitalists, 45.3% (95% CI, 40.4 to 50.1%) declared having prescribed HCQ to covid-19 patients. Two main profiles were discerned: HCQ prescribers who did not raise its efficacy as a motive, and non-prescribers who based their decision on evidence-based medicine. Multivariate analysis retained the following prescription determinants (adjusted odds ratio; 95% confidence interval): a departmental procedure for HCQ prescription (8.25; 4.79 to 14.20), having prescribed other treatments outside a therapeutic trial (3.21; 1.81 to 5.71), prior HCQ prescription (2.75; 1.5 to 5.03) and HCQ prescribed within the framework of a therapeutic trial (0.56; 0.33 to 0.95)., Conclusion: Almost half of the hospitalists prescribed HCQ. The physician's personality (questioning or not evidence-based-medicine principles in the context of the pandemic) and departmental therapeutic procedures were the main factors influencing HCQ prescription. Establishment of "therapeutic" procedures represents a potential means to improve the quality of therapeutic decision-making during a pandemic., Competing Interests: Dr. Mahé reports grants from BMS Pfizer, grants from LEO Pharma, personal fees and non-financial support from BMS Pfizer, personal fees and non-financial support from Leo Pharma, personal fees and non-financial support from Bayer, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The COVID-19 pandemic has had an immense and worldwide impact. In light of future pandemics or subsequent waves of COVID-19 it is crucial to focus on the ethical issues that were and still are raised in this COVID-19 crisis. In this paper, we look at issues that are raised in the testing and tracing of patients with COVID-19. We do this by highlighting and expanding on an approach suggested by Fineberg that could serve as a public health approach. In this way, we highlight several ethical issues. As regards testing, questions are raised such as whether it is ethical to use less reliable tests in order to increase testing capacity or minimize harm for patients. Another issue is how wide testing should be and whether selective testing is in accordance with principles of social justice. Patients who have recovered from COVID-19 might have some degree of immunity but attributing certain 'immunopriviliges' raises ethical questions. The use of various tracing methodologies (mobile apps or databases and trained tracers) raised evident questions of social justice and privacy. We argue why it is key to always uphold a test of proportionality where a fair balance must be sought., (© 2021 The Authors. Bioethics published by John Wiley & Sons Ltd.)

Interleukin (IL)-15 is a pleiotropic cytokine structurally close to IL-2 and sharing with the IL-2Rβ and γc receptor (R) subunits. IL-15 plays important roles in innate and adaptative immunity, supporting the activation and proliferation of NK, NK-T, and CD8 + T cells. Over-expression of IL-15 has been shown to participate to the development of inflammatory and autoimmune diseases and diverse T cell malignancies. This study is in continuity of our previous work through which a family of small-molecule inhibitors impeding IL-15/IL-2Rβ interaction with sub-micromolar activity has been identified using pharmacophore-based virtual screening and hit optimization methods. With the aim to improve the efficacy and selectivity of our lead inhibitor, specific modifications have been introduced on the basis of optimized SAR and modelisation. The new series of compounds generated have been evaluated for their capacity to inhibit the proliferation as well as the down-stream signaling of IL-15-dependent cells and to bind to IL-15., (Copyright © 2021. Published by Elsevier Ltd.)

