Correction Method for Optical Scaling of Fundoscopy Images: Development, Validation, and First Implementation.

Purpose: Although fundus photography is extensively used in ophthalmology, refraction prevents accurate distance measurement on fundus images, as the resulting scaling differs between subjects due to varying ocular anatomy. We propose a PARaxial Optical fundus Scaling (PAROS) method to correct for this variation using commonly available clinical data. Methods: The complete optics of the eye and fundus camera were modeled using ray transfer matrix formalism to obtain fundus image magnification. The subject's ocular geometry was personalized using biometry, spherical equivalent of refraction (RSE), keratometry, and/or corneal topography data. The PAROS method was validated using 41 different eye phantoms and subsequently evaluated in 44 healthy phakic subjects (of whom 11 had phakic intraocular lenses [pIOLs]), 29 pseudophakic subjects, and 21 patients with uveal melanoma. Results: Validation of the PAROS method showed small differences between model and actual image magnification (maximum 3.3%). Relative to the average eye, large differences in fundus magnification were observed, ranging from 0.79 to 1.48. Magnification was strongly inversely related to RSE (R2 = 0.67). In phakic subjects, magnification was directly proportional to axial length (R2 = 0.34). The inverse relation was seen in pIOL (R2 = 0.79) and pseudophakic (R2 = 0.12) subjects. RSE was a strong contributor to magnification differences (1%-83%). As this effect is not considered in the commonly used Bennett-Littmann method, statistically significant differences up to 40% (mean absolute 9%) were observed compared to the PAROS method (P < 0.001). Conclusions: The significant differences in fundus image scaling observed among subjects can be accurately accounted for with the PAROS method, enabling more accurate quantitative assessment of fundus photography.

Time Trends in the Treatment and Survival of 5036 Uveal Melanoma Patients in The Netherlands over a 30-Year Period.

BACKGROUND: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary UM in the Netherlands between 1989 and 2019. METHODS: A retrospective population-based cohort study based on patients with primary UM from the database of the Netherlands Cancer Registry (NCR), linked with the national population registry Statistics Netherlands on inhabitants' cause of death. Two time periods (1989-2004, 2005-2019) were compared with descriptive statistics. Kaplan-Meier and (multivariate) Cox proportional hazard models were used to assess changes over time for overall survival (OS) and cancer-specific survival (CSS). RESULTS: In total, 5036 patients were analyzed with a median age of 64.0 years at the time of diagnosis. The number of patients increased over time. In the first (1989-2004) and second (2005-2019) period, 32% versus 54% of the patients received radiotherapy (p < 0.001). The median FU time was 13.4 years. The median OS of the first and second periods was 9.5 (95% CI 8.7-10.3) versus 11.3 years (95% CI 10.3-12.3; p < 0.001). The median CSS was 30.0 years (95% CI NA) in the first period and not reached in the second period (p = 0.008). In multivariate analysis (MVA), female gender (HR 0.85; 95% CI 0.79-0.92, p < 0.001) and radiotherapy treatment (HR 0.73; 95% CI 0.64-0.83, p < 0.001) were associated with better OS. Radiotherapy treatment (HR 0.74; 95% CI 0.61-0.90, p = 0.002) was also associated with better CSS. The period of diagnosis was not associated with OS or CSS. CONCLUSIONS: In this study of patients with primary UM, there was a shift to the diagnosis of smaller tumors, possibly due to stage migration. There was also an increase in eye-preserving treatments over time. OS and CSS were modestly improved in the second time period; however, the time period was not associated with OS or CSS in multivariate analyses.

Magnetic Resonance Imaging in the Clinical Care for Uveal Melanoma Patients-A Systematic Review from an Ophthalmic Perspective.

Conversely to most tumour types, magnetic resonance imaging (MRI) was rarely used for eye tumours. As recent technical advances have increased ocular MRI's diagnostic value, various clinical applications have been proposed. This systematic review provides an overview of the current status of MRI in the clinical care of uveal melanoma (UM) patients, the most common eye tumour in adults. In total, 158 articles were included. Two- and three-dimensional anatomical scans and functional scans, which assess the tumour micro-biology, can be obtained in routine clinical setting. The radiological characteristics of the most common intra-ocular masses have been described extensively, enabling MRI to contribute to diagnoses. Additionally, MRI's ability to non-invasively probe the tissue's biological properties enables early detection of therapy response and potentially differentiates between high- and low-risk UM. MRI-based tumour dimensions are generally in agreement with conventional ultrasound (median absolute difference 0.5 mm), but MRI is considered more accurate in a subgroup of anteriorly located tumours. Although multiple studies propose that MRI's 3D tumour visualisation can improve therapy planning, an evaluation of its clinical benefit is lacking. In conclusion, MRI is a complementary imaging modality for UM of which the clinical benefit has been shown by multiple studies.

