Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors.

Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F (human leukocyte antigen F) regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes, suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded ß2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as ß2m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.

Beyond Prostate Imaging Reporting and Data System: Combining Magnetic Resonance Imaging Prostate Imaging Reporting and Data System and Prostate-Specific Membrane Antigen-Positron Emission Tomography/Computed Tomography PRIMARY Score in a Composite (P) Score for More Accurate Diagnosis of Clinically Significant Prostate Cancer.

PURPOSE: The Prostate Imaging Reporting and Data System (PI-RADS) score is standard of care for clinically significant prostate cancer (csPCa) diagnosis. The PRIMARY score (prostate-specific membrane antigen [PSMA]-positron emission tomography [PET]/CT) also has high diagnostic accuracy for csPCa. This study aimed to develop an easily calculated combined (P) score for csPCa detection (International Society of Urological Pathology [ISUP] ≥2) incorporating separately read PI-RADS and PRIMARY scores, with external validation. MATERIALS AND METHODS: Two datasets of men with suspected PCa, no prior biopsy, recent MRI and 68Ga-PSMA-11-PET/CT, and subsequent transperineal biopsy were evaluated. These included the development sample (n = 291, 56% csPCa) a prospective trial and the validation sample (n = 227, 67% csPCa) a multicenter retrospective database. Primary outcome was detection of csPCa (ISUP ≥2), with ISUP ≥ 3 cancer detection a secondary outcome. Score performance was evaluated by area under the curve, sensitivity, specificity, and decision curve analysis. RESULTS: The 5-point combined (P) score was developed in a prospective dataset. In the validation dataset, csPCa was identified in 0%, 20%, 52%, 96%, and 100% for P score 1 to 5. The area under the curve was 0.93 (95% CI: 0.90-0.96), higher than PI-RADS 0.89 (95% CI: 0.85-0.93, P = .039) and PRIMARY score alone 0.84 (95% CI: 0.79-0.89, P < .001). Splitting scores at 1/2 (negative) vs 3/4/5 (positive), P score sensitivity was 94% (95% CI: 89-97) compared to PI-RADS 89% (95% CI: 83-93) and PRIMARY score 86% (95% CI: 79-91). For ISUP ≥ 3, P score sensitivity was 99% (95% CI: 95-100) vs 94% (95% CI: 88-98) and 92% (95% CI: 85-97) for PI-RADS and PRIMARY scores respectively. A maximum standardized uptake value > 12 (P score 5) was ISUP ≥ 2 in all cases with 93% ISUP ≥ 3. CONCLUSIONS: The P score is easily calculated and improves accuracy for csPCa over both PI-RADS and PRIMARY scores. It should be considered when PSMA-PET is undertaken for diagnosis.

Prostate-specific membrane antigen positron emission tomography in addition to multiparametric magnetic resonance imaging and biopsies to select prostate cancer patients for focal therapy.

OBJECTIVE: To evaluate the additional value of prostate-specific membrane antigen positron emission tomography (PSMA-PET) to conventional diagnostic tools to select patients for hemi-ablative focal therapy (FT). PATIENTS AND METHODS: We performed a retrospective analysis on a multicentre cohort (private and institutional) of 138 patients who underwent multiparametric magnetic resonance imaging (mpMRI), PSMA-PET, and systematic biopsies prior to radical prostatectomy between January 2011 and July 2021. Patients were eligible when they met the consensus criteria for FT: PSA <15 ng/mL, clinical/radiological T stage ≤T2b, and International Society of Urological Pathology (ISUP) grade 2-3. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥2, extracapsular extension >0.5 mm or seminal vesicle involvement at final histopathology. The diagnostic accuracy of mpMRI, systematic biopsies and PSMA-PET for csPCa (separate and combined) was calculated within a four-quadrant prostate model by receiver-operating characteristic and 2 × 2 contingency analysis. Additionally, we assessed whether the diagnostic tools correctly identified patients suitable for hemi-ablative FT. RESULTS: In total 552 prostate quadrants were analysed and 272 (49%) contained csPCa on final histopathology. The area under the curve, sensitivity, specificity, positive predictive value and negative predictive value for csPCa were 0.79, 75%, 83%, 81% and 77%, respectively, for combined mpMRI and systematic biopsies, and improved after addition of PSMA-PET to 0.84, 87%, 80%, 81% and 86%, respectively (P < 0.001). On final histopathology 46/138 patients (33%) were not suitable for hemi-ablative FT. Addition of PSMA-PET correctly identified 26/46 (57%) non-suitable patients and resulted in 4/138 (3%) false-positive exclusions. CONCLUSIONS: Addition of PSMA-PET to the conventional work-up by mpMRI and systematic biopsies could improve selection for hemi-ablative FT and guide exclusion of patients for whom whole-gland treatments might be a more suitable treatment option.