Soluble interleukin (IL)-15 exists under two forms: as monomer (sIL-15) or as heterodimeric complex in association with sIL-15Rα (sIL-15/IL-15Rα). Both forms have been successfully tested in experimental tumor murine models and are currently undergoing investigation in phase I/II clinical trials. Despite more than 20 years research on IL-15, some controversial issues remain to be addressed. A first point concerns the detection of the sIL-15/IL-15Rα in plasma of healthy donors or patients with cancer and its biological significance. The second and third unsolved question regards the protumorigenic role of the IL-15/IL-15Rα complex in human cancer and the detrimental immunological consequences associated to prolonged exposure of natural killer (NK) cells to both forms of soluble IL-15, respectively. Data suggest that in vivo prolonged or repeated exposure to monomeric sIL-15 or the soluble complex may lead to NK hypo-responsiveness through the expansion of the CD8 + /CD44 + T cell subset that would suppress NK cell functions. In vitro experiments indicate that soluble complex and monomeric IL-15 may cause NK hyporesponsiveness through a direct effect caused by their prolonged stimulation, suggesting that this mechanism could also be effective in vivo. Therefore, a better knowledge of IL-15 and a more appropriate use of both its soluble forms, in terms of concentrations and time of exposure, are essential in order to improve their therapeutic use. In cancer, the overproduction of sIL-15/IL-15Rα could represent a novel mechanism of immune escape. The soluble complex may act as a decoy cytokine unable to efficiently foster NK cells, or could induce NK hyporesponsiveness through an excessive and prolonged stimulation depending on the type of IL-15Rα isoforms associated. All these unsolved questions are not merely limited to the knowledge of IL-15 pathophysiology, but are crucial also for the therapeutic use of this cytokine. Therefore, in this review, we will discuss key unanswered issues on the heterogeneity and biological significance of IL-15 isoforms, analyzing both their cancer-related biological functions and their therapeutic implications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cognitive training results in significant, albeit modest, improvements in specific cognitive functions across a range of mental illnesses. Inhibitory control, defined as the ability to stop the execution of an automatic reaction or a planned motor behavior, is known to be particularly important for the regulation of health behaviors, including addictive behaviors. For example, several studies have indicated that inhibitory training can lead to reduced alcohol consumption or a loss of weight/reduced energy intake. However, the exact neurocognitive mechanisms that underlie such behavioral changes induced by training are still matter of debate. In the present study, we investigated the long-term impact (ie, at 1 week posttraining) of an inhibitory training program (composed of 4 consecutive daily training sessions of 20 minutes each) on the performance of a Go/No-go task. Healthy participants were randomly assigned to 1 of 3 designated groups: (1) an Inhibition Training (IT) group that received training based on a hybrid flanker Go/No-go task; (2) a group that received a noninhibition-based (ie, episodic memory; EM) training; and (3) a No-Training (NT) group to control for test-retest effects. Each group underwent 3 sessions of a Go/No-go task concomitant with the recording of event-related potentials. Our results revealed a specific impact of the Inhibitory Training on the Go/No-go task, indexed by a faster process compared with the other 2 groups. This effect was neurophysiologically indexed by a faster N2 component on the difference NoGo-Go waveform. Importantly, effects at both the behavioral and at the neural level were still readily discernible 1 week posttraining. Thus, our data clearly corroborate the notion that cognitive training is effective, while also indicating that it may persist over time.

Objectives : Health care systems worldwide are changing and taking new forms. The old, more hierarchically oriented, model with individual institutional and bilateral interactions between primary, secondary, tertiary and quaternary care is being replaced by an integrated and dynamic network model. We aim to look at what role university hospitals will play in this future organization of health care. Method : In this paper, we look at the relevant literature on the history of academic medicine and university hospitals. Subsequently, we look at the challenges university hospitals are facing according to contemporary literature on the topic. Results : Our current model of academic medicine with its university hospitals finds its origin in the institutionalization of the academic mission in the late 18 th century. Currently, the sustainability of the model is under immense pressure. University hospitals are facing economic challenges, teaching challenges and research challenges. However, there is reason to believe that they can continue to play a role of importance in tomorrow's medicine. The organization of health care is undergoing two important changes. The first is the evolution towards a more dynamic and integrated network model. University hospitals can become an important hub within this network. The second change is an evolution towards evidence based medicine and translational research. Conclusion : Due to their unique tripartite mission, we argue that university hospitals can continue to play an important and critical role in promoting evidence-based medicine and speedy translation of new evidence.

Objective: To refine the predictive significance of muscle granuloma in patients with myositis., Methods: A group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM)., Results: All but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis., Conclusion: Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care., (© 2019 American Academy of Neurology.)

