Search

Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Cytomegalovirus (CMV) persists as the most frequent opportunistic infection among solid organ transplant recipients. This multicenter trial aimed to test whether treatment with everolimus (EVR) could decrease the incidence of CMV DNAemia and disease. We randomized 186 CMV seropositive kidney transplant recipients in a 1:1 ratio to receive EVR or mycophenolic acid (MPA) in association with basiliximab, cyclosporin, and steroids and 87 in each group were analyzed. No universal prophylaxis was administered to either group. The composite primary endpoint was the presence of CMV DNAemia, CMV treatment, graft loss, death, and discontinuation of the study at 6 months posttransplant. In the modified intent-to-treat analysis, 42 (48.3%) and 70 (80.5%) patients in the EVR and MPA groups reached the primary endpoint (OR = 0.21, 95% CI: 0.11-0.43, p < .0001). Fewer patients of the EVR group received treatment for CMV (21.8% vs. 47.1%, p = .0007). EVR was discontinued in 31 (35.6%) patients. Among the 56 patients with ongoing EVR treatment, only 7.4% received treatment for CMV. In conclusion, EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: To describe the investigation, follow-up, management, and outcomes in a cohort of chronic kidney disease (CKD) and kidney transplant recipients (KTR) exposed to a case of pulmonary tuberculosis (TB)., Methods: Contacts were investigated following a concentric circles approach and followed-up according to their level of priority. In those with evidence of latent TB infection, treatment decision was based on the level of exposure, individual vulnerability, as well as the results of an interferon-gamma release assay., Results: A total of 130 patients with CKD and 180 KTR were identified as contacts and followed-up over a 2-year period. Few vulnerable high-priority contacts received anti-TB treatment, including the two (100%) highly exposed patients in circle 1, 11/78 (14.1%) CKD patients and 4/142 (2.8%) KTR in circle 2, and 10/52 (19.2%) CKD patients and 2/36 (5.6%) KTR in circle 3; all had a positive interferon-gamma release assay result. No incident cases of TB disease occurred., Conclusions: These findings suggest that latent TB treatment, as recommended in European guidelines, might be reasonably avoided in vulnerable high-priority contacts of circle 2, with a negative interferon-gamma release assay and in countries with low prevalence of TB., (Copyright © 2021. Published by Elsevier Ltd.)

Patients in hemodialysis on central venous catheter as vascular access are at risk of infections. Catheter-related bloodstream infection is one of the most serious catheter-complications in hemodialysis patients. Its clinical and microbiological diagnosis is challenging. The implementation of empiric antibiotic therapy is based on old recommendations proposing the combination of a molecule targeting methicillin-resistant Staphylococcus aureus and a betalactamin active on P. aeruginosa, and also adapting this probabilistic treatment by carrying out a microbiological register on a local scale, which is rarely done. In our hemodialysis center at Bordeaux University Hospital, an analysis of the microorganisms causing all catheter-related bloodstream infection over the period 2018-2020 enabled us to propose, in agreement with the infectious disease specialists, an adapted probabilistic antibiotic therapy protocol. This approach allowed us to observe a low incidence of meticillinoresistance of Staphylococcus. For catheters inserted more than 6 months ago, we observed no Staphylococcus, no multi-resistant Pseudomonas, and only 2% of Enterobacteria resistant to cephalosporins. A frequent updating of the microbiological epidemiology of catheter-related bloodstream infection, in partnership with the infectious diseases team in each hemodialysis center, allowing an adaptation of the probabilistic antibiotic therapy, and seems to have a good feasibility. This strategy might favor the preservation of microbial ecology on an individual and collective scale in maintenance hemodialysis patients., (Copyright © 2021 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

This article describes 5 cases of bartonellosis with fever and atypical clinical presentations in kidney transplant recipients: thrombotic microangiopathies, recurrent hemophagocytosis, and immune reconstitution syndrome after treatment. The diagnosis, the pathological lesions, and treatments are described. Bartonellosis must be researched in solid organ transplant recipients with fever of undetermined origin., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unexplained., Methods: The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and in vitro mTORi effects on T-cell phenotype and functions were analyzed., Results: In KTRs who were R+ and treated with MPA, both αβ and γδ T cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTRs with severe CMV infection, as compared with the 17 KTRs without or with spontaneously resolving CMV infection. In patients treated with mTORis ( n =27), the proportion of PD-1+ and CD85j+ αβ and γδ T cells decreased, when compared with patients treated with MPA ( n =44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic γδ T cells and IFN γ -producing and cytotoxic αβ T cells. In vitro , mTORis increased proliferation, viability, and CMV-induced IFN γ production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMES low Hobit high profile. In γδ T cells, the mTORi effect was related to increased TCR signaling., Conclusion: Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment., Clinical Trial Registry Name and Registration Number: Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963., (Copyright © 2022 by the American Society of Nephrology.)

Unconventional T cells are a diverse and underappreciated group of relatively rare lymphocytes that are distinct from conventional CD4 + and CD8 + T cells, and that mainly recognize antigens in the absence of classical restriction through the major histocompatibility complex (MHC). These non-MHC-restricted T cells include mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, γδ T cells and other, often poorly defined, subsets. Depending on the physiological context, unconventional T cells may assume either protective or pathogenic roles in a range of inflammatory and autoimmune responses in the kidney. Accordingly, experimental models and clinical studies have revealed that certain unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic biomarkers. The responsiveness of human Vγ9Vδ2 T cells and MAIT cells to many microbial pathogens, for example, has implications for early diagnosis, risk stratification and targeted treatment of peritoneal dialysis-related peritonitis. The expansion of non-Vγ9Vδ2 γδ T cells during cytomegalovirus infection and their contribution to viral clearance suggest that these cells can be harnessed for immune monitoring and adoptive immunotherapy in kidney transplant recipients. In addition, populations of NKT, MAIT or γδ T cells are involved in the immunopathology of IgA nephropathy and in models of glomerulonephritis, ischaemia-reperfusion injury and kidney transplantation., (© 2021. Springer Nature Limited.)

