PD1 inhibits PKCθ-dependent phosphorylation of cytoskeleton-related proteins and immune synapse formation.

ABSTRACT: The inhibitory surface receptor programmed cell death protein 1 (PD1) is a major target for antibody-based cancer immunotherapies. Nevertheless, a substantial number of patients fail to respond to the treatment or experience adverse effects. An improved understanding of intracellular pathways targeted by PD1 is thus needed to develop better predictive and prognostic biomarkers. Here, via unbiased phosphoproteome analysis of primary human T cells, we demonstrate that PD1 triggering inhibited the phosphorylation and physical association with protein kinase Cθ (PKCθ) of a variety of cytoskeleton-related proteins. PD1 blocked activation and recruitment of PKCθ to the forming immune synapse (IS) in a Src homology-2 domain-containing phosphatase-1/2 (SHP1/SHP2)-dependent manner. Consequently, PD1 engagement led to impaired synaptic phosphorylation of cytoskeleton-related proteins and formation of smaller IS. T-cell receptor induced phosphorylation of the PKCθ substrate and binding partner vimentin was long-lasting and it could be durably inhibited by PD1 triggering. Vimentin phosphorylation in intratumoral T cells also inversely correlated with the levels of the PD1 ligand, PDL1, in human lung carcinoma. Thus, PKCθ and its substrate vimentin represent important targets of PD1-mediated T-cell inhibition, and low levels of vimentin phosphorylation may serve as a biomarker for the activation of the PD1 pathway.

Brain Metabolite Levels in Sedentary Women and Non-contact Athletes Differ From Contact Athletes.

White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy (MRS) in the prefrontal white matter at the beginning (In-Season) and end (Off-Season) of season in contact (N = 54, rugby players) and non-contact (N = 23, swimmers and rowers) varsity athletes. Sedentary women (N = 23) were scanned once, at a time equivalent to the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline.

Longitudinal changes of brain microstructure and function in nonconcussed female rugby players.

OBJECTIVE: To longitudinally assess brain microstructure and function in female varsity athletes participating in contact and noncontact sports. METHODS: Concussion-free female rugby players (n = 73) were compared to age-matched (ages 18-23) female swimmers and rowers (n = 31) during the in- and off-season. Diffusion and resting-state fMRI (rs-fMRI) measures were the primary outcomes. The Sports Concussion Assessment Tool and head impact accelerometers were used to monitor symptoms and impacts, respectively. RESULTS: We found cross-sectional (contact vs noncontact) and longitudinal (in- vs off-season) changes in white matter diffusion measures and rs-fMRI network connectivity in concussion-free contact athletes relative to noncontact athletes. In particular, mean, axial, and radial diffusivities were increased with decreased fractional anisotropy in multiple white matter tracts of contact athletes accompanied with default mode and visual network hyperconnectivity (p < 0.001). Longitudinal diffusion changes in the brainstem between the in- and off-season were observed for concussion-free contact athletes only, with progressive changes observed in a subset of athletes over multiple seasons. Axial diffusivity was significantly lower in the genu and splenium of the corpus callosum in those contact athletes with a history of concussion. CONCLUSIONS: Together, these findings demonstrate longitudinal changes in the microstructure and function of the brain in otherwise healthy, asymptomatic athletes participating in contact sport. Further research to understand the long-term brain health and biological implications of these changes is required, in particular to what extent these changes reflect compensatory, reparative, or degenerative processes.

Methylnaltrexone-Associated Bowel Perforation in Postoperative Opioid-Induced Constipation and Ogilvie Syndrome: A Case Report.

Pain management with opioids is often limited by medication side effects. One of the most common and distressing side effects is opioid-induced constipation (OIC), a syndrome that is now getting significant national attention. We report the case of an opioid-dependent 56-year-old man who underwent lumbar decompression for spinal stenosis. Postoperatively, he developed OIC and Ogilvie syndrome, then following treatment with methylnaltrexone experienced an acute bowel perforation. We briefly review the recommended management of OIC as well as indications and contraindications of methylnaltrexone and similar new medications.

Linked MRI signatures of the brain's acute and persistent response to concussion in female varsity rugby players.

Acute brain changes are expected after concussion, yet there is growing evidence of persistent abnormalities well beyond clinical recovery and clearance to return to play. Multiparametric MRI is a powerful approach to non-invasively study structure-function relationships in the brain, however it remains challenging to interpret the complex and heterogeneous cascade of brain changes that manifest after concussion. Emerging conjunctive, data-driven analysis approaches like linked independent component analysis can integrate structural and functional imaging data to produce linked components that describe the shared inter-subject variance across images. These linked components not only offer the potential of a more comprehensive understanding of the underlying neurobiology of concussion, but can also provide reliable information at the level of an individual athlete. In this study, we analyzed resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) within a cohort of female varsity rugby players (n = 52) through the in- and off-season, including concussed athletes (n = 21) who were studied longitudinally at three days, three months and six months after a diagnosed concussion. Linked components representing co-varying white matter microstructure and functional network connectivity characterized (a) the brain's acute response to concussion and (b) persistent alterations beyond clinical recovery. Furthermore, we demonstrate that these long-term brain changes related to specific aspects of a concussion history and allowed us to monitor individual athletes before and longitudinally after a diagnosed concussion.

Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.

The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.

The Association of Age With Short-Term and Long-Term Mortality in Adults Admitted to the Intensive Care Unit.

BACKGROUND: Based on the current literature, it is unclear whether advanced age itself leads to higher mortality in critically ill patients or whether it is due to the greater number of comorbidities in the elderly patients. We hypothesized that increasing age would increase the odds of short-term and long-term mortality after adjusting for baseline comorbidities in intensive care unit (ICU) patients. METHODS: We performed a retrospective cohort study of 57 160 adults admitted to any ICU over 5 years at 2 academic tertiary care centers. Patients were divided into age-groups, 18 to 39, 40 to 59, 60 to 79, and ≥80. The primary outcomes were 30-day and 365-day mortality. Results were analyzed with multivariate logistic regression adjusting for demographics and the Elixhauser-van Walraven Comorbidity Index. RESULTS: The adjusted 30-day mortality odds ratios (ORs) were 1.39 (95% confidence interval [CI]: 1.21-1.60), 2.00 (95% CI: 1.75-2.28), and 3.33 (95% CI: 2.90-3.82) for age-groups 40 to 59, 60 to 79, and ≥80, respectively, using the age-group 18 to 39 as the reference. The adjusted 365-day mortality ORs were 1.46 (95% CI: 1.32-1.61), 2.10 (95% CI: 1.91-2.31), and 2.96 (95% CI: 2.67-3.27). CONCLUSION: In critically ill patients, increasing age is associated with higher odds of short-term and long-term death after correcting for existing comorbidities.

The Anesthetic Implications of Aqueous Drainage Devices and Glaucoma: A Report of a Patient Undergoing Urgent Prone Cervical Decompression and Fusion.

The pathophysiology of glaucoma and perioperative visual loss is similar. A patient with glaucoma may be at increased risk of perioperative visual loss. For both, goals of management include optimizing ocular perfusion pressure and oxygen delivery. One treatment for refractory glaucoma is an aqueous drainage device; however, there is no published literature on the anesthetic management of patients with these devices. We present the case of a patient with recalcitrant glaucoma treated with an Ahmed Glaucoma Valve who underwent urgent prone surgery. Anesthetic implications of aqueous drainage devices and glaucoma are discussed, and recommendations are made.