Microphthalmia-Associated Transcription Factor: A Differentiation Marker in Uveal Melanoma.

Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. In cutaneous melanoma, MITF loss has been linked to an increased expression of stem cell markers, a shift in epithelial-to-mesenchymal transition (EMT)-related factors, and increased inflammation. We explored the role of MITF in Uveal Melanoma (UM) using a cohort of 64 patients enucleated at the Leiden University Medical Center. We analysed the relation between MITF expression and clinical, histopathological and genetic features of UM, as well as survival. We performed differential gene expression and gene set enrichment analysis using mRNA microarray data, comparing MITF-low with MITF-high UM. MITF expression was lower in heavily pigmented UM than in lightly pigmented UM (p = 0.003), which we confirmed by immunohistochemistry. Furthermore, MITF was significantly lower in UM with monosomy 3/BAP1 loss than in those with disomy 3/no BAP1 loss (p < 0.001) and with 8q gain/amplification 8q (p = 0.02). Spearman correlation analysis showed that a low MITF expression was associated with an increase in inflammatory markers, hallmark pathways involved in inflammation, and epithelial-mesenchymal transition. Similar to the situation in cutaneous melanoma, we propose that MITF loss in UM is related to de-differentiation to a less favourable EMT profile and inflammation.

MR-based follow-up after brachytherapy and proton beam therapy in uveal melanoma.

PURPOSE: MRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound. METHODS: Twenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline. RESULTS: Pre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 × 10-3mm2/s increase 12 months after treatment (p = 0.15). CONCLUSION: MR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound.

Increased Histological Tumor Pigmentation in Uveal Melanoma Is Related to Eye Color and Loss of Chromosome 3/BAP1.

Purpose: Heavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether pigmentation should be included in prognostic tests. Design: Retrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation. Participants: A total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and 2021. Methods: Cox regression and log-rank tests were used for survival analysis; the chi-square test and Mann-Whitney U test were used for correlation analysis. Main Outcome Measures: Uveal melanoma-related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors. Results: The 5-year UM-related mortality was 8% in patients with nonpigmented tumors (n = 54), 25% with lightly pigmented tumors (n = 489), 41% with moderately pigmented tumors (n = 333), and 33% with dark tumors (n = 178) (P < 0.001). The percentage of tumors with monosomy 3 (M3) or 8q gain increased with increasing pigmentation (31%, 46%, 62%, and 70% having M3 [P < 0.001], and 19%, 43%, 61%, and 63% having 8q gain [P < 0.001] in the 4 increasing pigment groups, respectively). BRCA-associated protein 1 (BAP1) loss (known for 204 cases) was associated with increased tumor pigmentation (P = 0.001). Cox regression analysis on survival showed that when chromosome status and pigmentation were both included, pigmentation was not an independent prognostic indicator. Preferentially expressed antigen in melanoma (PRAME) expression was a significant prognostic marker in light tumors (P = 0.02) but not in dark tumors (P = 0.85). Conclusions: Patients with moderately and heavily pigmented tumors showed a significantly higher UM-related mortality than patients with unpigmented and light tumors (P < 0.001), supporting prior reports on the relation between increased tumor pigmentation and a worse prognosis. Although we previously showed that a dark eye color was associated with tumor pigmentation, we now show that the tumor's genetic status (chromosome 3 and 8q/BAP1 status) is also related to tumor pigmentation. When pigmentation and chromosome 3 status are both included in a Cox regression analysis, pigmentation is not an independent prognostic factor. However, evidence from this and previous studies shows that chromosome changes and PRAME expression have a stronger association with survival when they occur in light tumors than in dark ones. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Inter-Observer Variability in MR-Based Target Volume Delineation of Uveal Melanoma.

