Structural and functional analysis of Ccr1l1, a Rodentia-restricted eosinophil-selective chemokine receptor homologue.

Mouse Ccr1l1 (Ccr1-like 1) encodes an orphan G-protein-coupled receptor (GPCR) with the highest homology to the inflammatory and highly promiscuous chemokine receptors Ccr1 and Ccr3 (70 and 50% amino acid identity, respectively). Ccr1l1 was first cloned in 1995, yet current knowledge of this putative chemokine receptor is limited to its gene organization and chromosomal localization. Here we report that Ccr1l1 is a Rodentia-specific gene selectively expressed in eosinophils. However, eosinophil phenotypes, development, and responsiveness to chemokines were all normal in naïve Ccr1l1 knockout mice. We demonstrate for the first time that recombinant Ccr1l1 is expressed on the plasma membrane of transfected cells and contains an extracellular N terminus and an intracellular C terminus, consistent with GPCR topology. Using receptor internalization, ß-arrestin recruitment, calcium flux, and chemotaxis assays, we excluded all 37 available mouse chemokines, including Ccr1 ligands, and two viral chemokines as Ccr1l1 ligands, and demonstrated that mouse Ccr1, but not Ccr1l1, exhibits constitutive signaling activity. However, sequence analysis and structural modeling revealed that Ccr1l1 is well equipped to act as a classical signaling GPCR, with N-terminal sulfotyrosines as the only signaling and chemokine-binding determinant absent in Ccr1l1. Hereof, we show that a sulfatable N-terminal Ccr1 Y18 residue is essential for chemotaxis and calcium responses induced by Ccl3 and Ccl9/10, but substituting the corresponding Ccr1l1 F19 residue with tyrosine failed to confer responsiveness to Ccr1 ligands. Although Ccr1l1 remains an extreme outlier in the chemokine receptor family, our study supports that it might respond to unidentified mouse chemokine ligands in eosinophil-driven immune responses.

Public Attitudes and Knowledge About Youth Sports Participation and Concussion Risk in an Urban Area.

BACKGROUND: Every year, millions of children in the United States participate in youth full-contact sports, which carry concussion risks-the long-term sequelae of which are not well understood. We examined the attitudes and knowledge of adults in Chicago about youth sports participation, concussion risk, and whether physicians should counsel against youth participation in full-contact sports. METHODS: An anonymous paper survey featuring 13 attitudinal, 13 demographic, and 9 knowledge questions was distributed to a convenience sample of adults ≥18 years in hospital waiting areas and four Chicago parks. Participants were asked to hypothetically consider themselves the parent of a 10-year-old child regarding attitudes towards full-contact sports participation. RESULTS: Between June 13 and July 27, 2016, 1091 partial or complete valid surveys were collected. Almost half (46%) of respondents would not allow a hypothetical 10-year-old son to play tackle football. The majority (74%) of respondents agreed that it was appropriate for physicians to counsel against youth participation in full-contact sports. Respondents obtained information about concussions from, on average, 2-3 sources, although only 34% received information from physicians. Respondents demonstrated a high concussion knowledge level (average: 6.75 of 9 questions). However, only 39% of respondents correctly answered that the following statement was false: "After a mild concussion, there are usually visible changes on medical imaging". CONCLUSIONS: Overall, respondents are well-informed about concussions. They are divided about the participation of youth in full-contact sports and are amenable to physician counseling against youth participation in full-contact sports.

Attitudes and Counseling Practices of Pediatricians Regarding Youth Sports Participation and Concussion Risks.

OBJECTIVE: To examine attitudes and practices of pediatricians toward sports-related head trauma and youth participation in tackle football and ice hockey. STUDY DESIGN: A respondent-anonymous electronic survey was distributed 3 times to members of the American Academy of Pediatrics Section of Bioethics, Council on Injury, Violence, and Poison Prevention, and Council on Sports Medicine and Fitness. RESULTS: Of 791 eligible pediatricians, 227 (29%) responded. Most respondents (189/223; 85%) treat sports-related concussions, among whom 83% (137/165) reported access to an established return-to-play protocol within their practice. Virtually all (160/166; 96%) reported increased parental awareness/concern regarding concussions and 85% (139/163) reported increased visits for head trauma. Overall, 77% (140/183) would not allow their son to play tackle football and 35% (64/181) and 34% (63/184) would not allow their son or daughter, respectively, to participate in ice hockey. Most respondents endorsed limiting or eliminating tackling (143/176; 81%) and checking (144/179; 80%) from practice. Respondents were evenly divided in their support for counseling against youth participation in full-contact sports, with 48% in favor (87/180). CONCLUSIONS: Most respondents would not allow their own child to play tackle football and endorsed limiting or eliminating tackling in practice. The American Academy of Pediatrics should consider recommending restrictions on tackling in football to support the current concussion concerns of its members.

Central Nervous System Relapse in T and NK cell Lymphomas.

PURPOSE OF REVIEW: T and NK cell lymphomas are relatively rare and heterogeneous forms of non-Hodgkin lymphoma that are associated with high rates of mortality. Central nervous system relapse carries significant morbidity, though management is largely extrapolated from literature in B cell neoplasms. As such, outcomes for central nervous system involvement in T/NK cell lymphomas are dismal with no standard of care. In this review, we discuss the epidemiology of central nervous system relapse in T/NK cell lymphomas and critically analyze available literature regarding prophylaxis and treatment. RECENT FINDINGS: Retrospective studies of central nervous system involvement in T/NK cell lymphomas have been limited by small sample sizes and heterogeneity of subtypes, though sites of extranodal involvement and disease subtypes are consistently reported as risk factors. Compelling evidence for the use of central nervous system-directed prophylactic therapy has not yet been established, though recent reports of central nervous system activity with novel agents may suggest promising therapeutic options. The overall rarity of T and NK cell lymphomas has precluded adequate study of prophylaxis and treatment of central nervous system relapse. Collaborative efforts are needed to better define strategies to address CNS disease in T/NK cell lymphomas. These should involve the use of targeted agents, which may hold an advantage over traditional cytotoxic drugs.

Interim Positron Emission Tomography During Frontline Chemoimmunotherapy for Follicular Lymphoma.

While most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population. We retrospectively identified 128 patients with grade 1-3A FL who had an interim PET after 2-4 cycles of frontline CIT at 2 academic centers. PET scans were analyzed using Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Interim PET DS was a significant predictor of PFS (P < 0.003). Patients with a DS of 3 had outcomes similar to those of patients with a DS of 4, so were categorized as PET-positive for additional analyses. Interim PET remained a strong predictor of PFS (DS 3-5, hazard ratio [HR] 2.4, P = 0.006) in a multivariable analysis and was also an early predictor of both a positive end-of-treatment PET (P < 0.001) and progression of disease within 24 months (POD24) (P = 0.006). An optimal ΔSUVmax cutoff of 75% was selected using the bootstrap method. ΔSUVmax <75% was also a significant predictor of PFS on univariable and multivariable analyses (HR 2.8, P < 0.003). In a separate cohort of 50 patients with high-grade FL, interim PET interpreted using either DS (P < 0.001) or ΔSUVmax75% (P = 0.034) was also a significant predictor of inferior PFS. In conclusion, interim PET is an independent predictor of PFS and may be useful as a tool for response-adapted treatment strategies in FL.

Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P < .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P < .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.

Prognostic value of minimal residual disease among patients with classical Hodgkin lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated.

Failure of a vagus nerve stimulator following a nearby lightning strike.

We recently reported our experience with implanted vagus nerve stimulators (VNS) in 62 children over a 7-year period. Here, we present a case of a VNS that successfully reduced the number and severity of seizures in a patient with an unusual seizure pattern, and failed to function shortly after a lightning storm. To our knowledge, the failure of VNS or any implantable electrical devices by lightning has not been reported in the literature. This mechanism of electrical interference, while unusual, may require more attention as these devices are expected to be used more frequently.

Genetic Testing by Sports Medicine Physicians in the United States: Attitudes, Experiences, and Knowledge.

It remains unknown whether and how sports medicine physicians currently utilize genetic testing in their clinical practice. This study sought to assess knowledge of, experience with, and attitudes towards genetic testing by sports medicine physicians in the United States (US). An email with a survey hyperlink was distributed twice to members of the American Medical Society for Sports Medicine (AMSSM) listserv in September 2016, with approximately a 10% response rate. Questions focused on knowledge of, experience with, and attitudes towards testing for different genes related to sports proficiency, injury risk, and disease risk. Few AMSSM physicians believe that genetic testing to adapt training (12%) or to choose a sport (2%) is ready for clinical adoption. Most respondents self-reported minimal knowledge about, and limited experience with, genetic testing. The main exception was screening for sickle cell trait (SCT) for which most (84%) reported moderate/significant/expert knowledge and over two-thirds had ordered testing. Although most respondents thought it appropriate to counsel and test for health conditions associated with cardiac and connective tissue disorders in the setting of a positive family history, only a minority had been asked to do so. Five or fewer respondents (2%) had been asked to test for performance-associated variants (Angiotensin Converting Enzyme (ACE) II and Alpha-Actinin 3 (ACTN3)), and five or fewer (2%) would recommend changes based on the results. Our study provides a baseline of current US sports medicine physicians' minimal experiences with, and knowledge of, genetic testing. The findings of our study indicate that sports medicine physicians require further genetics education as it relates to sports and exercise in order to be prepared to competently engage with their patients and to develop sound professional organizational policies.