Background: In the era of prophylaxis, Pneumocystis pneumonia (PCP) has become a late-onset opportunistic infection requiring indications for prolonged prophylaxis to be defined. The primary objective of our study was therefore to evaluate risk factors associated with late-onset PCP. The secondary objective was to assess the impact of this infection on graft and patient survival., Methods: We conducted a French case-control study in Bordeaux and Toulouse center by matching 1 case to 1-2 controls from the same center based on the transplant date and the type of induction treatment., Results: Seventy cases and 134 controls were included. PCP occurred at a median of 3 years after transplantation. The total lymphocyte count and CD4+ and CD8+ T-lymphocyte values were lower in the cases than in their matched controls on the day of infection and annually up to 4 years earlier. The covariables independently associated with PCP were the total lymphocyte count 1 year before Pneumocystis, mTOR inhibitors used as maintenance immunosuppressive drugs, and the administration of corticosteroid boluses used in acute rejection. A total lymphocyte count threshold <1000/µL offered the best predictive value for infection occurrence. PCP was associated with high incidence of graft loss and patient death (30% and 17% respectively, 3 years after PCP)., Conclusions: Pneumocystis pneumonia has dramatic consequences in kidney transplant recipients; a targeted prophylaxis based on simple criteria, such as chronic lymphopenia and/or history of corticosteroid boluses, could be useful to avoid life-threatening complications., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Microsporidiosis is an emerging opportunistic infection in renal transplantation (RT) recipients. We aimed to describe its clinical presentation and treatment., Materials and Methods: We collected microsporidiosis cases identified in RT recipients between 2005 and 2019 in six French centers from the Crystal, Divat and Astre prospective databases., Results: We report 68 RT recipients with intestinal microsporidiosis; the patients were predominantly male (61.8%), with a median age of 58 (46-69) years. Infection occurred at a median time of 3 (0.8-6.8) years posttransplant. Only Enterocytozoon bieneusi was found. Microsporidiosis manifested as diarrhea (98.5% of patients) with weight loss (72.1%) and acute renal injury (57.4%) without inflammatory biological parameters. The therapeutic approaches were no treatment (N = 9), reduction of the immunosuppressive regimen (∆IS) (N = 22), fumagillin alone (N = 9), fumagillin and ∆IS (N = 19), and albendazole or nitazoxanide and ∆IS (N = 9). Overall clinical remission was observed in 60 patients (88.2%). We observed no acute kidney rejection, renal transplant failure, or death within 6 months after microsporidiosis., Conclusion: E. bieneusi is an underestimated opportunistic pathogen in RT recipients, and infection with E. bieneusi leads to diarrhea with important dehydration and acute renal injury. The treatment is based on the reduction of the immunosuppressive regimen and the administration of fumagillin if available., (© 2021 Wiley Periodicals LLC.)

In this essay, we show that 3 distinct approaches to immunological exhaustion coexist and that they only partially overlap, generating potential misunderstandings. Exploring cases ranging from viral infections to cancer, we propose that it is crucial, for experimental and therapeutic purposes, to clarify these approaches and their interconnections so as to make the concept of exhaustion genuinely operational., Competing Interests: The authors have declared that no competing interests exist.

Child care-based interventions offer an opportunity to reach children at a young and impressionable age to support healthy eating and physical activity behaviors. Ideally, these interventions engage caregivers, including both childcare providers and parents, in united effort. This study evaluated the impact of the Healthy Me, Healthy We intervention on children's diet quality and physical activity. A sample of 853 three- to four-year-old children from 92 childcare centers were enrolled in this cluster-randomized control trial. Healthy Me, Healthy We was an 8-month, social marketing intervention delivered through childcare that encouraged caregivers (childcare providers and parents) to use practices that supported children's healthy eating and physical activity behaviors. Outcome measures, collected at baseline and post-intervention, assessed children's diet quality, physical activity, and BMI as well as caregivers' feeding and physical activity practices. Generalized Linear Mixed Models were used to assess change from baseline to post-intervention between intervention and control arms. No significant changes were noted in any of the outcome measures except for small improvements in children's sodium intake and select parent practices. Despite the negative findings, this study offers many lessons about the importance and challenges of effective parent engagement which is critical for meaningful changes in children's health behaviors., (© Society of Behavioral Medicine 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The effectiveness of interventions targeting children's eating and physical activity behaviors through childcare settings is inconsistent. To enhance public health impact, it is imperative to evaluate fidelity of implementing complex interventions in real-world settings. This study evaluated fidelity and contextual factors influencing implementation of Healthy Me, Healthy We (HMHW). HMHW was an 8-month social marketing campaign delivered through childcare to support children's healthy eating and physical activity. HMHW required two levels of implementation support (research team and childcare providers) and two levels of campaign delivery (childcare providers and parents). Process evaluation was conducted among childcare centers in the intervention group (n=48) of the cluster-randomized control trial. Measures included attendance logs, self-report surveys, observation checklists, field notes, and semi-structured interviews. A 35-item fidelity index was created to assess fidelity of implementation support and campaign delivery. The fidelity with which HMHW was implemented by childcare providers and parents was low (mean 17.4 out of 35) and decreased between childcare providers and parents. Childcare providers had high acceptability of the program and individual components (80 - 93%). Only half of parents felt intervention components were acceptable. Frequently cited barriers to implementation by childcare providers included time constraints, parent engagement, staff turnover, and restrictive policies. The lack of observable effect of HMHW on children's dietary or physical activity behaviors may be due to inadequate implementation at multiple levels. Different or additional strategies are necessary to support implementation of multilevel interventions, particularly when individuals are expected to deliver intervention components and support others in doing so., (© Society of Behavioral Medicine 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p = .37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p = .09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the Vγ9posVδ2pos T cells that respond to phosphoantigens but not to CMV. A third Vγ9negVδ2pos subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these Vγ9negVδ2pos T cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδ T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2pos T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T cells responded specifically to CMV-infected cells in a T-cell receptor-dependent manner and through strong interferon γ production. Finally, Vγ9negVδ2pos T cells were the only γδ T-cell subset in which expansion was tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T cells as an immune marker for CMV disease severity in immunocompromised patients., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Context: Limited data exist concerning differences in concussion-education exposure and how education exposures relate to care seeking and symptom disclosure, specifically by National Collegiate Athletic Association Division I student-athletes., Objective: To investigate demographic characteristics associated with concussion-education exposure and examine whether overall education exposure (yes versus no) and education-source exposure number (multiple sources versus a single source) affect concussion care-seeking and disclosure factors in Division I student-athletes., Design: Cross-sectional study., Setting: Classroom or online survey., Patients or Other Participants: Division I student-athletes (n = 341)., Main Outcome Measure(s): Frequencies and proportions were computed for sex, race, school year, sport, and concussion history across concussion-education groups. Prevalence ratios (PRs) and 95% CIs were calculated to quantify the associations between student-athlete characteristics and (1) overall concussion-education exposure and (2) source-exposure number. Separate multivariable linear regression models estimated adjusted mean differences (MDs) and 95% CIs, which allowed us to assess differences in concussion knowledge, attitudes, and perceived social norms relative to concussion-education exposure and exposure to multiple sources. Separate multivariable binomial regression models were performed to estimate adjusted PRs and 95% CIs in order to evaluate associations of intention, perceived control, and care-seeking or disclosure behaviors and overall concussion-education exposure and exposure to multiple sources. All models controlled for sex, sport, and concussion history., Results: Overall, 276 (80.9%) participants reported previous concussion education, with 179 (64.9%) being exposed to multiple sources. Student-athletes who participated in a contact sport (adjusted PR = 1.24; 95% CI = 1.06, 1.44) and those who had a concussion history (adjusted PR = 1.19; 95% CI = 1.09, 1.31) had higher prevalences of concussion-education exposure. Females had a lower prevalence of reporting multiple sources (adjusted PR = 0.82; 95% CI = 0.68, 0.99). Overall concussion-education exposure was significantly associated with more favorable perceived social norms surrounding concussion care seeking (adjusted MD = 1.37; 95% CI = 0.13, 2.61)., Conclusions: These findings highlighted the potential differences in overall concussion-education exposure and provide clinicians with information on groups who may benefit from additional targeted education., (© by the National Athletic Trainers' Association, Inc.)