Purpose: Several efforts are being undertaken toward MRI-based treatment planning for ocular proton therapy for uveal melanoma (UM). The interobserver variability of the gross target volume (GTV) on magnetic resonance imaging (MRI) is one of the important parameters to design safety margins for a reliable treatment. Therefore, this study assessed the interobserver variation in GTV delineation of UM on MRI. Methods and Materials: Six observers delineated the GTV in 10 different patients using the Big Brother contouring software. Patients were scanned at 3T MRI with a surface coil, and tumors were delineated separately on contrast enhanced 3DT1 (T1gd) and 3DT2-weighted scans with an isotropic acquisition resolution of 0.8 mm. Volume difference and overall local variation (median standard deviation of the distance between the delineated contours and the median contour) were analyzed for each GTV. Additionally, the local variation was analyzed for 4 interfaces: sclera, vitreous, retinal detachment, and tumor-choroid interface. Results: The average GTV was significantly larger on T1gd (0.57cm3) compared with T2 (0.51cm3, P = .01). A not significant higher interobserver variation was found on T1gd (0.41 mm) compared with T2 (0.35 mm). The largest variations were found at the tumor-choroid interface due to peritumoral enhancement (T1gd, 0.62 mm; T2, 0.52 mm). As a result, a larger part of this tumor-choroid interface appeared to be included on T1gd-based GTVs compared with T2, explaining the smaller volumes on T2. Conclusions: The interobserver variation of 0.4 mm on MRI are low with respect to the voxel size of 0.8 mm, enabling small treatment margins. We recommend delineation based on the T1gd-weighted scans, as choroidal tumor extensions might be missed.

Comparison of Magnetic Resonance Imaging-Based and Conventional Measurements for Proton Beam Therapy of Uveal Melanoma.

OBJECTIVE: Conventionally, ocular proton therapy (PT) is planned using measurements obtained by an ophthalmologist using ultrasound, fundoscopy, biometry, and intraoperative assessments. Owing to the recent advances in magnetic resonance imaging (MRI) of uveal melanoma (UM), it is possible to acquire high-resolution 3-dimensional images of the eye, providing the opportunity to incorporate MRI in ocular PT planning. In this study, we described how these measurements can be obtained using MRI, compared the MRI-based measurements with conventional ophthalmic measurements, and identified potential pitfalls for both modalities. DESIGN: Cross-sectional study. SUBJECTS: Data from 23 consecutive patients with UM treated with PT were retrospectively evaluated. METHODS: Magnetic resonance imaging-based measurements of axial length, tumor height and basal diameter, and marker-tumor distances were compared with the conventional ophthalmic measurements, and discrepancies were evaluated in a multidisciplinary setting. MAIN OUTCOME MEASURES: Tumor prominence and basal diameters on MRI and ultrasound, axial length on MRI and biometry, tumor-marker distances on MRI and measured intraoperatively. RESULTS: The mean absolute differences of the tumor height and basal diameter measurements between ultrasound and MRI were 0.57 mm and 1.44 mm, respectively. Larger absolute differences in height and basal diameter were observed when the full tumor extent was not visible on ultrasound (0.92 mm and 1.67 mm, respectively) compared with when the full tumor extent was visible (0.44 mm and 1.15 mm, respectively). When the full tumor was not visible on ultrasound, MRI was considered more reliable. Tumor-marker distances measured using MRI and intraoperative techniques differed < 1 mm in 55% of the markers. For anteriorly located and mushroom-shaped tumors (25% of the markers), MRI provided more accurate measurements. In flat UM (15% of the markers), however, it was difficult to delineate the tumor on MRI. The mean absolute difference in axial length between optical biometry and MRI was 0.50 mm. The presence of the tumor was found to influence optical biometry in 15 of 22 patients; the remaining patients showed a better agreement (0.30 mm). Magnetic resonance imaging-based biometry was considered more reliable in patients with UM. CONCLUSIONS: Magnetic resonance imaging allowed for the 3-dimensional assessment of the tumor and surrounding tissue. In specific patients, it provided a more reliable measurement of axial length, tumor dimensions, and marker-tumor distances and could contribute to a more accurate treatment planning. Nevertheless, a combined evaluation remains advised, especially for flat UM.

Automatic Three-Dimensional Magnetic Resonance-based measurements of tumour prominence and basal diameter for treatment planning of uveal melanoma.

