mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αß and γδ T cells in Kidney Transplantation.

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 αß 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+ αß 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 IFNγ-producing and cytotoxic αß T cells. In vitro, mTORis increased proliferation, viability, and CMV-induced IFNγ production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMESlow Hobithigh 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.

Incidence of cytomegalovirus infection in seropositive kidney transplant recipients treated with everolimus: A randomized, open-label, multicenter phase 4 trial.

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.

Effects of a Mindfulness-Based Intervention versus Health Self-Management on Subclinical Anxiety in Older Adults with Subjective Cognitive Decline: The SCD-Well Randomized Superiority Trial.

INTRODUCTION: Older adults experiencing subjective cognitive decline (SCD) have a heightened risk of developing dementia and frequently experience subclinical anxiety, which is itself associated with dementia risk. OBJECTIVE: To understand whether subclinical anxiety symptoms in SCD can be reduced through behavioral interventions. METHODS: SCD-Well is a randomized controlled trial designed to determine whether an 8-week mindfulness-based intervention (caring mindfulness-based approach for seniors; CMBAS) is superior to a structurally matched health self-management program (HSMP) in reducing subclinical anxiety. Participants were recruited from memory clinics at 4 European sites. The primary outcome was change in anxiety symptoms (trait subscale of the State-Trait Anxiety Inventory; trait-STAI) from pre- to postintervention. Secondary outcomes included a change in state anxiety and depression symptoms postintervention and 6 months postrandomization (follow-up). RESULTS: One hundred forty-seven participants (mean [SD] age: 72.7 [6.9] years; 64.6% women; CMBAS, n = 73; HSMP, n = 74) were included in the intention-to-treat analysis. There was no difference in trait-STAI between groups postintervention (adjusted change difference: -1.25 points; 95% CI -4.76 to 2.25) or at follow-up (adjusted change difference: -0.43 points; 95% CI -2.92 to 2.07). Trait-STAI decreased postintervention in both groups (CMBAS: -3.43 points; 95% CI -5.27 to -1.59; HSMP: -2.29 points; 95% CI -4.14 to -0.44) and reductions were maintained at follow-up. No between-group differences were observed for change in state anxiety or depression symptoms. CONCLUSIONS: A time-limited mindfulness intervention is not superior to health self-management in reducing subclinical anxiety symptoms in SCD. The sustained reduction observed across both groups suggests that subclinical anxiety symptoms in SCD are modifiable. ClinicalTrials.gov identifier: NCT03005652.

Impacts of three inspiratory muscle training programs on inspiratory muscles strength and endurance among intubated and mechanically ventilated patients with difficult weaning: a multicentre randomised controlled trial.

BACKGROUND: Inspiratory muscle training (IMT) is well-established as a safe option for combating inspiratory muscles weakness in the intensive care setting. It could improve inspiratory muscle strength and decrease weaning duration but a lack of knowledge on the optimal training regimen raise to inconsistent results. We made the hypothesis that an innovative mixed intensity program for both endurance and strength improvement could be more effective. We conducted a multicentre randomised controlled parallel trial comparing the impacts of three IMT protocols (low, high, and mixed intensity) on inspiratory muscle strength and endurance among difficult-to-wean patients. METHODS: Ninety-two patients were randomly assigned to three groups with different training programs, where each performed an IMT program twice daily, 7 days per week, from inclusion until successful extubation or 30 days. The primary outcome was maximal inspiratory pressure (MIP) increase. Secondary outcomes included peak pressure (Ppk) increase as an endurance marker, mechanical ventilation (MV) duration, ICU length of stay, weaning success defined by a 2-day ventilator-free after extubation, reintubation rate and safety. RESULTS: MIP increases were 10.8 ± 11.9 cmH2O, 4.5 ± 14.8 cmH2O, and 6.7 ± 14.5 cmH2O for the mixed intensity (MI), low intensity (LI), and high intensity (HI) groups, respectively. There was a non-statistically difference between the MI and LI groups (mean adjusted difference: 6.59, 97.5% CI [- 14.36; 1.18], p = 0.056); there was no difference between the MI and HI groups (mean adjusted difference: - 3.52, 97.5% CI [- 11.57; 4.53], p = 0.321). No significant differences in Ppk increase were observed among the three groups. Weaning success rate observed in MI, HI and LI group were 83.7% [95% CI 69.3; 93.2], 82.6% [95% CI 61.2; 95.0] and 73.9% [95% CI 51.6; 89.8], respectively. MV duration, ICU length of stay and reintubation rate had similar values. Over 629 IMT sessions, six adverse events including four spontaneously reversible bradycardia in LI group were possibly related to the study. CONCLUSIONS: Among difficult-to-wean patients receiving invasive MV, no statistically difference was observed in strength and endurance progression across three different IMT programs. IMT appears to be feasible in usual cares, but some serious adverse events such as bradycardia could motivate further research on the specific impact on cardiac system. Trial registration Clinicaltrials.gov identifier: NCT02855619. Registered 28 September 2014.