Background: Rituximab has been proposed as induction therapy in kidney transplant recipients (KTRs) with preformed donor-specific antibodies (DSA) or a positive flow cross-match. We here evaluated whether adding rituximab was associated with a higher incidence of post-transplant malignancies (PTM) due to greater immunosuppression., Patients and Methods: Forty-eight HLA-sensitized KTRs received induction therapy with anti-thymocyte globulin (ATG) and rituximab because of preformed DSA or a positive flow cross-match (RTX group). They were compared with a control group of 154 patients receiving ATG alone., Results: Thirty-nine of 202 (19.3%) patients developed PTM; the rate was similar in the RTX and no-RTX groups (14.6% vs. 20.8%, respectively, P = .3). The distributions of the types of cancer were similar between the two groups, with the majority being non-melanoma skin cancer (NMSC, n = 24). The risk factors for PTM were male gender, age, history of cancer, and azathioprine., Conclusion: Our data do not indicate a higher rate of post-transplantation de novo malignancies after kidney transplantation in high-immunological risk patients who received induction therapy based on ATG and rituximab., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Timely disclosure and identification of concussion symptoms are essential to proper care. Perceived social norms are a potential driving factor in many health-related decisions. The study purpose was to describe concussion disclosure behaviours and identify the association between perceived social norms and these disclosure behaviours. First-year student-athletes (n = 391) at two NCAA institutions completed a cross-sectional survey about concussion disclosure and disclosure determinants. Log-binomial regression models identified factors associated with concussion disclosure behaviour prevalence for: higher intention to disclose symptoms, disclosed all at time of injury, eventually disclosed all, and never participated with concussion symptoms. More favourable perceived social norms were associated with higher prevalence of intention to disclose (PR = 1.34; 95%CI: 1.18, 1.53) and higher prevalence of never participating in sports with concussion symptoms (PR = 1.50; 95%CI: 1.07, 2.10). Clinicians, coaches, sports administrators, and healthcare practitioners should be mindful of the need to create supportive social environments to improve concussion symptom disclosure.

Purpose of Review: Urinary tract infection (UTI) is the most common infection in kidney transplant recipients (KTRs). Several elements increase the risk of UTI and/or modify its clinical presentation among KTRs (e.g. immunosuppressive therapy, kidney allograft denervation, and use of urinary catheters). Also, KTRs may have UTIs because of difficult-to-identify and/or difficult-to-treat organisms. We provide an overview of the current knowledge regarding bacterial UTIs in KTRs, with a focus on recent findings., Recent Findings: There is accumulating evidence from clinical trials that screening for and treating asymptomatic bacteriuria is not beneficial in most KTRs (i.e. those who are ≥1-2 months posttransplant and do not have a urinary catheter). These patients have a point-prevalence of asymptomatic bacteriuria of only 3% and treating asymptomatic bacteriuria probably does not improve their outcomes. There is no clinical trial evidence to guide the management of symptomatic UTI in KTRs. Several important clinical questions remain unanswered, especially regarding the management of posttransplant pyelonephritis and the prevention of UTI in KTRs., Summary: Despite its frequency and associated morbidity, UTI after kidney transplantation is an understudied infection. In an era of increasing antimicrobial resistance and limited resources, further research is needed to ensure optimal use of antimicrobials in KTRs with UTI.