Synchronous vs independent reading of prostate-specific membrane antigen positron emission tomography (PSMA-PET) and magnetic resonance imaging (MRI) to improve diagnosis of prostate cancer.

OBJECTIVES: To identify whether synchronous reading of multiparametric magnetic resonance imaging (mpMRI) and 68 Ga-PSMA-11 positron emission tomography (PET)/computed tomography (prostate-specific membrane antigen [PSMA-PET]) images can improve diagnostic performance and certainty compared with mpMRI/PSMA-PET reported independently and synthesized, while also assessing concordance between imaging modalities and agreement with histopathology. METHODS: This was a retrospective analysis of 100 patients randomly selected from the PRIMARY trial, a prospective Phase II multicentre imaging trial. Three dual-trained radiologist/nuclear medicine physicians re-reported the mpMRI and PSMA-PET both independently and synchronously for the same patients in random order, blinded to previous results. Diagnostic performance was assessed for mpMRI/PSMA-PET images read synchronously or independently and then synthesized. Agreement between imaging results and histopathology was examined. 'Concordance' between imaging modalities was defined as overlapping lesions. Reporting certainty was evaluated by the individual reporters for each modality. RESULTS: International Society of Urological Pathology Grade Group ≥2 cancer was present in 60% of patients on biopsy. Synchronous reading of mpMRI/PSMA-PET increased sensitivity compared to mpMRI or PSMA-PET alone (93% vs 80% vs 88%, respectively), although specificity was not improved (63% vs 58% vs 78%, respectively). No significant difference in diagnostic performance was noted between mpMRI/PSMA-PET read synchronously and mpMRI or PSMA-PET reported independently and then synthesized. Most patients had concordant imaging (60%), while others had discordant lesions only (28%) or a mixture (concordant and discordant lesions; 12%). When mpMRI/PSMA-PET findings were concordant and positive, 95% of patients had clinically significant prostate cancer (csPCa). When PSMA-PET alone was compared to synchronous PSMA-PET/MRI reads, there was an improvement in reader certainty in 20% of scans. CONCLUSION: Synchronous mpMRI/PSMA-PET reading improves reader certainty and sensitivity for csPCa compared to mpMRI or PSMA-PET alone. However, synthesizing the results of independently read PSMA-PET and mpMRI reports provided similar diagnostic performance to synchronous PSMA-PET/MRI reads. This may provide greater flexibility for urologists in terms of referral patterns, reducing healthcare system costs and improving efficiencies in prostate cancer diagnosis.

The Triple HIT: Perioperative Management of Heparin-Induced Thrombocytopenia Using Plasma Exchange, Intravenous Immunoglobulin, and Protamine Infusion for Left Ventricular Assist Device Implantation.

Heparin-induced thrombocytopenia (HIT) is a serious complication in patients exposed to heparin, leading to thrombocytopenia and, potentially, thrombosis. This disorder is challenging in cardiac surgery when anticoagulation for cardiopulmonary bypass is required. Herein a patient with HIT who had active thrombosis and successfully underwent urgent left ventricular assist device implantation managed with plasma exchange, intravenous immunoglobulin, and protamine infusion is described. These therapies reduce the immune response to heparin and minimize thrombosis when heparin reexposure is planned. These approaches to perioperative management of HIT represent an attractive alternative to the use of non-heparin anticoagulants in the cardiac and vascular surgical population.

