Citations

Abstract Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. In this article, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L mAb (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD model in both preventative and therapeutic modes. Mechanistically, blocking OX40L–OX40 interaction with an anti-hOX40L reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21– and TNF-producing T cell responses while promoting regulatory T cell responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L–OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L–OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.

BackgroundThe 3D breast magnetic resonance fingerprinting (MRF) technique enables T1 and T2 mapping in breast tissues. Combined repeatability and reproducibility studies on breast T1 and T2 relaxometry are lacking.PurposeTo assess test–retest and two‐visit repeatability and interscanner reproducibility of the 3D breast MRF technique in a single‐institution setting.Study TypeProspective.SubjectsEighteen women (median age 29 years, range, 22–33 years) underwent Visit 1 scans on scanner 1. Ten of these women underwent test–retest scan repositioning after a 10‐minute interval. Thirteen women had Visit 2 scans within 7–15 days in same menstrual cycle. The remaining five women had Visit 2 scans in the same menstrual phase in next menstrual cycle. Five women were also scanned on scanner 2 at both visits for interscanner reproducibility.Field Strength/SequenceTwo 3T MR scanners with the 3D breast MRF technique.AssessmentT1 and T2 MRF maps of both breasts.Statistical TestsMean T1 and T2 values for normal fibroglandular tissues were quantified at all scans. For variability, between and within‐subjects coefficients of variation (bCV and wCV, respectively) were assessed. Repeatability was assessed with Bland–Altman analysis and coefficient of repeatability (CR). Reproducibility was assessed with interscanner coefficient of variation (CoV) and Wilcoxon signed‐rank test.ResultsThe bCV at test–retest scans was 9–12% for T1, 7–17% for T2, wCV was <4% for T1, and <7% for T2. For two visits in same menstrual cycle, bCV was 10–15% for T1, 13–17% for T2, wCV was <7% for T1 and <5% for T2. For two visits in the same menstrual phase, bCV was 6–14% for T1, 15–18% for T2, wCV was <7% for T1, and <9% for T2. For test–retest scans, CR for T1 and T2 were 130 msec and 11 msec. For two visit scans, CR was <290 msec for T1 and 10–14 msec for T2. Interscanner CoV was 3.3–3.6% for T1 and 5.1–6.6% for T2, with no differences between interscanner measurements (P = 1.00 for T1, P = 0.344 for T2).Data Conclusion3D breast MRF measurements are repeatable across scan timings and scanners and may be useful in clinical applications in breast imaging.Level of Evidence: 2Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2019;50:1133–1143.

Acute‐on‐chronic liver failure (ACLF) is characterized by multiple organ failure (OF) with high short‐term mortality. There is lack of population‐based data on trends on etiology specific ACLF related burden. National Inpatient Sample (2006‐2014) was queried using ICD‐09 codes for admissions with cirrhosis and ACLF (≥2 extrahepatic OF). Of 1,928,764 admissions for cirrhosis between 2006 and 2014, 112,174 (5.9%) had ACLF (4.5%, 1.2%, and 0.2% with ACLF 1, 2, and 3, respectively). The brain was the most common OF in 11.9%, followed by respiratory failure in 7.7%, cardiac failure in 6.3%, and renal failure in 5.6%. ACLF increased by 24% between 2006 and 2014 with a 63% increase in 179,104 patients with nonalcoholic steatohepatitis (NASH) cirrhosis (3.5% to 5.7%); a 28% increase in patients with 429,306 alcoholic cirrhosis (5.6% to 7.2%); a 25% increase in patients with 1,091,053 with other etiologies (5.2% to 6.5%); and no significant change in 229,301 patients with viral hepatitis (VH) (4.0% to 4.1%). In‐hospital mortality was higher among ACLF patients compared with patients without ACLF (44% versus 4.7%; P < 0.0001). Each NASH‐related ACLF patient compared with other etiologies had a longer mean length of stay (14 versus 12 days), was associated with higher median total charges (US $151,196 versus US $134,597), and had more frequent use of dialysis (45% versus 36%) and longterm care (32% versus 26%; P < 0.0001 for all). Results remained similar in a subgroup analysis after including half of admissions with cryptogenic cirrhosis as NASH. In conclusion, NASH cirrhosis is the most rapidly growing indication for ACLF‐related hospitalization and use of hospital resources. In the setting of improved treatment options for chronic hepatitis, the health care burden of chronic viral‐related liver disease remains stable. Population‐based strategies are needed to reduce the health care burden of cirrhosis, particularly related to NASH.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

AbstractBackgroundLeadless cardiac pacing (LCP) has emerged as a new modality for permanent pacing. We sought to describe comparative outcomes between LCP and transvenous pacemakers.MethodsPatients receiving LCP (Micra [Medtronic, Minneapolis, MN, USA] and Nanostim [St. Jude Medical/Abbott Laboratories, Chicago, IL, USA]) between 2014 and 2017 at the Mayo Clinic Heart Rhythm Enterprise practice (Rochester, MN, USA; Jacksonville, FL, USA; and Scottsdale, AZ, USA) were identified. We identified 1:1 age‐ and sex‐matched controls receiving single‐chamber transvenous ventricular pacemakers (TVP). Statistical analyses were performed with JMP 13.0.0 (SAS, Institute Cary, NC, USA).ResultsNinety patients underwent LCP implantation (73 Micra and 17 Nanostim) with a median follow‐up duration of 62 (interquartile range 28‐169) days. Both groups had 100% successful device implant rates. There were no differences in procedure‐related major (0% vs 1%) or minor complications (8% vs 3%) in the LCP versus TVP groups (P > 0.05). Excluding Nanostim patients, there was a lower rate of device‐related revision or extraction in the Micra versus TVP groups (0% vs 5%, P = 0.028). Device endocarditis was more common in the TVP group (0% vs 3%, P = 0.04). Estimated longevity was greater for the LCP group (median 12.0 vs 10.0 years, P < 0.0001). An increase in severity of tricuspid valve regurgitation (TR) by ≥2 grades occurred in none of the LCP patients, and in 19% of the TVP patients (P = 0.017).ConclusionThere are no significant differences in procedural complications among patients receiving LCP versus TVP. The Micra group had lower rates of device‐related revision/extraction compared to the TVP group. Patients with leadless pacemaker were less likely to develop endocarditis or worsening TR.