Background: In the organization of health care and health care systems, there is an increasing trend towards integrated care. Policy-makers from different countries are creating policies intended to promote cooperation and collaboration between health care providers, while facilitating the integration of different health care services. Hopes are high, as such collaboration and integration of care are believed to save resources and improve quality. However, policy-makers are likely to encounter various challenges and limitations when attempting to turn these great ideas into effective policies. In this paper, we look into these challenges., Main Body: We argue that the organization of health care and integrated care is of public concern, and should thus be of crucial interest to policy-makers. We highlight three challenges or limitations likely to be encountered by policy-makers in integrated care. These are: (1) conceptual challenges; (2) empirical/methodological challenges; and (3) resource challenges. We will argue that it is still unclear what integrated care means and how we should measure it. 'Integrated care' is a single label that can refer to a great number of different processes. It can describe the integration of care for individual patients, the integration of services aimed at particular patient groups or particular conditions, or it can refer to institution-wide collaborations between different health care providers. We subsequently argue that health reform inevitably possesses a political context that should be taken into account. We also show how evidence supporting integrated care may not guarantee success in every context. Finally, we will discuss how promoting collaboration and integration might actually demand more resources. In the final section, we look at three different paradigmatic examples of integrated care policy: Norway, the UK's NHS, and Belgium., Conclusions: There seems widespread agreement that collaboration and integration are the way forward for health care and health care systems. Nevertheless, we argue that policy-makers should remain careful; they should carefully consider what they hope to achieve, the amount of resources they are willing to invest, and how they will evaluate the success of their policy.

Interleukin (IL)-15 plays an important role in the communication between immune cells. It delivers its signal through different modes involving three receptor chains: IL-15Rα, IL-2Rβ and IL-2Rγc. The combination of the different chains result in the formation of IL-15Rα/IL-2Rβ/γc trimeric or IL-2Rβ/γc dimeric receptors. In this study, we have investigated the role of the IL-15Rα chain in stabilizing the cytokine in the IL-2Rβ/γc dimeric receptor. By analyzing the key amino acid residues of IL-15 facing IL-2Rβ, we provide evidence of differential interfaces in the presence or in the absence of membrane-anchored IL-15Rα. Moreover, we found that the anchorage of IL-15Rα to the cell surface regardless its mode of presentation - i.e. cis or trans - is crucial for complete signaling. These observations show how the cells can finely modulate the intensity of cytokine signaling through the quality and the level of expression of the receptor chains., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Natural Killer (NK) cells are a type of cytotoxic lymphocytes that play an important role in the innate immune system. They are of particular interest for their role in elimination of intracellular pathogens, viral infection and tumor cells. As such, numerous strategies are being investigated in order to potentiate their functions. One of these techniques aims at promoting the function of their activating receptors. However, different observations have revealed that providing activation signals could actually be counterproductive and lead to NK cells' hyporesponsiveness. This phenomenon can occur during the NK cell education process, under pathological conditions, but also after treatment with different agents, including cytokines, that are promising tools to boost NK cell function. In this review, we aim to highlight the different circumstances where NK cells become hyporesponsive and the methods that could be used to restore their functionality.

Interleukin 15 (IL-15), a four-helix bundle cytokine, is involved in a plethora of different cellular functions and, particularly, plays a key role in the development and activation of immune responses. IL-15 forms receptor complexes by binding with IL-2Rβ- and common γ(γc)-signaling subunits, which are shared with other members of the cytokines family (IL-2 for IL-2Rβ- and all other γc- cytokines for γc). The specificity of IL-15 is brought by the non-signaling α-subunit, IL-15Rα. Here we present the results of molecular dynamics simulations carried out on four relevant forms of IL-15: its monomer, IL-15 interacting individually with IL-15Rα (IL-15/IL-15Rα), with IL-2Rβ/γc subunits (IL-15/IL-2Rβ/γc) or with its three receptors simultaneously (IL-15/IL-15Rα/IL-2Rβ/γc). Through the analyses of the various trajectories, new insights on the structural features of the interfaces are highlighted, according to the considered form. The comparison of the results with the experimental data, available from X-ray crystallography, allows, in particular, the rationalization of the importance of IL-15 key residues (e.g. Asp8, Lys10, Glu64). Furthermore, the pivotal role of water molecules in the stabilization of the various protein-protein interfaces and their H-bonds networks are underlined for each of the considered complexes., Competing Interests: The authors declare no conflict of interest.