Context: There are limited data concerning differences in concussion education exposure and how education exposures relates to care-seeking and symptom disclosure, specifically in Division I student-athletes., Objective: Investigate demographic characteristics associated with concussion education exposure and examine whether overall education exposure (yes vs. no) and education source exposure number (multiple sources vs. single source) affects concussion care-seeking and disclosure factors in Division I student-athletes., Design: Cross-sectional survey., Setting: Classroom or online., Participants: NCAA Division I student-athletes (n=341)., Main Outcome Measure(s): Frequencies and proportions were computed for sex, race, school year, sport, and concussion history across concussion education groups. Prevalence ratios (PR) and 95% confidence intervals (CI) quantified the association between student-athlete characteristics and 1) overall concussion education exposure and 2) source exposure number. Separate multivariable linear regression models estimated adjusted mean differences (MD) and 95%CI to assess differences in concussion knowledge, attitudes, and perceived social norms relative to concussion education exposure and exposure to multiple sources. Separate multivariable binomial regression models estimated adjusted PRs and 95%CI to assess associations of intention, perceived control, and care-seeking/disclosure behaviors and overall concussion education exposure and exposure to multiple sources. All models controlled for sex, sport, and concussion history., Results: Overall, n=276 (80.9%) reported previous concussion education, with 179 (64.9%) exposed to multiple sources. Student-athletes that participated in a contact sport (adjusted PR=1.24, 95%CI=1.06,1.44) and those who had a concussion history (adjusted PR=1.19, 95%CI=1.09,1.31) had higher prevalence of previous concussion education exposure. Females had a lower prevalence of reporting multiple sources (adjusted PR=0.82, 95%CI=0.68, 0.99). Overall concussion education exposure was significantly associated with more favorable perceived social norms surrounding concussion care-seeking (adjusted MD=1.37, 95%CI=0.13,2.61)., Conclusions: Findings highlight potential differences in overall concussion education exposure and provide clinicians with information on groups who may benefit from targeted additional education., (© by the National Athletic Trainers' Association, Inc.)

Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αβ and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Myasthenia gravis (MG), a chronic neuromuscular disorder, can adversely affect patients' health-related quality of life (HRQoL), especially in women. The study aimed to evaluate the difference in HRQoL of women and men MG patients and explore the factors that mediate the relationship between gender and HRQoL., Methods: A cross-sectional study was conducted among 1815 patients with MG in China. The revised 15-item MG quality of life scale (MG-QOL15r) was used to access patients' HRQoL in overall, physical, social and emotional domains. Socio-demographic information, diagnosis and treatment history, comorbidities, social support, active lifestyle and the MG activities of daily living scale (MG-ADL) were recorded and compared between women and men using the Student's t-test and Pearson's Chi-square test. Multivariable regression analyses were conducted to identify independent contributors to HRQoL, especially those affecting different gender., Results: On average, female patients with MG reported a lower MG-QOL15r score than the males (44.49 ± 29.10 vs 49.32 ± 29.18). The association between gender and patients' HRQoL interacted with the number of comorbidities across the overall, physical and social domains of patients. As the number of comorbidities increased, the scores of HRQoL decreased and it was faster among females than the males (p < 0.05). Moreover, unemployment, exacerbation of the disease, and active lifestyle contributed to the patients' HRQoL across all domains. Unemployment (β = - 4.99 [95%CI, - 7.80 to - 2.18], p < 0.001) and exacerbations (β = - 8.49 [95%CI, - 11.43 to - 5.54], p < 0.001) were correlated with poorer HRQoL; while an active lifestyle had a positive impact on HRQoL (β = 0.28 [95%CI, 0.16 to 0.40], p < 0.001)., Conclusions: The results indicate that the HRQoL of women MG patients was lower than that of men. The relationship between gender and HRQoL is modulated by the number of comorbidities. Thus, to improve the HRQoL of women MG patients, symptomatic treatments might not be enough, their comorbid conditions should be considered as well. Additionally, employment status, MG exacerbations, and an active lifestyle have been found as determining factors of the patients' HRQoL, which suggests future interventions should cope with these factors to improve their quality of life.

mTOR inhibitors exert a preventive effect on cytomegalovirus (CMV) disease in CMV seropositive (R+) kidney transplant recipients, but their impact during the curative treatment of CMV disease in high-risk kidney transplant recipients has not been investigated. We aimed to evaluate the efficacy and tolerance of mTOR inhibitors compared with mycophenolic acid in 63 consecutive kidney transplant recipients (80% of D+R-) suffering from CMV disease with a persistent or a recurrent CMV DNAemia. In this monocentric retrospective study, 16 had their treatment converted to mTOR inhibitors and 47 did not. The Kaplan-Meier curves did not show any significant differences in CMV DNAemia eradication (77% vs. 88% respectively; hazard ratio (HR), 1.648 [95% confidence interval (CI), 0.913-2.973]; log-rank test, P = .132), DNAemia recurrence (36% vs. 47%; HR, 1.517 [95% CI, 0.574-4.007]; log-rank test, P = .448) and CMV clinical recurrence (17% vs. 27%; HR, 1.375 [95% CI, 0.340-5.552]; log-rank test, P = .677) between patients who received mTOR inhibitors and those who did not. These results were confirmed in uni- and multivariate time-dependent Cox regressions. In summary, conversion from mycophenolic acid to mTOR inhibitors seems inadequate for improving CMV clearance or in better preventing CMV recurrences during severe or persistent CMV disease., (© 2020 The Societies and John Wiley & Sons Australia, Ltd.)

Objectives: Particulate air pollution is linked to adverse cardiovascular effects, including arterial stiffness. The aim of the study was to investigate the effect of short-term exposure to indoor fine and ultrafine particles on augmentation index (AIx), augmentation pressure (AP), and pulse wave velocity (PWV), early signs of vascular damage., Methods: We analyzed the association of particle emissions from typical indoor sources (candle burning - CB, toasting bread - TB, and frying sausages - FS) with changes in pulse wave analysis indices in 55 healthy adults in a randomized cross-over controlled exposure study. Particle mass concentration (PMC), size-specific particle number concentration (PNC) and lung-deposited particle surface area concentration (PSC) were measured during the 2 h exposure. AIx and AP were measured before, directly, 2, 4 and 24 h after exposure. PWV was measured directly and 24 h after exposure. We performed multiple mixed linear regression analyses of different particle metrics and AIx, AP and PWV., Results: The highest mean PMC was observed during FS reaching a maximum of 210 μg/m 3 PM 10 . The maximal PNC for UFP <100 nm was reached during CB with 2.3 million particles/cm 3 . PSC was similar across all three exposures (about 3000 μm 2 /cm³). Strongest associations between different particles metrics and arterial stiffness indices could be observed for UFP from CB and FS and for PMC from TB. The highest mean increase could be observed for the UFP fraction <10 nm, measured during CB, and AIx with an increase of 9.5%-points (95%-CI: 3.1; 15.9). PSC seemed to follow the pattern of PNC. PM 10 and PM 2.5 from TB led to clear changes in AIx with biggest increases for PM 10 of 5.8%-points (95%-CI: 3.2; 8.4) 2 h after exposure and for PM 2.5 of 8.1%-points (95%-CI: 2.5; 13.7) directly after exposure., Conclusions: Our study indicates effects of indoor exposure to fine and ultrafine particles on systemic arterial stiffness indices that depend on the indoor source as well as on particle metric. Differences in size-specific physical characteristics of source-specific particles might account for these differential effects. We did not observe clear and stable associations of indoor particle exposure and PWV., (Copyright © 2019. Published by Elsevier GmbH.)