High Critical Shoulder Angle Values Are Associated With Full-Thickness Posterosuperior Cuff Tears and Low Values With Primary Glenohumeral Osteoarthritis.

PURPOSE: To compare critical shoulder angle (CSA) measurements using high-quality radiographs in the following groups: Group 1: symptomatic atraumatic full-thickness rotator cuff (RC) tears; Group 2: symptomatic primary glenohumeral osteoarthritis (GHOA); and Group 3: no RC tear or primary GHOA being treated for glenohumeral instability or symptomatic labral pathology (control group). METHODS: A prospective observational case control study with 10 shoulders in each group was performed GHOA and full-thickness RC tears were diagnosed by radiographs and magnetic resonance imaging (MRI). For these three groups, the exclusion criteria were the following: Group 1) partial thickness RC tears, traumatic RC tears, isolated subscapularis tears, and advanced cuff tear arthropathy with erosion of the superior glenoid; Group 2) secondary causes of glenohumeral arthritis; coexistent full-thickness RC tear; and Group 3) glenoid bone lesions that may affect the CSA measurement. Only shoulders with adequate radiographic quality (Suter-Henninger type A and C) were eligible. A one-way ANOVA, followed by Tukey multiple pairwise-comparisons test, was performed to compare the groups. Interobserver and intraobserver reliability was assessed using Intraclass Correlation Coefficients (ICC). RESULTS: Mean CSA values were 37.4° ± 4.7 (RC tear group), 28.9° ± 2.4 (GHOA group), and 32.8° ± 1.1 (control group). The CSA of the RC group was higher than the control group (P = .006) and the GHOA group (P = .000). The CSA of the GHOA group was lower than the control group (P = .027). Intraobserver and interobserver reliabilities for the CSA measurement were excellent (Observer 1 [ICC]: .986 [95% CI .970-.993]; Observer 2 [ICC]: .976[95% CI .951-.989]; and Observer 1v2: 0.968[95% CI .933-.985]). CONCLUSIONS: There is a difference in the CSA between patients with symptomatic atraumatic full-thickness RC tears (4.6° higher than the control group), symptomatic GHOA (3.8° lower than the control group), and glenohumeral instability or labral pathology with no RC tear or GHOA. LEVEL OF EVIDENCE: Level 2, prospective observational case control diagnostic study.

Preoperative Factors and Patient-Reported Outcomes After Total Hip Arthroplasty: Multivariable Prediction Modeling.

BACKGROUND: Although total hip arthroplasty (THA) has been established as a cost-effective intervention, some patients experience ongoing pain and dissatisfaction. There is interest in predicting postoperative outcomes based on preoperative data, but the relative contribution of different preoperative factors is unclear. The study's aim was to develop multivariable prediction models for the assessment of patient-reported outcomes. METHOD: Registry data on 1412 patients undergoing THA for osteoarthritis at two hospitals between 2013 and 2018 was used. Potential predictors included age, sex, body mass index, spoken language, education level, previous THA, American Society of Anaesthesiologists (ASA) score, lower back pain, depression/anxiety, other lower limb arthritis, number of other comorbidities, the preoperative expectation of pain and function, EuroQol Visual Analogue Scale (EQ-VAS) and preoperative OHS. Radiographic scores were also used: joint space narrowing (JSN), osteophytes, sclerosis, and an overall grade based on the Kellgren-Lawrence (KL) classification. Outcomes assessed were the patient-rated improvement, satisfaction, and OHS at six months. RESULTS: JSN or overall KL scores were the most important predictors (P < .001) for all outcomes, with better radiographic scores associated with worse outcomes. Other predictors associated with poorer outcomes were lower back pain and lower expectation (predicting poor improvement), lower education and higher ASA (predicting lower satisfaction) and younger age, female sex, non-English speakers, lower preoperative EQ-VAS, lower education, back pain, and anxiety/depression (predicting lower OHS). CONCLUSION: Preoperative radiological scores are an important predictor of patient-reported outcomes at six months postoperatively. Understanding the relative strengths and significance of different factors in predicting outcomes will help the clinician and patient decision-making for THA.