Background and Purpose: Three-dimensional (3D) Magnetic Resonance Imaging (MRI) is increasingly used to complement conventional two-dimensional ultrasound in the assessment of tumour dimension measurement of uveal melanoma. However, the lack of definitions of the 3D measurements of these tumour dimensions hinders further adaptation of MRI in ocular radiotherapy planning. In this study, we composed 3D MR-based definitions of tumour prominence and basal diameter and compared them to conventional ultrasound. Materials and methods: Tumours were delineated on 3DT2 and contrast-enhanced 3DT1 (T1gd) MRI for 25 patients. 3D definitions of tumour prominence and diameter were composed and evaluated automatically on the T1gd and T2 contours. Automatic T1gd measurements were compared to manual MRI measurements, to automatic T2 measurements and to manual ultrasound measurements. Results: Prominence measurements were similar for all modalities (median absolute difference 0.3 mm). Automatic T1gd diameter measurements were generally larger than manual MRI, automatic T2 and manual ultrasound measurements (median absolute differences of 0.5, 1.6 and 1.1 mm respectively), mainly due to difficulty defining the axis of the largest diameter. Largest differences between ultrasound and MRI for both prominence and diameter were found in anteriorly located tumours (up to 1.6 and 4.5 mm respectively), for which the tumour extent could not entirely be visualized with ultrasound. Conclusions: The proposed 3D definitions for tumour prominence and diameter agreed well with ultrasound measurements for tumours for which the extent was visible on ultrasound. 3D MRI measurements generally provided larger diameter measurements than ultrasound. In anteriorly located tumours, the MRI measurements were considered more accurate than conventional ultrasound.

An Er3+ doped Ba2MgWO6 double perovskite: a phosphor for low-temperature thermometry.

A bifunctional luminescent material is one of the most intriguing topics in recent years with significant growth in the number of investigations. Herein, we report the potential of Ba2MgWO6 doped with Er3+ as a candidate for white-light emitting phosphor and noncontact luminescent thermometry. The synthesis of the samples was carried out by the co-precipitation method. The influence of the dopant concentration on the emission intensity, as well as the capability of temperature readout, was investigated for the first time. The highest emission intensity exhibits a sample comprising 4% Er3+; above it, the concentration quenching process by the dipole-dipole interaction occurs. However, high quality white light generates Ba2MgWO6 with 0.5% of Er3+ due to the coexistence of the host and erbium ion emission with a CIE of (0.30, 0.35). To construct a non-contact luminescent thermometer based on Er3+, the ratio of the emission from 4I11/2 → 4I15/2 to the host emission was examined. The highest sensitivity Sr of the obtained luminescent thermometers was 2.78% K-1 at 198 K. The repeatability of the calculated results and the uncertainty δT of the temperature readout were investigated.

A novel digital PCR-based method to quantify (switched) B cells reveals the extent of allelic involvement in different recombination processes in the IGH locus.

B cells fulfill an important role in the adaptive immunity. Upon activation and immunoglobulin (IG) class switching, these cells function in the humoral immunity compartment as plasma cells. For clinical applications, it can be important to quantify (switched) B cells accurately in a variety of body fluids and tissues of benign, inflammatory and malignant origin. For decades, flow cytometry and immunohistochemistry (IHC) have been the preferred methods for quantification. Although these methods are widely used, both depend on the accessibility of B cell epitopes and therefore require intact (fixed) cells. Whenever samples are low in quantity and/or quality, accurate quantification can be difficult. By shifting the focus from epitopes to DNA markers, quantification of B cells remains achievable. During differentiation and maturation, B cells are subjected to programmed genetic recombination processes like VDJ rearrangements and class switch recombination (CSR), which result in deletion of specific sequences of the IGH locus. These cell type-specific DNA "scars" (loss of sequences) in IG genes can be exploited as B cell markers in digital PCR (dPCR) based quantification methods. Here, we describe a novel, specific and sensitive digital PCR-based method to quantify mature and switched B cells in DNA specimens of benign and (copy number unstable) malignant origin. We compared this novel way of B cell quantitation with flow cytometric and immunohistochemical methods. Through cross-validation with flow cytometric sorted B cell subpopulations, we gained quantitative insights into allelic involvement in different recombination processes in the IGH locus. Our newly developed method is accurate and independent of the cellular context, offering new possibilities for quantification, even for (limited) small samples like liquid biopsies.

Clinical Outcomes after International Referral of Uveal Melanoma Patients for Proton Therapy.

OBJECTIVE: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. MATERIALS AND METHODS: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan-Meier's methodology and Cox proportional hazards models. RESULTS: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6-26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. CONCLUSION: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy.

Incidence of Infection of Enterovirus 71 and Coxsackieviruses A6 and A16 among Household Contacts of Index Cases in Dong Thap Province, Southern Vietnam.