Background: France is the European country with the lowest level of confidence in vaccines. Measurement of patients' acceptability towards a future therapeutic HIV vaccine is critically important. Thus, the aim of this study was to evaluate patients' acceptability of a future therapeutic HIV vaccine in a representative cohort of French patients living with HIV-AIDS (PLWHs)., Methods: This multicentre study used quantitative and qualitative methods to assess PLWHs' opinions and their potential acceptance of a future therapeutic HIV vaccine. Cross-sectional study on 220 HIV-1 infected outpatients, aged 18-75 years., Results: The participants' characteristics were similar to those of the overall French PLWH population. Responses from the questionnaires showed high indices of acceptance: the mean score for acceptability on the Visual Analog Scale VAS was 8.4 of 10, and 92% of patients agreed to be vaccinated if a therapeutic vaccine became available. Acceptability depended on the expected characteristics of the vaccine, notably the duration of its effectiveness: 44% of participants expected it to be effective for life. This acceptance was not associated with socio-demographic, clinical (mode of contamination, duration of disease), quality of life, or illness-perception parameters. Acceptability was also strongly correlated with confidence in the treating physician., Conclusion: The PLWHs within our cohort had high indices of acceptance to a future therapeutic HIV vaccine., Trial Registration: This study was retroactively registered on ClinicalTrials.gov with ID: NCT02077101 in February 21, 2014.

Aim: The aim of this article was to promote a methodology in the endodontic management of complex premolars with multiple root canals Background: The success of endodontic treatment depends on a meticulous clinical and radiographic analysis, the creation of a suitable access cavity and chemical and mechanical preparation, followed by three-dimensional filling of the entire root canal system. Consequently, it is essential to look for the presence of additional root canals to prevent endodontic treatment failure Case description: Two cases are presented. The first case concerned a 50-year-old male patient of North African origin who consulted in the context of a global prosthetic restoration including endodontic treatment of the maxillary left first premolar (tooth no. 24). The second case concerned a 29-year-old male patient of North African origin who was referred to us by his primary care practitioner in an urgent context of pain and infection present for two weeks (tooth no. 44). In both cases, it was the in-depth radiographic analysis, combined with manual exploration under the surgical micro- scope, that led to the relatively rare identification of a third root canal. Shaping, disinfection and three-dimensional filling of the entire root canal system were then performed in accordance with widely validated protocols., Conclusion: The maxillary and mandibular premolars, due to their highly variable root canal system configuration and a number of root canals and roots, appear to be teeth for which treatment is potentially complex. The acuteness of digital-tactile sense and the advent of 3D imaging and optical aids optimize the treatment of all the root canals of a tooth Clinical significance: These case reports demonstrate the importance of clinical and radiographic inspections to guide practitioners in the search for additional root canals in premolars and promote a methodological approach.

The organisation of health care is rapidly changing. There is a trend to move away from individual health care institutions towards transmural integrated care and interorganizational collaboration in networks. However, within such collaboration and network there is often likely to be a pluralism of values as different health care institutions often have very different values. For this paper, we examine three different models of how we believe institutions can come to collaborate in networks, and thus reap the potential benefits of such collaboration, despite having different moral beliefs or values. A first way is the pragmatic way in which the different health care institutions avoid ethical reflection and focus on solutions. A second possible route is that of consensus where health care institutions base their collaboration on values that they all share. The third, and final, approach is that of compromise. Although moral compromise is often seen in a negative light, we argue that in many cases compromise might be necessary and ethically justified. In a final section, we will shift our focus from discussing various theoretical methods to allow collaboration to the potential content of consensus or compromise.

Background: New options for first-line treatment of human immunodeficiency virus type 2 (HIV-2) infection are needed. We evaluated an integrase inhibitor (raltegravir)-containing regimen., Methods: Antiretroviral therapy (ART)-naive adults with symptomatic infection by HIV-2 only, CD4 count <500 cells/μL or CD4 decrease >50 cells/μL/year over the past 3 years, or a confirmed plasma HIV-2 RNA (pVL) load ≥100 copies/mL were eligible for this noncomparative trial. The composite primary endpoint was survival at 48 weeks without any of the following: CD4 gain from baseline <100 cells/μL, confirmed pVL ≥40 copies/mL from week 24, raltegravir permanent discontinuation, or incident B or C event. HIV-2 ultrasensitive pVL (uspVL) and total DNA were assessed using in-house polymerase chain reaction (PCR) assays., Results: Baseline median CD4 count of 30 enrolled individuals (67% women) was 436 cells/µL (interquartile range [IQR], 314-507 cells/µL); pVL was ≥40 copies/mL in 67% of them, uspVL was ≥5 copies/mL in 92%, and total DNA was >6 copies by PCR in 32%. At week 48, the composite endpoint of success was reached in 40% [95% confidence interval, 22.7%-59.4%]. Failure was mainly (50%) due to CD4 gain <100 cells/µL; uspVL was <5 copies/mL in 87% and total DNA >6 copies by PCR in 12% of participants. Median CD4 gain was 87 cells/µL (IQR, 38-213 cells/µL; n = 28). No serious adverse reactions were reported., Conclusions: Raltegravir-containing ART is a safe option for first-line treatment of HIV-2 infection, yielding a comparable success rate to protease inhibitors., Clinical Trials Registration: NCT 01605890.