Background: Rabbit antithymocyte globulin (rATG) induction is associated with profound immunosuppression, leading to a higher risk of cytomegalovirus (CMV) infection compared with anti-interleukin 2 receptor antibody (anti-IL-2RA). However, this risk, depending on the baseline CMV serological recipient/donor status, is still controversial., Methods: The CMV DNAemia-free survival between rATG- and anti-IL-2RA-treated patients was analyzed in donor-positive/recipient-negative (D+R-) and recipient-positive (R+) patients in 1 discovery cohort of 559 kidney transplant recipients (KTRs) and 2 independent cohorts (351 and 135 kidney KTRs). The CMV-specific cell-mediated immunity (CMI) at baseline and at different time points after transplantation was assessed using an interferon γ enzyme-linked immunosorbent spot assay., Results: rATG increased the risk of CMV DNAemia in R+ but not in D+R- KTRs. In R+ CMI-positive (CMI+) patients, the CMV DNAemia rate was higher in rATG-treated than in anti-IL-2RA-treated patients; no difference was observed among R+ CMI-negative (CMI-) patients. Longitudinal follow-up demonstrated a deeper depletion of preformed CMV CMI in R+ rATG-treated patients., Conclusions: D+R- KTRs have the highest risk of CMV DNAemia, but rATG adds no further risk. Among R+ KTRs, we described 3 groups, the least prone being R+CMI+ KTRs without rATG, then R+CMI+ KTRs with rATG, and finally R+CMI- KTRs. CMV serostatus, baseline CMV-specific CMI, and induction therapy may lead to personalized preventive therapy in further studies., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Although social marketing principles have been successfully employed in school-based interventions to prevent obesity, use in early care and education (ECE) settings has been limited. This paper describes the use of the social marketing approach to develop an ECE-based intervention that encourages an ECE provider-parent partnership to improve the quality of preschool children's diets and their level of physical activity. A six-step social marketing approach for public health interventions guided the development of this ECE-based intervention. These steps were as follows: (i) initial planning, (ii) formative research, (iii) strategy development, (iv) program development, (v) implementation, and (vi) monitoring and evaluation. During this process, we reviewed current literature, conducted focus groups with ECE providers and parents, developed a detailed conceptual model and content map, created and tested the campaign concept, and developed final campaign materials along with strategies for its implementation. The final intervention resulting from this process was an 8-month campaign known as Healthy Me, Healthy We. The campaign is delivered by the child care center and includes branded materials for use in the classroom and at home. The final campaign is being evaluated in a cluster-randomized trial. Healthy Me, Healthy We offers an innovative approach to promoting healthy eating and physical activity during early childhood, a key developmental period, that leverages partnership between ECE providers and parents to affect behavior change., (© Society of Behavioral Medicine 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t -distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV + and CMV - donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions., Competing Interests: The authors declare no conflict of interest.

Objectives: Non-disclosure of concussion complicates concussion management, but almost nothing is known about non-disclosure in military settings. This study describes concussion disclosure-related knowledge, attitudes, perceived social norms, perceived control, and intention. Additionally, the study identifies determinants of high intention to disclose concussion symptoms., Design: Cross sectional survey., Methods: First-year service academy cadets completed a cross-sectional survey to assess perceptions of concussion disclosure. Independent variables included: gender, race, ethnicity, high school athlete status, NCAA athlete status, previous concussion history, previous concussion education, socioeconomic proxy, concussion-related knowledge, attitudes about concussion, perceived social norms (perceived peer/organizational support and actions), and perceived control over disclosure. Log-binomial regression was used to identify determinants of high intention to disclose concussion symptoms., Results: A total of 972 first-year military service academy cadets completed the survey [85% response; age=18.4±0.9y]. In the simple models, previous concussion history was associated with lower intention to disclose concussion symptoms. High perceived control over disclosure, higher concussion knowledge, more favorable attitudes and social norms about concussion were associated with high intention to disclose. In the multivariable model, a 10% shift towards more favorable perceived social norms (PR=1.28; p<0.001) and attitudes (PR=1.07; p=0.05) about concussion were associated with high intention to disclose concussion symptoms. High perceived control over disclosure was associated with high intention to disclose concussion symptoms (PR=1.39; p=0.08)., Conclusions: Concussion-related perceived social norms, attitudes, and perceived control are associated with intention to disclose. Organizationally appropriate intervention strategies can be developed from these data., (Copyright © 2018 Sports Medicine Australia. All rights reserved.)