BACKGROUND: Scarce information exists about immunity to hand, foot, and mouth disease (HFMD) among household contacts of index cases in Vietnam and what that means for reducing ongoing HFMD transmission in the community. METHODS: We analyzed neutralizing antibodies (NT) and the incidence of enterovirus (EVs) infection among household contacts of index cases in a province where HFMD remains endemic. Throat swab and 2 mL blood samples from household contacts were collected at enrollment, during and after 2 weeks follow-up. RESULTS: The incidence of EV-A71 infection among household contacts was 40/84 (47.6%, 95% Cl: 36.9-58.3%), compared with 106/336 (31.5%, 95% Cl: 26.6-36.5%) for CV-A6 and 36/107 (33.6%, 95% Cl: 24.7-42.6%) for CV-A16. The incidence of CV-A6 infection was fairly constant across ages; in contrast, CV-A71 and CV-A16 had some variation across ages. At baseline, higher geometric mean titer (GMT) of EV-A71, CV-A6, and CV-A16 antibody titers was found for 25-34-year groups (range 216.3 to 305.0) compared to the other age groups. There was a statistically significant difference in GMT values of CV-A6 and CV-A16 between those who had an infection or did not have infection among households with an index case of these serotypes. CONCLUSIONS: Our results indicated that adults were becoming infected with HFMD and could be contributing to the transmission. There is, therefore, a need for considering the household setting as an additional target for intervention programs for HFMD.

Diagnostic Accuracy and Scope of Intraoperative Transoral Ultrasound and Transoral Ultrasound-Guided Fine-Needle Aspiration of Retropharyngeal Masses.

The use of transoral sonography-guided fine-needle aspiration for intraoperative localization of retropharyngeal masses has been described by Fornage et al. The purpose of this study was to assess the accuracy of this technique. We reviewed the images and medical records of 26 patients with a retropharyngeal lesion suspicious for a metastatic lymph node of Rouviere identified on CT and/or PET/CT. There were 14 patients with a history of thyroid cancer, 7 with mucosal squamous cell carcinoma, 1 with renal cell carcinoma, 1 with parotid acinic cell cancer, 1 with metastatic colon adenocarcinoma, and 2 with no history of cancer. Intraoperative transoral sonography was performed using a commercially available endovaginal transducer. A transoral sonography-guided fine-needle aspiration was performed with a 25-cm-long 20-ga Chiba needle through a needle guide attached to the transducer shaft. Cytopathologic results were categorized as malignant, benign, or nondiagnostic. Transoral sonography and transoral sonography-guided fine-needle aspiration were performed in all patients. A diagnostic specimen was obtained in 25 of 26 (96%) patients with a 100% overall accuracy. Twelve patients underwent subsequent transoral resection of the retropharyngeal mass. In each patient, surgical pathology confirmed the fine-needle aspiration biopsy result. In 4 patients, transoral sonography-guided injection of methylene blue was used to facilitate intraoperative localization of the metastatic retropharyngeal mass. Transoral sonography and transoral sonography-guided fine-needle aspiration of suspicious masses in the retropharyngeal space are highly accurate procedures for identification and cytologic evaluation of benign and metastatic lymph nodes of Rouviere and for presurgical localization.

Role of vitamin D in cell-cell interaction of fetal endothelial progenitor cells and umbilical cord endothelial cells in a preeclampsia-like model.

Maternal endothelial dysfunction is a cental feature of preeclampsia (PE), a hypertensive disorder of pregnancy. Factors in the maternal circulation are thought to contribute to this endothelial dysfunction. Although understudied, factors in the fetal circulation may influence fetal endothelial cell interactions with endothelial progenitor cells as critical steps in placental angiogenesis. We hypothesize that cell-cell interactions that are important for pregnancy health are impaired by fetal serum from PE pregnancies and that 1,25(OH)2-vitamin D3 attenuates the negative effects of this serum on cell function. We tested the ability of fetal cord blood-derived endothelial progenitor cells [endothelial colony-forming cells (ECFCs)] to invade into established monolayers and capillary tubule-like structures of human fetal umbilical venous endothelial cells (HUVECs), while in the presence/absence of fetal cord serum from uncomplicated or PE pregnancies, and tested the ability of 1,25(OH)2-vitamin D3 to modulate the serum-mediated effects. PE cord serum reduced the invasion of fetal ECFCs into HUVEC monolayers or tubule networks. Vitamin D attenuated these effects of PE fetal serum on endothelial functional properties. Immunocytochemical studies revealed involvement of VE-cadherin contacts in interactions between ECFCs and mature fetal endothelial cells. PE cord serum reduces the ability of fetal endothelial progenitor cells to incorporate into fetal endothelial cell networks. Physiologic concentrations of vitamin D reverse these PE serum-mediated effects. These data appear consistent with lines of evidence that vitamin D has antipreeclampsia effects.