IL-15 is a cytokine playing a crucial role in the function of immune cells, including NK and CD8 T cells. In this study, we demonstrated that in vivo, in mice, IL-15-prestimulated NK cells were no longer able to respond to a second cycle of IL-15 stimulation. This was illustrated by defects in cell maturation, proliferation, and activation, seemingly linked to the environment surrounding NK cells but not related to the presence of CD4 regulatory T cells, TGF-β, or IL-10. Moreover, NK cells from immunodeficient mice could respond to two cycles of IL-15 stimulation, whereas an adoptive transfer of CD44 + CD8 + cells impaired their responsiveness to the second cycle. Conversely, in immunocompetent mice, NK cell responsiveness to a second IL-15 stimulation was restored by the depletion of CD8 + cells. These biological findings refine our understanding of the complex mode of action of NK cells in vivo, and they should be taken into consideration for IL-15-based therapy., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Much is changing in health care organization today. A perspective or paradigm that is gaining ever increasing momentum is that of translational, extramural and integrated care. Current research suggests many potential benefits for integrated care and health care networks but the ethical issues are less frequently emphasized. Showing that integrated care can be beneficial, does not mean it is automatically ethically justified. We will argue for three ethical requirements such health care networks should meet. Subsequently we will look at the mechanisms driving the formation of networks and examine how these can cause networks to meet or fail to meet these ethical requirements or obligations. The three mechanisms we will examine are government, civil society and market mechanisms, which, we argue, should be balanced properly. Each mechanism is able to provide a relevant ethical perspective to health care networks. However, when the balance is skewed towards a single mechanism, health care networks might fail to promote one or more of the ethical requirements.

Background: Health care organization is entering a new age. Focus is increasingly shifting from individual health care institutions to interorganizational collaboration and health care networks. Much hope is set on such networks which have been argued to improve economic efficiency and quality of care. However, this does not automatically mean they are always ethically justified. A relevant question that remains is what ethical obligations or duties one can ascribe to these networks especially because networks involve many risks. Due to their often amorphous and complex structure, collective responsibility and accountability may increase while individual responsibility goes down., Main Body: We argue that a business ethics approach to ethical obligations for health care networks, is problematic and we propose to opt for a patient perspective. Using the classic four principles of biomedical ethics (justice, nonmaleficence, beneficence and autonomy) it is possible to identify specific ethical duties. Based on the principle of justice, health care networks have an ethical duty to provide just and fair access for all patients and to be transparent to patients about how access is regulated. The principle of nonmaleficence implies an obligation to guarantee patient safety, whereas the principle of beneficence implies an obligation for health care networks to guarantee continuity of care in all its dimensions. Finally, the principle of autonomy is translated into a specific obligation to promote and respect patient choice. Networks that fail to meet any of these conditions are suspect and cannot be justified ethically., Conclusions: Faced with daunting challenges, the health care system is changing rapidly. Currently many hopes ride on integrated care and broad health care networks. Such networks are the topic of empirical debate, but more attention should be given to the ethical aspects. Health care networks raise new and pressing ethical issues and we are in need of a framework for assessing how and when such networks are justified.

Background: Multiple studies have investigated the outcome of integrated care programs for chronically ill patients. However, few studies have addressed the specific role hospitals can play in the downstream collaboration for chronic disease management. Our objective here is to provide a comprehensive overview of the role of the hospitals by synthesizing the advantages and disadvantages of hospital interference in the chronic discourse for chronically ill patients found in published empirical studies., Method: Systematic literature review. Two reviewers independently investigated relevant studies using a standardized search strategy., Results: Thirty-two articles were included in the systematic review. Overall, the quality of the included studies is high. Four important themes were identified: the impact of transitional care interventions initiated from the hospital's side, the role of specialized care settings, the comparison of inpatient and outpatient care, and the effect of chronic care coordination on the experience of patients., Conclusion: Our results show that hospitals can play an important role in transitional care interventions and the coordination of chronic care with better outcomes for the patients by taking a leading role in integrated care programs. Above that, the patient experiences are positively influenced by the coordinating role of a specialist. Specialized care settings, as components of the hospital, facilitate the coordination of the care processes. In the future, specialized care centers and primary care could play a more extensive role in care for chronic patients by collaborating.

Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/γ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15- and IL-2-dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2-dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Purpose: To assess the influence of applicator tip diameter on the inclusion of porosities in three different flowable resin composites., Methods: The initial porosity of three syringes [Filtek Supreme XTE Flowable (XTE), Grandio Flow (GRF), Gradia Direct Flo (GDF)] was determined by 3D tomography. 25 samples per syringe, i.e. 75 samples in total, were prepared using five applicator tips of different diameters (n= 5). The porosity of the 75 samples was assessed by 3D tomography., Results: For each of the materials, the applicator tips, irrespective of type, all generated an increase in the average porosity percentage compared to the initial porosity of the syringes. For XTE and GRF, the applicator tips, irrespective of type, all generated a decrease in the average porosity volume compared to the initial average porosity volume in their respective syringes. Conversely, for GDF the average porosity volume of the samples was increased. Furthermore, for each of the materials, varying the diameter of the applicator tips had no significant influence on the porosity percentage and volume. Using the present study conditions, the applicator tip generated a variation in the initial porosity of the materials; however, the diameter of the tip had no influence on said variation., Clinical Significance: It appears that practitioners can choose an applicator tip with a diameter that best suits the size and shape of the cavity to be filled using a syringe of flowable resin composite without this having any impact on the percentage and volume of porosities in the final filling of the cavity., Competing Interests: The authors declared no conflict of interest.

Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12-66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0-301) and 101/μl (20-610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18-120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV-infected patients with worsening neurological symptoms after initiation or resumption of effective cART, independently of CD4 cell count prior to cART. If PCR for JCV is negative in CSF, brain biopsy should be discussed. Only large multicentric randomized trials could potentially demonstrate the possible efficacy of corticosteroids and/or CCR5 antagonists in the management of PML-IRIS.

Background: This study compared the storage modulus (E'), the loss modulus (E'') and the loss tangent (tan δ) of various flowable resin composites., Material and Methods: Grandio Flow (GRF), GrandioSo Heavy Flow (GHF), Filtek Supreme XTE (XTE) and Filtek Bulk Fill (BUL) flowable resins and Clinpro Sealant (CLI) ultra-flowable pit and fissure sealant resin were used. 25 samples were tested using a dynamical mechanical thermal analysis system in bending mode. Measurements were taken within a temperature range of 10 to 55°C. The results were statistically analyzed using mixed-effect and repeated-measure analysis of variance followed by paired multiple comparisons., Results: For all the materials, the E' values decrease with temperature, whereas the tan δ values increase. Irrespective of the temperature, GHF and GRF present E' and E'' values significantly higher than all the other materials and CLI presents values significantly lower than all the other materials. Observation of the values for all the materials reveals a linear progression of the tan δ values with temperature., Conclusions: A variation in temperature within a physiological range generates modifications in mechanical properties without damaging the material, however. Filler content in volume terms appears to be the crucial parameter in the mechanical behavior of tested materials. Key words: Dynamic mechanical thermal analysis, elastic modulus, filler content, flowable resin composites, loss modulus, loss tangent., Competing Interests: The authors declare that they have no conflict of interest.

Objectives: The objectives of this study were to determine the filler content, the surface microhardness (at baseline and after immersion in water for 2 years), and the rheological properties of various flowable resin composites., Methods: Three flowable resin composites (Grandioso Heavy Flow [GHF], Grandio Flow [GRF], Filtek Supreme XTE Flow [XTE]), one pit and fissure sealant resin composite (ClinPro [CLI]), and three experimental flowable resin composites with the same matrix and a variable filler content (EXPA, EXPB, EXPC) were tested. The filler content was determined by calcination. The Vickers surface microhardness was determined after polymerization and then after immersion in distilled water at 37°C for 7, 60, 180, 360, and 720 days. The rheological measurements were performed using a dynamic shear rheometer., Results: The determined filler contents differed from the manufacturers' data for all the materials. The materials with the highest filler content presented the highest microhardness, but filler content did not appear to be the only influencing parameter. With respect to the values recorded after photopolymerization, the values were maintained or increased after 720 days compared with the initial microhardness values, except for GHF. For the values measured after immersion for 7 days, an increase in microhardness was observed for all the materials over time. All the materials were non-Newtonian, with shear-thinning behavior. At all the shear speeds, GRF presented a lower viscosity to GHF and XTE., Conclusions: GRF presented a low viscosity before photopolymerization, associated with high filler content, thereby providing a good compromise between spreadability and mechanical properties after photopolymerization.

