ABSTRACT We describe the development and application of a Global Astrometric Solution (GAS) to the problem of Pan-STARRS1 (PS1) astrometry. Current PS1 astrometry is based on differential astrometric ...measurements using 2MASS reference stars, and thus PS1 astrometry inherits the errors of the 2MASS catalog. The GAS, based on a single, least-squares adjustment to approximately 750 k "grid stars" using over 3000 extragalactic objects as reference objects, avoids this catalog-to-catalog propagation of errors to a great extent. The GAS uses a relatively small number of quasi-stellar objects (QSOs, or distant active galactic nuclei) with very accurate (<1 mas) radio positions, referenced to the ICRF2. These QSOs provide a hard constraint in the global least-squares adjustment. Solving such a system provides absolute astrometry for all of the stars simultaneously. The concept is much cleaner than conventional astrometry but is not easy to perform for large catalogs. In this paper, we describe our method and its application to Pan-STARRS1 data. We show that large-scale systematic errors are easily corrected but our solution residuals for position (∼60 mas) are still larger than expected based on simulations (∼10 mas). We provide a likely explanation for the reason the small-scale residual errors are not corrected in our solution as would be expected.
Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract ...and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (
; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSL
mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSL
diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSL
also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human
deficiency as a novel cause of a combined immunodeficiency.
Summary We conducted a prospective, randomized, controlled trial to compare functional outcomes, complications, and reoperation rates in elderly patients with displaced intra-articular, distal ...humeral fractures treated with open reduction–internal fixation (ORIF) or primary semiconstrained total elbow arthroplasty (TEA). Forty-two patients were randomized by sealed envelope. Inclusion criteria were age greater than 65 years; displaced, comminuted, intra-articular fractures of the distal humerus (Orthopaedic Trauma Association type 13C); and closed or Gustilo grade I open fractures treated within 12 hours of injury. Both ORIF and TEA were performed following a standardized protocol. The Mayo Elbow Performance Score (MEPS) and Disabilities of the Arm, Shoulder and Hand (DASH) score were determined at 6 weeks, 3 months, 6 months, 12 months, and 2 years. Complication type, duration, management, and treatment requiring reoperation were recorded. An intention-to-treat analysis and an on-treatment analysis were conducted to address patients randomized to ORIF but converted to TEA intraoperatively. Twenty-one patients were randomized to each treatment group. Two died before follow-up and were excluded from the study. Five patients randomized to ORIF were converted to TEA intraoperatively because of extensive comminution and inability to obtain fixation stable enough to allow early range of motion. This resulted in 15 patients (3 men and 12 women) with a mean age of 77 years in the ORIF group and 25 patients (2 men and 23 women) with a mean age of 78 years in the TEA group. Baseline demographics for mechanism, classification, comorbidities, fracture type, activity level, and ipsilateral injuries were similar between the 2 groups. Operative time averaged 32 minutes less in the TEA group ( P = .001). Patients who underwent TEA had significantly better MEPSs at 3 months (83 vs 65, P = .01), 6 months (86 vs 68, P = .003), 12 months (88 vs 72, P = .007), and 2 years (86 vs 73, P = .015) compared with the ORIF group. Patients who underwent TEA had significantly better DASH scores at 6 weeks (43 vs 77, P = .02) and 6 months (31 vs 50, P = .01) but not at 12 months (32 vs 47, P = .1) or 2 years (34 vs 38, P = .6). The mean flexion-extension arc was 107° (range, 42°-145°) in the TEA group and 95° (range, 30°-140°) in the ORIF group ( P = .19). Reoperation rates for TEA (3/25 12%) and ORIF (4/15 27%) were not statistically different ( P = .2). TEA for the treatment of comminuted intra-articular distal humeral fractures resulted in more predictable and improved 2-year functional outcomes compared with ORIF, based on the MEPS. DASH scores were better in the TEA group in the short term but were not statistically different at 2 years' follow-up. TEA may result in decreased reoperation rates, considering that 25% of fractures randomized to ORIF were not amenable to internal fixation. TEA is a preferred alternative for ORIF in elderly patients with complex distal humeral fractures that are not amenable to stable fixation. Elderly patients have an increased baseline DASH score and appear to accommodate to objective limitations in function with time.
Follicular B helper T (Tfh) cells support high affinity and long-term antibody responses. Here we found that within circulating CXCR5+ CD4+ T cells in humans and mice, the CCR7loPD-1hi subset has a ...partial Tfh effector phenotype, whereas CCR7hiPD-1lo cells have a resting phenotype. The circulating CCR7loPD-1hi subset was indicative of active Tfh differentiation in lymphoid organs and correlated with clinical indices in autoimmune diseases. Thus the CCR7loPD-1hi subset provides a biomarker to monitor protective antibody responses during infection or vaccination and pathogenic antibody responses in autoimmune diseases. Differentiation of both CCR7hiPD-1lo and CCR7loPD-1hi subsets required ICOS and BCL6, but not SAP, suggesting that circulating CXCR5+ helper T cells are primarily generated before germinal centers. Upon antigen reencounter, CCR7loPD-1hi CXCR5+ precursors rapidly differentiate into mature Tfh cells to promote antibody responses. Therefore, circulating CCR7loPD-1hi CXCR5+ CD4+ T cells are generated during active Tfh differentiation and represent a new mechanism of immunological early memory.
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•Circulating CXCR5+ CD4+ T cells comprise CCR7loPD-1hi and CCR7hiPD-1lo subsets•Circulating CXCR5+ CD4+ T cells are primarily generated before participating in GC•Circulating CCR7loPD-1hi CXCR5+ CD4+ T cells correlate with Tfh cell activity•Circulating CCR7loPD-1hi CXCR5+ CD4+ T cells promote antibody responses
OBJECTIVE:To perform an unbiased assessment of first postoperative day (POD 1) drain amylase level and pancreatic fistula (PF) after pancreaticoduodenectomy (PD).