Pericardiectomy for Constrictive Pericarditis: Analysis of Outcomes.

Constrictive pericarditis is caused by pericardial inflammation and fibrosis, leading to diastolic heart failure. The diagnosis requires a high index of suspicion because it often can mimic restrictive myocardial disease and cardiac tamponade and can be associated with severe tricuspid regurgitation and chronic liver disease. Patients who remain undiagnosed can experience a 90% mortality rate, and for those who undergo pericardiectomy, the survival rate varies significantly, depending on the underlying etiology and preoperative functional class of the patient. In this article, the authors review the pathophysiology, echocardiographic findings, management, and surgical outcomes of constrictive pericarditis to aid the cardiothoracic anesthesiologist in the perioperative management of this disorder.

Does the Walch type B shoulder have a transverse force couple imbalance? A volumetric analysis of segmented rotator cuff muscles in osteoarthritic shoulders.

BACKGROUND: The etiology of the Walch type B shoulder remains unclear. We hypothesized that a scapulohumeral muscle imbalance, due to a disturbed transverse force couple (TFC) between the anterior and posterior rotator cuff muscles, may have a role in the pathogenesis of the type B morphology. The purpose of this study was to determine whether there is a TFC imbalance in the Walch type B shoulder using an imaging-based 3-dimensional (3D) volumetric and fatty infiltration assessment of segmented rotator cuff muscles. METHODS: Computed tomography images of 33 Walch type A and 60 Walch type B shoulders with the complete scapula and humerus including the distal humeral epicondyles were evaluated. The 3D volumes of the entire subscapularis, supraspinatus, and infraspinatus-teres minor (Infra-Tm) were manually segmented and analyzed. Additionally, anthropometric parameters including glenoid version, glenoid inclination, posterior humeral head subluxation, and humeral torsion were measured. The 3D muscle analysis was then compared with the anthropometric parameters using the Wilcoxon rank sum and Kruskal-Wallis tests. RESULTS: There were no significant differences (P > .200) in muscle volume ratios between the Infra-Tm and the subscapularis in Walch type A (0.93) and type B (0.96) shoulders. The fatty infiltration percentage ratio, however, was significantly greater in type B shoulders (0.94 vs. 0.75, P < .001). The Infra-Tm to subscapularis fatty infiltration percentage ratio was significantly larger in patients with >75% humeral head subluxation than in those with 60%-75% head subluxation (0.97 vs. 0.74, P < .001) and significantly larger in patients with >25° of retroversion than in those with <15° of retroversion (1.10 vs. 0.75, P = .004). The supraspinatus fatty infiltration percentage was significantly lower in Walch type B shoulders than type A shoulders (P = .004). Walch type A shoulders had mean humeral retrotorsion of 22° ± 10° whereas Walch type B shoulders had humeral retrotorsion of only 14° ± 9° relative to the epicondylar axis (P < .001). CONCLUSION: The TFC is in balance in the Walch type B shoulder in terms of 3D volumetric rotator cuff muscle analysis; however, the posterior rotator cuff does demonstrate increased fatty infiltration. Posterior humeral head subluxation and glenoid retroversion, which are pathognomonic of the Walch type B shoulder, may lead to a disturbance in the length-tension relationship of the posterior rotator cuff, causing fatty infiltration.

The Critical Shoulder Angle Shows a Reciprocal Change in Magnitude When Evaluating Symptomatic Full-Thickness Rotator Cuff Tears Versus Primary Glenohumeral Osteoarthritis as Compared With Control Subjects: A Systematic Review and Meta-analysis.