Objectives: Effective and efficient communication is crucial in healthcare. Written communication remains the most prevalent form of communication between specialised and primary care. We aimed at reviewing the literature on the quality of written communication, the impact of communication inefficiencies and recommendations to improve written communication in healthcare., Design: Narrative literature review., Methods: A search was carried out on the databases PubMed, Web of Science and The Cochrane Library by means of the (MeSH)terms 'communication', 'primary health care', 'correspondence', 'patient safety', 'patient handoff' and 'continuity of patient care'. Reviewers screened 4609 records and 462 full texts were checked according following inclusion criteria: (1) publication between January 1985 and March 2014, (2) availability as full text in English, (3) categorisation as original research, reviews, meta-analyses or letters to the editor., Results: A total of 69 articles were included in this review. It was found that poor communication can lead to various negative outcomes: discontinuity of care, compromise of patient safety, patient dissatisfaction and inefficient use of valuable resources, both in unnecessary investigations and physician worktime as well as economic consequences., Conclusion: There is room for improvement of both content and timeliness of written communication. The delineation of ownership of the communication process should be clear. Peer review, process indicators and follow-up tools are required to measure the impact of quality improvement initiatives. Communication between caregivers should feature more prominently in graduate and postgraduate training, to become engraved as an essential skill and quality characteristic of each caregiver., (© 2015 The Authors. International Journal of Clinical Practice Published by John Wiley & Sons Ltd.)

Background: Combined antiretroviral therapy (cART) initiation during primary human immunodeficiency virus (HIV) infection (PHI) yields a larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the timing of cART initiation on CA-HIV-DNA decay., Methods: We included patients enrolled during PHI in the Agence Nationale de Recherche sur le Sida PRIMO cohort, treated within the month following enrollment and achieving sustained virologic response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation., Results: Three hundred twenty-seven patients were included, accounting for 1305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (interquartile range, 33-54 days). Median follow-up under cART was 2.3 years (range, 0.4-16.6 years). The timing of cART initiation had significant impact on the first slope of decrease: The earlier cART was initiated after HIV infection, the faster CA-HIV-DNA level decreased during the first 8 months of cART: -0.171, -0.131, and -0.068 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs) per month when cART was initiated 15 days, 1 month, and 3 months after infection, respectively (P < .0001). The predicted mean CA-HIV-DNA level achieved after 5 years of successful cART was 1.62 and 2.24 log10 copies/10(6) PBMCs when cART was initiated 15 days and 3 months after infection, respectively (P = .0006)., Conclusions: This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