Transnational exchanges have existed for centuries, with both economic and cultural effects. At the end of the 18 th century, in the aftermath of the French Revolution, medical education in France underwent radical innovations, prefiguring the training system now almost universally accepted. This paper presents 19 th and early 20 th century neurology-related exchanges between the United States (US) and Europe, particularly, Paris, which had become a major medical center and where many US neurologists were trained. We discuss some of the intense neurology-related exchanges between the USA and Europe, notably the role of US neurology founders William Alexander Hammond, Silas Weir Mitchell, Edward Seguin as well as Mauritius-born Charles Edouard Brown-Séquard and a few others. We emphasize the mutual benefits that resulted from such exchanges. In later years, the trend reversed with many foreigners, particularly Europeans coming to improve their knowledge in the US. More recently, a shared pattern of travel and enrichment is occurring despite current threats caused by isolationism and undue stress on local identity., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Formation of diet and physical activity habits begins during early childhood. However, many preschool-aged children in the United States do not achieve recommendations for a nutritious diet or active lifestyle. Two important spheres of influence, home and child care, could ensure that children receive consistent health messages. Innovative approaches that engage both parents and child care providers in a substantial way are needed. Social marketing, a promising approach for health promotion targeting children, uses principles that recognize the need to engage multiple stakeholders and to emphasize benefits and overcome barriers associated with behavior change. Yet, application of social marketing principles in interventions for preschool-age children is limited., Methods: Healthy Me, Healthy We (HMHW) is 2-arm, cluster randomized controlled trial to evaluate the effect of a 8-month social marketing campaign on the diet and physical activity behaviors of preschool children (3-4years old), their parents, and child care providers. The campaign is delivered by the child care center and includes branded classroom and at-home activities and materials. Primary outcomes are children's diet quality (assessed with Healthy Eating Index scores) and minutes of non-sedentary activity (measured via accelerometers). Secondary outcomes assess children's body mass index, nutrition and physical activity practices at the child care center and at home, and health behaviors of child care providers and parents., Conclusion: HMHW is an innovative approach to promoting healthy eating and physical activity in preschool children. The campaign targets children during a key developmental period and leverages a partnership between providers and parents to affect behavior change., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Exposure to airborne agents needs to be assessed in the personal breathing zone by the use of personal measurement equipment. Specific measurement devices for assessing personal exposure to airborne nanomaterials have only become available in the recent years. They can be differentiated into direct-reading personal monitors and personal samplers that collect the airborne nanomaterials for subsequent analyses. This article presents a review of the available personal monitors and samplers and summarizes the available literature regarding their accuracy, comparability and field applicability. Due to the novelty of the instruments, the number of published studies is still relatively low. Where applicable, literature data is therefore complemented with published and unpublished results from the recently finished nanoIndEx project. The presented data show that the samplers and monitors are robust and ready for field use with sufficient accuracy and comparability. However, several limitations apply, e.g. regarding the particle size range of the personal monitors and their in general lower accuracy and comparability compared with their stationary counterparts. The decision whether a personal monitor or a personal sampler shall be preferred depends strongly on the question to tackle. In many cases, a combination of a personal monitor and a personal sampler may be the best choice to obtain conclusive results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Personal monitors based on unipolar diffusion charging (miniDiSC/DiSCmini, NanoTracer, Partector) can be used to assess the individual exposure to nanoparticles in different environments. The charge acquired by the aerosol particles is nearly proportional to the particle diameter and, by coincidence, also nearly proportional to the alveolar lung-deposited surface area (LDSA), the metric reported by all three instruments. In addition, the miniDiSC/DiSCmini and the NanoTracer report particle number concentration and mean particle size. In view of their use for personal exposure studies, the comparability of these personal monitors was assessed in two measurement campaigns. Altogether 29 different polydisperse test aerosols were generated during the two campaigns, covering a large range of particle sizes, morphologies and concentrations. The data provided by the personal monitors were compared with those obtained from reference instruments: a scanning mobility particle sizer (SMPS) for LDSA and mean particle size and a ultrafine particle counter (UCPC) for number concentration. The results indicated that the LDSA concentrations and the mean particle sizes provided by all investigated instruments in this study were in the order of ±30% of the reference value obtained from the SMPS when the particle sizes of the test aerosols generated were within 20-400nm and the instruments were properly calibrated. Particle size, morphology and concentration did not have a major effect within the aforementioned limits. The comparability of the number concentrations was found to be slightly worse and in the range of ±50% of the reference value obtained from the UCPC. In addition, a minor effect of the particle morphology on the number concentration measurements was observed. The presence of particles >400nm can drastically bias the measurement results of all instruments and all metrics determined., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Social marketing is a promising planning approach for influencing voluntary lifestyle behaviours, but its application to nutrition and physical activity interventions in the early care and education setting remains unknown., Methods: PubMed, ISI Web of Science, PsycInfo and the Cumulative Index of Nursing and Allied Health were systematically searched to identify interventions targeting nutrition and/or physical activity behaviours of children enrolled in early care centres between 1994 and 2016. Content analysis methods were used to capture information reflecting eight social marketing benchmark criteria., Results: The review included 135 articles representing 77 interventions. Two interventions incorporated all eight benchmark criteria, but the majority included fewer than four. Each intervention included behaviour and methods mix criteria, and more than half identified audience segments. Only one-third of interventions incorporated customer orientation, theory, exchange and insight. Only six interventions addressed competing behaviours. We did not find statistical significance for the effectiveness of interventions on child-level diet, physical activity or anthropometric outcomes based on the number of benchmark criteria used., Conclusion: This review highlights opportunities to apply social marketing to obesity prevention interventions in early care centres. Social marketing could be an important strategy for early childhood obesity prevention efforts, and future research investigations into its effects are warranted., (© 2017 World Obesity Federation.)

Objectives: Particulate air pollution is linked to adverse cardiovascular effects. The aim of the study was to investigate the effect of short-term exposure to indoor particles on blood pressure (BP)., Methods: We analyzed the association of particle emissions from indoor sources (candle burning, toasting bread, frying sausages) with BP changes in 54 healthy volunteers in a randomized cross-over controlled exposure study. Particle mass concentration (PMC), size-specific particle number concentration (PNC) and lung-deposited particle surface area concentration (PSC) were measured during the 2h exposure. Systolic and diastolic blood pressure were measured before, during, directly, 2, 4 and 24h after exposure. We performed multiple mixed linear regression analyses of different particle metrics and BP., Results: BP significantly increased with increasing PMC, PSC and PNC resulting from toasting bread. For example, an increase per 10µg/m 3 PM 10 and PM 2.5 , systolic BP increased at all time points with largest changes 1h after exposure initiation of 1.5mmHg (95%-CI: 1.1; 1.9) and of 2.2mmHg (95%-CI: 1.3; 3.1), respectively., Conclusions: Our study suggests an association of short-term exposure to fine and ultrafine particles emitted from toasting bread with increases in BP. Particles emitted from frying sausages and candle burning did not consistently affect BP., (Copyright © 2017. Published by Elsevier Inc.)