PURPOSE: To determine whether a high critical shoulder angle (CSA) is associated with symptomatic full-thickness rotator cuff (RC) tears and/or whether a low CSA is associated with primary glenohumeral osteoarthritis (GHOA). METHODS: A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All observational studies that examined an association between CSA and full-thickness RC tears and/or primary GHOA were included. A primary meta-analysis was performed including all studies that met the inclusion criteria regardless of radiographic quality. A secondary meta-analysis was performed to explore the hypothesis that radiographic quality was a source of heterogeneity, which excluded those studies in which radiograph quality was not strictly defined and controlled. RESULTS: For the primary meta-analysis, 11 studies met the inclusion criteria for RC tears and 5 for primary GHOA. The CSA was greater in the RC tear group than the control group (mean difference 4.03°, 95% confidence interval 2.95°-5.11, 95% prediction interval 0.0487°-8.01°; P < .001). The CSA was lower in the GHOA group than the control group (mean difference -3.98°, 95% confidence interval -5.66° to -2.31°, 95% prediction interval -10.2° to -2.19°; P < .001).A high level of heterogeneity was observed in the RC tear analysis (I2 = 88.4), which decreased after the exclusion of 5 studies based on radiographic quality (I2 = 75.3). A high level of heterogeneity also was observed in the primary GHOA analysis (I2 = 87.3), which decreased after the exclusion of 2 studies based on the radiographic quality (I2 = 48.2). CONCLUSIONS: There is a reciprocal change in magnitude of the CSA when evaluating symptomatic full-thickness RC tears versus primary GHOA as compared with control subjects. Radiographic quality is a source of heterogeneity in studies that investigate a link between CSA and RC tears and primary GHOA. LEVEL OF EVIDENCE: Level III, systematic review and meta-analysis of Level III studies.

Biomechanical comparison of knotless wide suture double-row SutureBridge rotator cuff repair to double-row standard suture repair.

BACKGROUND: A comparison of self-reinforcement and footprint compression between standard- and wide-diameter suture material in double-row SutureBridge repair techniques has not been performed. The aim of this study was to compare the self-reinforcement and footprint contact pressure generated under progressive tensile loads between 2 double-row SutureBridge rotator cuff repair techniques: 1 performed with FiberWire and 1 performed with FiberTape in a knotless technique. MATERIALS AND METHODS: Rotator cuff repairs were performed in 10 pairs of ovine shoulders. One group underwent a double-row SutureBridge repair using FiberWire. The other group underwent an identical repair with FiberTape. Footprint contact pressure was measured from 0° to 60° of abduction under loads of 0-60 N. Pull-to-failure tests were then performed. RESULTS: In both repair constructs at 0° of abduction, each 10-N increase in rotator cuff tensile load led to a significant increase in footprint contact pressure (P < .05). The rate of increase in footprint contact pressure was greater in the FiberTape construct (ratio, 1.68; P = .00035). In both repair constructs, the highest values for footprint contact pressure were seen at 0° of abduction. No difference in pull to failure, peak load, or total energy was found between the groups. CONCLUSION: Self-reinforcement was seen in both double-row SutureBridge repairs with standard- and wide-diameter suture material but was greater in the repair with the wide-diameter suture material construct. Footprint compression is greater in a knotless double-row SutureBridge repair with wide-diameter suture material than in a knotted double-row SutureBridge repair with standard-diameter suture material at 20° of abduction.

Topology optimization of freeform large-area metasurfaces.

We demonstrate optimization of optical metasurfaces over 105-106 degrees of freedom in two and three dimensions, 100-1000+ wavelengths (λ) in diameter, with 100+ parameters per λ2. In particular, we show how topology optimization, with one degree of freedom per high-resolution "pixel," can be extended to large areas with the help of a locally periodic approximation that was previously only used for a few parameters per λ2. In this way, we can computationally discover completely unexpected metasurface designs for challenging multi-frequency, multi-angle problems, including designs for fully coupled multi-layer structures with arbitrary per-layer patterns. Unlike typical metasurface designs based on subwavelength unit cells, our approach can discover both sub- and supra-wavelength patterns and can obtain both the near and far fields.