IL-34 is a challenging cytokine sharing functional similarities with M-CSF through M-CSFR activation. It also plays a singular role that has recently been explained in the brain, through a binding to the receptor protein tyrosine phosphatase RPTPβ/ζ. The aim of this paper was to look for alternative binding of IL-34 on other cell types. Myeloid cells (HL-60, U-937, THP-1) were used as cells intrinsically expressing M-CSFR, and M-CSFR was expressed in TF-1 and HEK293 cells. IL-34 binding was studied by Scatchard and binding inhibition assays, using 125I-radiolabelled cytokines, and surface plasmon resonance. M-CSFR activation was analysed by Western blot after glycosaminoglycans abrasion, syndecan-1 overexpression or repression and addition of a blocking anti-syndecan antibody. M-CSF and IL-34 induced different patterns of M-CSFR phosphorylations, suggesting the existence of alternative binding for IL-34. Binding experiments and chondroitinase treatment confirmed low affinity binding to chondroitin sulphate chains on cells lacking both M-CSFR and RPTPβ/ζ. Amongst the proteoglycans with chondroitin sulphate chains, syndecan-1 was able to modulate the IL-34-induced M-CSFR signalling pathways. Interestingly, IL-34 induced the migration of syndecan-1 expressing cells. Indeed, IL-34 significantly increased the migration of THP-1 and M2a macrophages that was inhibited by addition of a blocking anti-syndecan-1 antibody. This paper provides evidence of alternative binding of IL-34 to chondroitin sulphates and syndecan-1 at the cell surface that modulates M-CSFR activation. In addition, IL-34-induced myeloid cell migration is a syndecan-1 dependent mechanism., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to describe the proportion of liver-related diseases (LRDs) as a cause of death in HIV-infected patients in France and to compare the results with data from our five previous surveys., Methods: In 2010, 24 clinical wards prospectively recorded all deaths occurring in around 26 000 HIV-infected patients who were regularly followed up. Results were compared with those of previous cross-sectional surveys conducted since 1995 using the same design., Results: Among 230 reported deaths, 46 (20%) were related to AIDS and 30 (13%) to chronic liver diseases. Eighty per cent of patients who died from LRDs had chronic hepatitis C, 16.7% of them being coinfected with hepatitis B virus (HBV). Among patients who died from an LRD, excessive alcohol consumption was reported in 41%. At death, 80% of patients had undetectable HIV viral load and the median CD4 cell count was 349 cells/μL. The proportion of deaths and the mortality rate attributable to LRDs significantly increased between 1995 and 2005 from 1.5% to 16.7% and from 1.2‰ to 2.0‰, respectively, whereas they tended to decrease in 2010 to 13% and 1.1‰, respectively. Among liver-related causes of death, the proportion represented by hepatocellular carcinoma (HCC) dramatically increased from 5% in 1995 to 40% in 2010 (p = 0.019)., Conclusions: The proportion of LRDs among causes of death in HIV-infected patients seems recently to have reached a plateau after a rapid increase during the decade 1995-2005. LRDs remain a leading cause of death in this population, mainly as a result of hepatitis C virus (HCV) coinfection, HCC representing almost half of liver-related causes of death., (© 2014 British HIV Association.)

Amelogenesis imperfecta (AI) is a hereditary disorder caused by mutations of genes primarily involved in the enamel formation. Several different types of AI have been identified, based on the phenotype and on the mode of inheritance. Regardless of the type, the dental treatment tends to be the same, favoring the complete removal of the compromised enamel late in the patient's life. With the new dentistry guidelines that orient clinicians towards minimal invasiveness, it should be mandatory to intercept patients affected by AI earlier, not only to protect the dentition from further degradation but also to help patients improve their self-esteem. This article examines the restorative dentistry performed on a 24-year-old Caucasian female suffering from the hypoplastic type of AI, using only adhesive procedures. Due to the complex needs of the patient, an interdisciplinary approach was followed, involving orthodontics, periodontics, and restorative dentistry. A full-mouth adhesive rehabilitation was achieved by means of direct composite restorations, veneer/onlays and facial/palatal veneers. No elective endodontic therapy was necessary for restorative purposes. The esthetics, mechanics, and biological success were achieved and maintained. The bond to the enamel did not show signs of degradation (eg, discoloration or infiltration) even after 5 years of function. This is encouraging as it shows that adhesive techniques may be a reliable approach even in the presence of a compromised enamel layer.

Background: Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates., Methods: A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography-mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150-850 ng/ml efficacy-tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery., Results: 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported., Conclusions: In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.

Introduction: Rapid-onset of sensorineural hearing loss in a patient at risk of genital or oral exposure to treponema can be secondary to early neurosyphilis, for which delayed treatment may result in irreversible sequelae., Summary of the Case Report: A 40-year-old, HIV seropositive man with a CD4 lymphocyte count greater than 500/mm(3) presented with rapid-onset of bilateral sensorineural hearing loss over a period of one week. Otorhinolaryngological examination was normal. The audiogram showed bilateral hearing loss of 25 and 30 decibels, respectively. He subsequently developed loss of visual acuity, leading to the diagnosis of syphilitic meningitis affecting the optic and auditory nerves., Discussion: In about one half of cases, neurosyphilis is an early manifestation of the disease occurring several weeks or months after contamination. Rapid- or even sudden-onset of hearing loss may be due to auditory neuritis. Clinical interview and syphilis serology in a patient at risk of exposure can allow rapid diagnosis and treatment, consisting of two weeks parenteral penicillin. Recovery of hearing loss is inconstant but can be complete., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)