Human γδ T cells comprise a first line of defense through T-cell receptor (TCR) recognition of stressed cells. However, the molecular determinants and stress pathways involved in this recognition are largely unknown. Here we show that exposure of tumor cells to various stress situations led to tumor cell recognition by a Vγ8Vδ3 TCR. Using a strategy that we previously developed to identify antigenic ligands of γδ TCRs, annexin A2 was identified as the direct ligand of Vγ8Vδ3 TCR, and was found to be expressed on tumor cells upon the stress situations tested in a reactive oxygen species-dependent manner. Moreover, purified annexin A2 was able to stimulate the proliferation of a Vδ2 neg γδ T-cell subset within peripheral blood mononuclear cells and other annexin A2-specific Vδ2 neg γδ T-cell clones could be derived from peripheral blood mononuclear cells. We thus propose membrane exposure of annexin A2 as an oxidative stress signal for some Vδ2 neg γδ T cells that could be involved in an adaptive stress surveillance.

For exposure and risk assessment in occupational settings involving engineered nanomaterials (ENMs), it is important to understand the mechanisms of release and how they are influenced by the ENM, the matrix material, and process characteristics. This review summarizes studies providing ENM release information in occupational settings, during different industrial activities and using various nanomaterials. It also assesses the contextual information - such as the amounts of materials handled, protective measures, and measurement strategies - to understand which release scenarios can result in exposure. High-energy processes such as synthesis, spraying, and machining were associated with the release of large numbers of predominantly small-sized particles. Low-energy processes, including laboratory handling, cleaning, and industrial bagging activities, usually resulted in slight or moderate releases of relatively large agglomerates. The present analysis suggests that process-based release potential can be ranked, thus helping to prioritize release assessments, which is useful for tiered exposure assessment approaches and for guiding the implementation of workplace safety strategies. The contextual information provided in the literature was often insufficient to directly link release to exposure. The studies that did allow an analysis suggested that significant worker exposure might mainly occur when engineering safeguards and personal protection strategies were not carried out as recommended., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=-0.68±0.28, p=0.029; replication cohort: β±SD=-0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (-61%; p<0.0001). The efflux process was almost abolished in cells expressing MRP4 rs11568658 variant protein. Molecular dynamic simulations of GCV membrane crossing showed a preferred location of the drug just beneath the polar head group region, which supports its interaction with efflux transporters., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Purpose: Glucocorticoids (GCs) are the mainstay treatment of myasthenia gravis (MG). However, wide inter-individual variability exists in the response to GCs., Methods: A Chinese cohort of 257 MG patients treated with GCs was evaluated for the association between 19 single nucleotide polymorphisms in the GR gene and clinical response to the initial 3 month GC therapy. A quantitative MG score decreasing by ≥3 units or becoming zero was defined as sensitivity to GCs., Results: The rs17209237* G allele was less frequent in the GC insensitive group compared with the GC sensitive group [P = 0.013, odds ratio (OR) 0.119]. The rs9324921* A allele was more frequent in the GC insensitive group than in the GC sensitive group (P = 0.046, OR 1.94). Carriers of the rs17209237 G allele were less frequent in the GC insensitive group than in the GC sensitive group (dominant model, P = 0.009). Carriers of the rs9324921 A allele were more frequent in the GC insensitive group than in the GC sensitive group (dominant model, P = 0.037). Multivariate logistic regression revealed that the rs17209237 G allele carrier (P = 0.037, OR 0.12) and disease duration before GC treatment (P = 0.011, OR 3.45) were independent factors that contributed to GC efficacy., Conclusion: rs17209237 in the GR gene was identified as an independent factor that contributes to GC efficacy in MG patients. The genetic variations of the GR gene may play a role in predicting response to GC treatment., (© 2016 EAN.)

Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and γδ T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late-onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R-). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2-negative (Vδ2(neg) ) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R- KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05-0.55; p = 0.01) and shorter anti-CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2(neg) γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R- KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Cytomegalovirus (CMV) is the major opportunistic virus encountered after transplantation, and resistant variants challenge antiviral treatment. We studied the emergence and evolution of the canonical UL97 L595S mutation in four kidney recipients by comparing Sanger sequencing with a specific next-generation sequencing (NGS) assay, and assessed the global evolution of UL97 gene variability., Study Design: Plasmids harbouring wild-type and/or L595S mutated UL97 genes were used to assess the analytical performances of NGS assay. UL97 gene was retrospectively analysed in patients' samples drawn during CMV infection follow-up, Shannon entropy (Sn) was calculated and phylogenetic analyses were performed., Results: Wild-type and L595S plasmids PCR products were mixed to obtain L595S concentrations of 0, 1, 2, 5, 10, 20 and 100%. Mean triplicate NGS results were 0, 0.71, 1.79, 5.30, 13.17, 17 and 100%, respectively, while Sanger sequencing only detected L595S when above 20%. The NGS mean error rate was 0.196±0.07%. In the four patients, emergence of L595S mutation under ganciclovir treatment was followed-up. After foscarnet rescue therapy, leading to undetectable CMV viral load, in two patients, L595S mutant re-emerged, but was only detected by NGS technology (14% and 9.6%). Using NGS data, phylogenetic trees and Sn showed a complex evolution of concomitant viral subpopulations., Conclusions: NGS technology allowed a deeper discrimination of the emergence and persistence of a drug resistance mutation, which could be pertinent to investigate when routine Sanger sequencing detects only wild-type strains. Moreover, NGS improved sensitivity helps in studying viral abundance, dynamics and diversity, less approachable with Sanger sequencing., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Cytomegalovirus (CMV) infection in solid-organ transplantation is associated with increased morbidity and mortality, particularly if a CMV mutant strain with antiviral resistance emerges. Monitoring CMV-specific T cell response could provide relevant information for patient care. We and others have shown the involvement of Vδ2(neg) γδ T cells in controlling CMV infection. Here, we assessed if Vδ2(neg) γδ T cell kinetics in peripheral blood predict CMV infection resolution and emergence of a mutant strain in high-risk recipients of kidney transplants, including 168 seronegative recipients receiving organs from seropositive donors (D+R-) and 104 seropositive recipients receiving antithymocyte globulins (R+/ATG). Vδ2(neg) γδ T cell percentages were serially determined in patients grafted between 2003 and 2011. The growing phase of Vδ2(neg) γδ T cells was monitored in each infected patient, and the expansion rate during this phase was estimated individually by a linear mixed model. A Vδ2(neg) γδ T cell expansion rate of ˃0.06% per day predicted the growing phase. The time after infection at which an expansion rate of 0.06% per day occurred was correlated with the resolution of CMV DNAemia (r=0.91; P<0.001). At 49 days of antiviral treatment, Vδ2(neg) γδ T cell expansion onset was associated with recovery, whereas absence of expansion was associated with recurrent disease and DNAemia. The appearance of antiviral-resistant mutant CMV strains was associated with delayed Vδ2(neg) γδ T cell expansion (P<0.001). In conclusion, longitudinal surveillance of Vδ2(neg) γδ T cells in recipients of kidney transplants may predict CMV infection resolution and antiviral drug resistance., (Copyright © 2016 by the American Society of Nephrology.)