Solitary Parathyroid Adenoma Localization in Technetium Tc99m Sestamibi SPECT and Multiphase Multidetector 4D CT.

BACKGROUND AND PURPOSE: Minimally invasive parathyroid surgery relies critically on image guidance, but data comparing the efficacy of various imaging modalities are scarce. Our aim was to perform a blinded comparison of the localizing capability of technetium Tc99m sestamibi SPECT, multiphase multidetector 4D CT, and the combination of these 2 modalities (technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT). MATERIALS AND METHODS: We reviewed the records of 31 (6 men, 25 women; median age, 56 years) consecutive patients diagnosed with biochemically confirmed primary hyperparathyroidism between November 2009 and March 2010 who underwent preoperative technetium Tc99m sestamibi SPECT and multiphase multidetector 4D CT performed on the same scanner with pathologic confirmation by resection of a single parathyroid adenoma. Accuracy was determined separately for localization to the correct side and quadrant using surgical localization as the standard of reference. RESULTS: Surgical resection identified 14 left and 17 right parathyroid adenomas and 2 left inferior, 12 left superior, 11 right inferior, and 6 right superior parathyroid adenomas. For left/right localization, technetium Tc99m sestamibi SPECT achieved an accuracy of 93.5% (29 of 31), multiphase multidetector 4D CT achieved 96.8% accuracy (30 of 31), and technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT achieved 96.8% accuracy (30 of 31). For quadrant localization, technetium Tc99m sestamibi SPECT accuracy was 67.7% (21 of 31), multiphase multidetector 4D CT accuracy was 87.1% (27 of 31), and technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT accuracy was 93.5% (29 of 31). Reader diagnostic confidence was consistently ranked lowest for technetium Tc99m sestamibi SPECT and highest for technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT. CONCLUSIONS: For left/right localization of parathyroid adenomas, all modalities performed equivalently. For quadrant localization, technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT is superior to technetium Tc99m sestamibi SPECT.

Author Correction: Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma.

The originally published version of this Article contained an error in Figure 4. The bar chart in panel f was inadvertently replaced with a duplicate of the bar chart in panel e. This error has now corrected in both the PDF and HTML versions of the Article.

Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma.

Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.

Childhood hospitalisation and related deaths in Hanoi, Vietnam: a tertiary hospital database analysis from 2007 to 2014.

OBJECTIVE: To describe hospital admission and emergency visit rates and potential risk factors of prolonged hospitalisation and death among children in Hanoi. STUDY DESIGN: A retrospective study reviewed 212 216 hospitalisation records of children (aged 0-17) who attended the Vietnam National Children's Hospital in Hanoi between 2007 and 2014. Four indicators were analysed and reported: (1) rate of emergency hospital visits, (2) rate of hospitalisation, (3) length of hospital stay and (4) number of deaths. The risk of prolonged hospitalisation was investigated using Cox proportion hazard, and the risk of death was investigated through logistic regressions. RESULTS: During 2007-2014, the average annual rate of emergency visits was 2.2 per 1000 children and the rate of hospital admissions was 13.8 per 1000 children. The annual rates for infants increased significantly by 3.9 per 1000 children during 2012-2014 for emergency visits and 25.1 per 1000 children during 2009-2014 for hospital admissions. Digestive diseases (32.0%) and injuries (30.2%) were common causes of emergency visits, whereas respiratory diseases (37.7%) and bacterial and parasitic infections (19.8%) accounted for most hospital admissions. Patients with mental and behavioural disorders remained in the hospital the longest (median=12 days). Morbidities related to the perinatal period dominated mortality causes (32.5% of deaths among those admitted to the hospital. Among the respiratory diseases, pneumonia was the leading cause of both prolonged hospitalisation and death. CONCLUSIONS: Preventable health problems, such as common bacterial infections and respiratory diseases, were the primary causes of hospital admissions in Vietnam.

Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization.

Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelators which form highly stable and inert complexes with gadolinium ions. In this context, three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar.