Citations

The lymphocyte crossmatch is currently the only cell‐based compatibility assay performed by histocompatibility laboratories for transplant purposes. While in many transplant programs the complement‐dependent cytotoxicity crossmatch (CDCXM) remains in use, when available, the flow cytometry crossmatch (FCXM) is the method of choice because of its superior sensitivity and specificity. Unfortunately, the maintenance and cost of a flow cytometer is a considerable limitation for small histocompatibility laboratories. Therefore, in this study, we evaluated the use of the Cellometer Vision CBA image cytometer (Nexcelom Bioscience LLC, Lawrence, Massachusetts) as an alternative instrument to perform the crossmatch assay. The 3‐color FCXM protocol was modified into two separate 2‐color panel image cytometry crossmatches (IXMs), one for T cells and one for B cells. After initial serum and cell incubation, a cocktail consisting of PE/Cy5‐conjugated anti‐human CD3 or CD19 and PE‐conjugated anti‐human IgG F(ab′)2was added to the T cell and B cell panels, respectively. The final cell preparation was added to a separate counting chamber. Images were captured using the Cellometer Vision CBA, an image cytometer designed for cell counting, size analysis and fluorescence intensity measurement. Thirty‐nine IXMs were performed and compared with the FCXM. We obtained a concordance sensitivity of 94.1% and 100% and specificity of 100% and 88.9% for T cells and B cells, respectively. The linearity of the system was verified using dilutions of a sample containing known donor‐specific anti‐HLA antibodies (DSA) against the target cells. This feasibility study demonstrates that the FCXM test could be easily adapted to the Cellometer Vision CBA image cytometer without compromising specificity and sensitivity. The low instrumentation cost, minimal maintenance, and simple operation allow for efficient implementation or transition from the FCXM to the IXM method.

OBJECTIVEThe AANS launched the Quality Outcomes Database (QOD), a prospective longitudinal registry that includes demographic, clinical, and patient-reported outcome (PRO) data to measure the safety and quality of spine surgery. Registry data offer “real-world” insights into the utility of spinal fusion and decompression surgery for lumbar spondylolisthesis. Using the QOD, the authors compared the initial 12-month outcome data for patients undergoing fusion and those undergoing laminectomy alone for grade 1 degenerative lumbar spondylolisthesis.METHODSData from 12 top enrolling sites were analyzed and 426 patients undergoing elective single-level spine surgery for degenerative grade 1 lumbar spondylolisthesis were found. Baseline, 3-month, and 12-month follow-up data were collected and compared, including baseline clinical characteristics, readmission rates, reoperation rates, and PROs. The PROs included Oswestry Disability Index (ODI), back and leg pain numeric rating scale (NRS) scores, and EuroQol–5 Dimensions health survey (EQ-5D) results.RESULTSA total of 342 (80.3%) patients underwent fusion, with the remaining 84 (19.7%) undergoing decompression alone. The fusion cohort was younger (60.7 vs 69.9 years, p < 0.001), had a higher mean body mass index (31.0 vs 28.4, p < 0.001), and had a greater proportion of patients with back pain as a major component of their initial presentation (88.0% vs 60.7%, p < 0.001). There were no differences in 12-month reoperation rate (4.4% vs 6.0%, p = 0.93) and 3-month readmission rates (3.5% vs 1.2%, p = 0.45). At 12 months, both cohorts improved significantly with regard to ODI, NRS back and leg pain, and EQ-5D (p < 0.001, all comparisons). In adjusted analysis, fusion procedures were associated with superior 12-month ODI (β −4.79, 95% CI −9.28 to −0.31; p = 0.04).CONCLUSIONSSurgery for grade 1 lumbar spondylolisthesis—regardless of treatment strategy—was associated with significant improvements in disability, back and leg pain, and quality of life at 12 months. When adjusting for covariates, fusion surgery was associated with superior ODI at 12 months. Although fusion procedures were associated with a lower rate of reoperation, there was no statistically significant difference at 12 months. Further study must be undertaken to assess the durability of either surgical strategy in longer-term follow-up.

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

Introduction: Shared decision making (SDM) incorporates patient and physician values and preferences into treatment selection. While multiple therapeutic options are available for stroke prevention in atrial fibrillation (AF), few studies have examined factors associated with SDM regarding choice of antithrombotic strategy. Methods: We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 sites participating in a substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II), an outpatient AF registry in the US. Patients were asked: “When choosing your blood thinner(s), who made this treatment decision?”, and SDM was defined as a response of “equally me and my healthcare provider (HCP)”, “mostly me” or “entirely me”, while no SDM was defined as a response of “mostly my HCP” or “entirely my HCP”. Multivariable logistic regression models evaluated associations between 13 patient-level factors, self-reported understanding of treatment options, and SDM for antithrombotic therapy. Results: Most patients allowed their HCP to make the therapeutic decisions on antithrombotic strategy, with 246 (24.5%) reporting SDM. Patients reporting SDM were more often female (47.2% vs. 40.5%) and were more frequently insured by Medicare (40.2% vs. 34.5%) than patients reporting no SDM. Among patients taking warfarin, median time in therapeutic range was higher among patients reporting SDM than among those not reporting SDM. In multivariable models, chronic obstructive pulmonary disease was associated with lower odds of SDM while self-reported understanding of blood thinner options was associated with higher odds of SDM (Table). Conclusion: One in four patients in an outpatient AF registry reported that their current antithrombotic strategy was the result of a shared decision making process. Additional work is need to determine whether patient-reported SDM is associated with medication adherence and outcomes of therapy.

321 Background: G3 NENs are aggressive, and optimal systemic treatment is unclear. Temozolomide (TEM)-based regimens have been used to treat grade 1-2 NETs, but their efficacy in G3 NENs (Ki-67 > 20%) remains undetermined. Aims: To assess the clinical efficacy of TEM-containing regimens in advanced grade III gastroenteropancreatic NENs (GEPNENs). Methods: A multicentre retrospective review (2008-2017) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports without formal RECIST criteria. Results: 118 patients in six centers were included (median age 55, 65% male, 15% functional, 75% pancreatic NEN). 57% were well-differentiated, 35% poorly-differentiated, and 18% unknown based on local pathology reports. The regimen used was CAPTEM in 93% and TEM in 7%. Best radiological responses were: complete response (1%), partial response (39%), stable disease (22%), progressive disease (31%), unknown (7%) not by RECIST. Median TTF was 150 days and median overall survival (OS) 18.0 months. Fifteen patients (14%) required dose reductions/discontinuation due to adverse events. TTF was shorter for patients on TEM alone (p = 0.02, Table 1). Well-differentiated NENs had better response rate (52% vs 26%, p = 0.02) and overall survival (30.1 vs 12.0 mo, p = 0.008) compared to poorly-differentiated NEN. Conclusions: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NET centers. 40% of patients showed some degree of response, and treatment was generally well-tolerated. TEM-based regimens should be considered a viable treatment option in this setting. Prospective confirmatory trials (such as EA2142) may face difficulties in accrual due to disease rarity. [Table: see text]

Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3–dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ–accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3+ CD4+ T cell proliferation, thereby amplifying organ inflammation. Consequently, Il3−/− mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.

Background Progressive solitary sclerosis is a unifocal demyelinating disease recently proposed as a possible multiple sclerosis variant. Objective To compare myelin content and brain metabolite ratio qualitatively in the normal-appearing white matter of progressive solitary sclerosis cases compared to multiple sclerosis and healthy control participants. Methods Case report. Results Progressive solitary sclerosis cases showed abnormal myelin in normal-appearing white matter tracts and global normal-appearing white matter as well as lower N-acetyl-aspartate to total creatine ratio compared to multiple sclerosis and healthy control groups. Conclusion Despite a single demyelinating lesion along the corticospinal tract in progressive solitary sclerosis, we showed evidence of more extensive abnormality within the normal-appearing white matter.