Cytomegalovirus infection in kidney transplantation is associated with increased morbidity and mortality through direct and indirect effects. International guidelines had been recently updated, focusing on diagnostic, prevention strategies and curative treatment. Cytomegalovirus-specific immune response plays also an important function in controlling the virus. Here, we propose to present the different components of this specific immune response and the advantages of immune monitoring for patient's management: identification of patients who require a treatment, adaptation of curative treatment length, guidance for resistance genotypic testing., (Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Introduction: To address alarming rates of youth obesity, multiple stakeholder perspectives must be understood and considered when developing nutrition interventions. The purpose of this qualitative study was to examine adults' perceptions of school food in rural North Carolina and their opinions about potential changes to encourage students to eat more fruits and vegetables in school meals., Methods: We conducted semistructured key informant interviews by telephone from February through March 2013 to determine adult opinions regarding elementary school food and child health. Participants included parents, teachers, school administrators, and a cafeteria staff member. Interview transcripts were thematically analyzed using Dedoose qualitative analysis software., Results: Four themes emerged from key informant interviews regarding school meals and increasing fruit and vegetable consumption: 1) schools are an appropriate place for nutritious food, 2) current school food is bland and unappealing, 3) school cafeterias can use simple strategies to increase fruit and vegetable intake, and 4) federal school meal guidelines are perceived as barriers to increased fruit and vegetable intake during school meals., Conclusion: Study findings suggest that training and support for cafeteria staff on healthy food preparation and presentation are critical and that there should be a "meeting in the middle" between child appeal and health. Nutritious and appealing school food options may have the potential to greatly increase fruit and vegetable consumption in rural elementary schools in North Carolina.

Particulate air pollution is linked to impaired respiratory health. We analyzed particle emissions from common indoor sources (candles burning (CB), toasting bread (TB), frying sausages (FS)) and lung function in 55 healthy volunteers (mean age 33.0 years) in a randomized cross-over controlled exposure study. Lung-deposited particle surface area concentration (PSC), size-specific particle number concentration (PNC) up to 10 µm, and particle mass concentration (PMC) of PM1, PM2.5 and PM10 were determined during exposure (2 h). FEV1, FVC and MEF25%-75% was measured before, 4 h and 24 h after exposure. Wilcoxon-rank sum tests (comparing exposure scenarios) and mixed linear regression using particle concentrations and adjusting for personal characteristics, travel time and transportation means before exposure sessions were performed. While no effect was seen comparing the exposure scenarios and in the unadjusted model, inverse associations were found for PMC from CB and FS in relation to FEV1 and MEF25%-75%. with a change in 10 µg/m3 in PM2.5 from CB being associated with a change in FEV1 of -19 mL (95%-confidence interval:-43; 5) after 4 h. PMC from TB and PNC of UFP were not associated with lung function changes, but PSC from CB was. Elevated indoor fine particles from certain sources may be associated with small decreases in lung function in healthy adults.

Maribavir (MBV), a UL97 inhibitor, shows good oral bioavailability, low host cell toxicity, and theoretical benefits to inhibit cross-resistant viruses. We herein examined clinical and virological outcomes of 12 patients, including 3 bone marrow recipients and 9 organ recipients infected with resistant cytomegalovirus (CMV) and treated with MBV during 2011-2012. All received at least 800-mg daily doses. They had developed clinical (12/12) and/or virological (11/12) resistance to CMV infection. Based on a decrease of viral load in blood >1.5 log copies/mL half of them responded to MBV treatment. The individual changes varied from a rapid decrease in viral load (n = 4) to no response (n = 3) with some late response slowly decreasing viremia (n = 3). In 2 cases MBV was used as secondary prophylaxis. No clear parameter emerged as a clinical surrogate for nonresponse to MBV. These results contrast with the lack of efficacy in phase III trials of MBV prophylaxis among stem cell recipients, which were possibly due to low doses or inadequate timing of drug initiation in the study. Additional clinical and surrogate laboratory markers are needed to determine antiviral responses to guide MBV use. Dosage ranging studies might benefit future MBV use., (Copyright © 2013. Published by Elsevier Inc.)

Aim: In the present study, we aimed to elucidate the effects of chronic vasopressin administration on renal medullary oxygen levels., Methods: Adult Sprague Dawley or vasopressin-deficient Brattleboro rats were treated with the vasopressin V2 receptor agonist, desmopressin (5 ng/h; 3d), or its vehicle via osmotic minipumps. Immunostaining for pimonidazole and the transcription factor HIF-1α (hypoxia-inducible factor-1α) were used to identify hypoxic areas. Activation of HIF-target gene expression following desmopressin treatment was studied by microarray analysis., Results: Pimonidazole staining was detected in the outer and inner medulla of desmopressin-treated rats, whereas staining in control animals was weak or absent. HIF-1α immunostaining demonstrated nuclear accumulation in the papilla of desmopressin-treated animals, whereas no staining was observed in the controls. Gene expression analysis revealed significant enrichment of HIF-target genes in the group of desmopressin-regulated gene products (P = 2.6*10(-21) ). Regulated products included insulin-like growth factor binding proteins 1 and 3, angiopoietin 2, fibronectin, cathepsin D, hexokinase 2 and cyclooxygenase 2., Conclusion: Our results demonstrate that an activation of the renal urine concentrating mechanism by desmopressin causes renal medullary hypoxia and an upregulation of hypoxia-inducible gene expression., (Acta Physiologica © 2013 Scandinavian Physiological Society.)