Autoreactivity to Sulfatide by Human Invariant NKT Cells.

Invariant NKT (iNKT) cells are innate-like lymphocytes that recognize lipid Ags presented by CD1d. The prototypical Ag, α-galactosylceramide, strongly activates human and mouse iNKT cells, leading to the assumption that iNKT cell physiology in human and mouse is similar. In this article, we report the surprising finding that human, but not mouse, iNKT cells directly recognize myelin-derived sulfatide presented by CD1d. We propose that sulfatide is recognized only by human iNKT cells because of the unique positioning of the 3-O-sulfated ß-galactose headgroup. Surface plasmon resonance shows that the affinity of human CD1d-sulfatide for the iNKT cell receptor is relatively low compared with CD1d-α-galactosylceramide (KD of 19-26 µM versus 1 µM). Apolipoprotein E isolated from human cerebrospinal fluid carries sulfatide that can be captured by APCs and presented by CD1d to iNKT cells. APCs from patients with metachromatic leukodystrophy, who accumulate sulfatides due to a deficiency in arylsulfatase-A, directly activate iNKT cells. Thus, we have identified sulfatide as a self-lipid recognized by human iNKT cells and propose that sulfatide recognition by innate T cells may be an important pathologic feature of neuroinflammatory disease and that sulfatide in APCs may contribute to the endogenous pathway of iNKT cell activation.

Replication timing is regulated by the number of MCMs loaded at origins.

Replication timing is a crucial aspect of genome regulation that is strongly correlated with chromatin structure, gene expression, DNA repair, and genome evolution. Replication timing is determined by the timing of replication origin firing, which involves activation of MCM helicase complexes loaded at replication origins. Nonetheless, how the timing of such origin firing is regulated remains mysterious. Here, we show that the number of MCMs loaded at origins regulates replication timing. We show for the first time in vivo that multiple MCMs are loaded at origins. Because early origins have more MCMs loaded, they are, on average, more likely to fire early in S phase. Our results provide a mechanistic explanation for the observed heterogeneity in origin firing and help to explain how defined replication timing profiles emerge from stochastic origin firing. These results establish a framework in which further mechanistic studies on replication timing, such as the strong effect of heterochromatin, can be pursued.

The retest distribution of the visual field summary index mean deviation is close to normal.

PURPOSE: When modelling optimum strategies for how best to determine visual field progression in glaucoma, it is commonly assumed that the summary index mean deviation (MD) is normally distributed on repeated testing. Here we tested whether this assumption is correct. METHODS: We obtained 42 reliable 24-2 Humphrey Field Analyzer SITA standard visual fields from one eye of each of five healthy young observers, with the first two fields excluded from analysis. Previous work has shown that although MD variability is higher in glaucoma, the shape of the MD distribution is similar to that found in normal visual fields. A Shapiro-Wilks test determined any deviation from normality. Kurtosis values for the distributions were also calculated. RESULTS: Data from each observer passed the Shapiro-Wilks normality test. Bootstrapped 95% confidence intervals for kurtosis encompassed the value for a normal distribution in four of five observers. When examined with quantile-quantile plots, distributions were close to normal and showed no consistent deviations across observers. CONCLUSIONS: The retest distribution of MD is not significantly different from normal in healthy observers, and so is likely also normally distributed - or nearly so - in those with glaucoma. Our results increase our confidence in the results of influential modelling studies where a normal distribution for MD was assumed.

Human adipose-derived mesenchymal progenitor cells engraft into rabbit articular cartilage.

Mesenchymal stem cells (MSCs) are known to have the potential for articular cartilage regeneration, and are suggested for the treatment of osteoarthritis (OA). Here, we investigated whether intra-articular injection of xenogeneic human adipose-derived mesenchymal progenitor cells (haMPCs) promoted articular cartilage repair in rabbit OA model and engrafted into rabbit articular cartilage. The haMPCs were cultured in vitro, and phenotypes and differentiation characteristics of cells were evaluated. OA was induced surgically by anterior cruciate ligament transection (ACLT) and medical meniscectomy of knee joints. At six weeks following surgery, hyaluronic acid (HA) or haMPCs was injected into the knee joints, the contralateral knee served as normal control. All animals were sacrificed at the 16th week post-surgery. Assessments were carried out by macroscopic examination, hematoxylin/eosin (HE) and Safranin-O/Fast green stainings and immunohistochemistry. The data showed that haMPC treatment promoted cartilage repair. Signals of human mitochondrial can be directly detected in haMPC treated cartilage. The haMPCs expressed human leukocyte antigen I (HLA-I) but not HLA-II-DR in vivo. These results suggest that intra-articular injection of haMPCs promotes regeneration of articular cartilage in rabbit OA model, and support the notion that MPCs are transplantable between HLA-incompatible individuals.

Accelerating simulation of ensembles of locally differing optical structures via a Schur complement domain decomposition.

We present a Schur complement domain decomposition method that can significantly accelerate simulation of ensembles of locally differing optical structures. We apply the method to design a multi-spatial-mode photonic crystal waveguide splitter that exhibits high transmission and preservation of modal content, showing design acceleration by more than a factor of 20.

CSF complications following intradural spinal surgeries in children.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is a complication of intradural spinal surgery and is associated with poor wound healing and infection. The incidence of CSF leak is reported at ∼16% in adults, but little information is available in children. PURPOSE: The aim of this study is to determine the CSF leak rate and predisposing factors after intradural pediatric spinal surgeries. METHODS: This study was a retrospective chart review of 638 intradural spinal operations at BC Children's Hospital. CSF leak was defined as pseudomeningocele or CSF leak through incision. Primary operations to untether lipomyelomeningoceles, myelomeningocele/meningocele closure, and Chiari decompressions were excluded. RESULTS: CSF leaks occurred in 7.1%, with 3% having overt CSF leaks through skin (OCSF leak). CSF leaks, specifically OCSF leaks, were associated with postoperative wound infection (P = 0.0016). Sixteen of 45 cases of CSF leak required reoperation. The type of dural suture used, site of operation, or use of fibrin glue did not affect CSF leak rates. Previous spinal surgery (P < 0.0001), use of dural graft (P = 0.0043), method of dural suturing (P = 0.0023), and procedure performed (P < 0.001) were associated with postoperative CSF leakage. Patients with CSF leak were older than those without leak (98 vs. 72 months, P = 0.002). CONCLUSIONS: Our results provide evidence on intraoperative factors that may predispose to CSF leaks after spinal intradural surgery and may help guide surgical practice. This study confirms that the pediatric population shares many of the same risk factors for CSF leak as in adult populations. Further research is needed to explain how specific factors are associated with CSF leaks.

The Mannoprotein Cig1 supports iron acquisition from heme and virulence in the pathogenic fungus Cryptococcus neoformans.

Iron acquisition is critical for virulence of the human pathogenic fungus Cryptococcus neoformans. The cryptococcal transcript for the extracellular mannoprotein Cig1 is highly regulated by iron and abundant in iron-starved cells, suggesting a role in iron acquisition. Indeed, loss of Cig1 resulted in delayed growth on heme at physiological pH. Expression of CIG1 is regulated by the pH-responsive transcription factor Rim101, and loss of Rim101 also impaired growth on heme. A cig1Δ mutant was less susceptible than the wild-type strain to noniron metalloporphyrins, further indicating a role for Cig1 in heme uptake. Recombinant Cig1 exhibited the absorbance spectrum of a heme-binding protein upon heme titration, and Cig1 may therefore function as a hemophore at the cell surface. Cig1 contributed to virulence in a mouse model of cryptococcosis but only in a mutant that also lacked the high-affinity iron uptake system. Overall, Cig1-mediated heme uptake is a potential therapeutic target in C. neoformans.