BACKGROUND:Recent evidence ...demonstrated that drain abandonment in PD is unsafe. Early drain amylase levels have been proposed as predictors of PF after PD, allowing for selection of patients for early drain removal.
METHODS:Daily drain amylase levels were correlated with the development of PF in 2 independent cohorts of patients undergoing PDtraining cohort (n = 126; year 2008) and validation cohort (n = 369; years 2009–2012).
RESULTS:POD 1 drain amylase level had the highest predictive ability (concordance index0.911) for PF in the training cohort. An amylase level of 612 U/L or higher showed the best accuracy (86%), sensitivity (93%), and specificity (79%). Thus, a cutoff value of 600 U/L was utilized. In the validation cohort, 229 (62.1%) patients had a POD 1 drain amylase level of lower than 600 U/L, and PF developed in only 2 (0.9%) cases; whereas in patients with POD 1 drain amylase level of 600 U/L or higher (n = 140) the PF rate was 31.4% (odds ratio OR = 52, P < 0.0001). On multivariate analysis, POD 1 drain amylase level of lower than 600 U/L (OR = 0.0192, P < 0.0001) was a stronger predictor of the absence of PF than pancreatic gland texture (OR = 0.193, P = 0.002) and duct diameter (OR = 0.861, P = 0.835).
CONCLUSIONS:After PD, the risk of PF is less than 1% if POD 1 drain amylase level is lower than 600 U/L. We propose that in this group, which comprise more than 60% of patients, drains should be removed on POD 1.
Abstract Introduction It is our impression that many biomechanical studies invest substantial resources studying the obvious: that more and larger metal is stronger. The purpose of this study is to ...evaluate if a subset of biomechanical studies comparing fixation constructs just document common sense. Methods Using a web-based survey, 274 orthopaedic surgeons and 81 medical students predicted the results of 11 biomechanical studies comparing fracture fixation constructs (selected based on the authors’ sense that the answer was obvious prior to performing the study). Sensitivity, specificity, and accuracy were calculated according to standard formulas. The agreement among the observers was calculated by using a multirater kappa, described by Siegel and Castellan. Results The accuracy of predicting outcomes was 80% or greater for 10 of 11 studies. Accuracy was not influenced by level of experience (i.e., time in practice and medical students vs. surgeons). There were substantial differences in accuracy between observers from different regions. The overall categorical rating of inter-observer reliability according to Landis and Koch was moderate ( κ = 0.55; standard error (SE) = 0.01). Conclusion The results of a subset of biomechanical studies comparing fracture fixation constructs can be predicted prior to doing the study. As these studies are time and resource intensive, one criterion for proceeding with a biomechanical study should be that the answer is not simply a matter of common sense.
MicroRNAs act locally and systemically to impact osteoarthritis (OA) pathophysiology, but comprehensive profiling of the circulating miRNome in early vs late stages of OA has yet to be conducted. ...Sequencing has emerged as the preferred method for microRNA profiling since it offers high sensitivity and specificity. Our objective was to sequence the miRNome in plasma from 91 patients with early Kellgren–Lawrence (KL) grade 0 or 1 (n = 41) or late KL grade 3 or 4 (n = 50) symptomatic radiographic knee OA to identify unique microRNA signatures in each disease state.
MicroRNA libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq 550. Counts were produced for microRNAs captured in miRBase and for novel microRNAs. Statistical, bioinformatics, and computational biology approaches were used to refine and interpret the final list of microRNAs.
From 215 differentially expressed microRNAs (FDR < 0.01), 97 microRNAs showed an increase or decrease in expression in ≥85% of samples in the early OA group as compared to the median expression in the late OA group. Increasing this threshold to ≥95%, seven microRNAs were identified: hsa-miR-335-3p, hsa-miR-199a-5p, hsa-miR-671-3p, hsa-miR-1260b, hsa-miR-191-3p, hsa-miR-335-5p, and hsa-miR-543. Four novel microRNAs were present in ≥50% of early OA samples and had 27 predicted gene targets in common with the prioritized set of predicted gene targets from the 97 microRNAs, suggesting common underlying mechanisms.
Sequencing of well-characterized patient cohorts produced unbiased profiling of the circulating miRNome and identified a unique panel of 11 microRNAs in early radiographic knee OA.
Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is a short intracellular molecule that is mutated in humans with X-linked lymphoproliferative (XLP) disease. Although the ...exact role and mechanism of action of SAP are not known, it has the capacity to interact with the cytoplasmic region of SLAM and other related immune cell receptors. As SAP is composed almost exclusively of a Src homology 2 (SH2) domain, it has been proposed that it functions as a natural blocker of SH2 domain--mediated interactions. We report here that the SLAM receptor is capable of triggering a protein tyrosine phosphorylation signal in T cells via a mechanism that is strictly dependent on SAP expression. This signal involves the SH2 domain--containing inositol phosphatase (SHIP); the adaptor molecules Dok2, Dok1 and Shc; and Ras GTPase--activating protein RasGAP. SAP is essential for this pathway because it facilitates the selective recruitment and activation of the Src-related protein tyrosine kinase FynT. We also show that signaling via the SLAM-SAP pathway in an established T cell line can alter the profile of cytokine production during T cell activation. These findings identify a mechanism by which a putative adaptor molecule is required for receptor-mediated signaling events in the immune system. They also provide insights into the pathophysiology of a severe human lymphoproliferative disease.
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