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Supplemental material, sj-pdf-2-pmj-10.1177_02692163221074876 for Risk factors associated with poorer experiences of end-of-life care and challenges in early bereavement: Results of a national online survey of people bereaved during the COVID-19 pandemic by Lucy Ellen Selman, DJJ Farnell, M Longo, S Goss, K Seddon, A Torrens-Burton, CR Mayland, D Wakefield, B Johnston, A Byrne and E Harrop in Palliative Medicine

Supplemental material, sj-pdf-1-pmj-10.1177_02692163221074876 for Risk factors associated with poorer experiences of end-of-life care and challenges in early bereavement: Results of a national online survey of people bereaved during the COVID-19 pandemic by Lucy Ellen Selman, DJJ Farnell, M Longo, S Goss, K Seddon, A Torrens-Burton, CR Mayland, D Wakefield, B Johnston, A Byrne and E Harrop in Palliative Medicine

OBJECTIVE: To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). METHODS: We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: A comparison between all patients with AAU and healthy control subjects showed strong association over HLA-B, corresponding to the HLA-B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non-major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10(-8) ). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10(-6) ). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. CONCLUSION: These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

By virtue of their target cell specificity, chemokines have the potential to selectively recruit leukocyte subpopulations into sites of inflammation. Their role in regulation of T lymphocyte traffic into lymph nodes during the development of an immune response has not previously been explored. The sensitization phase of contact hypersensitivity induced by the hapten, dinitrofluorobenzene (DNFB) in the mouse was used as a model of T lymphocyte trafficking in response to antigenic stimulation. Rapid accumulation of CD8+ and CD4+ T cells in the draining lymph nodes was closely associated with strongly enhanced expression of macrophage inflammatory protein (MIP)-1α and MIP-1β mRNAs and proteins. Mast cells accumulating in the nodes during DNFB sensitization were the predominant source of MIP-1β, whereas MIP-1α was expressed by multiple cell types. Neutralization of these chemokines profoundly inhibited T lymphocyte trafficking into lymph nodes and altered the outcome of a subsequent challenge to DNFB. Thus, β-chemokines regulate T lymphocyte emigration from the circulation into lymph nodes during an immune response and contribute significantly to the immunologic outcome.

Pterygia are a proliferative and inflammatory growth of limbal epithelial stem cell origin, characterized by corneal tissue invasion and extensive matrix remodeling including the destruction of Bowman's layer (BL). The purpose of this study was to determine the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) at the advancing pterygium edge.Formalin-fixed, paraffin-embedded whole eyes (n = 11) with pterygia attached, were serially sectioned and analyzed immunohistochemically to determine the spatial distribution of four MMPs and three TIMPs. Tear samples were collected from other patients with pterygia (n = 11) and displayed by gelatin zymography.Collagenase-1 was expressed by pterygium epithelial cells, corneal stromal fibroblasts and pterygium fibroblasts that had migrated between the epithelium and BL at the advancing pterygium edge. Collagenase-3 and gelatinases A and B were detected in all pterygia, intensely staining columnar epithelial cells directly adjacent to the denatured BL. In addition, gelatinase A immunoreactivity was observed on BL. Immunoreactivity for TIMP-1 and -3 paralleled that of the gelatinases, with more intense staining in epithelial cells and fibroblasts where BL was absent. TIMP-2 was faintly detected in pterygium epithelial cells but intensely stained pterygium fibroblasts. Gelatinase B was the most abundant gelatinolytic enzyme present in tears, elevated approximately twofold in eyes with pterygia versus the contralateral control eyes.This investigation is the first to identify the expression pattern of MMPs and TIMPs at the advancing pterygium edge in specimens of human eyes and in tears derived from patients with pterygia. These enzymes may be responsible for the destruction of BL, and their pattern of differential expression suggests that each may play a selective role in the pathogenesis of pterygia.

The effect of HIV infection on the production of tumor necrosis factor-alpha (TNF-alpha) was examined in patients with advanced human immunodeficiency virus (HIV) infection in the absence of AIDS-related secondary infections. Serum TNF-alpha and TNF-alpha production in vitro were measured by enzyme-linked immunosorbent assay in 26 male homosexuals with CDC stage IV HIV infection without active AIDS-related secondary infections. In vitro TNF-alpha production was assayed from cultured peripheral blood mononuclear cells (PBMs) or whole blood cultures under conditions for minimising endotoxin contamination. PBMs and whole blood were cultured with and without lipopolysaccharide (LPS). Results were compared with those for 13 HIV-seronegative age- and sex-matched controls. Serum TNF-alpha concentrations were 5 +/- 16 pg/ml in HIV-infected patients and 12 +/- 17 pg/ml in controls. TNF-alpha levels in unstimulated cultures of PBMs obtained from patients were 426 +/- 511 pg/ml and 456 +/- 428 pg/ml in control cultures. There was no difference between groups in the maximal responses of cultured PBMs to stimulation with LPS (2,229 +/- 1,593 pg/ml vs. 2,504 +/- 961 pg/ml). TNF-alpha levels from unstimulated and LPS-stimulated whole blood cultures were not significantly different after adjusting for the number of cultured monocytes (2,038 +/- 1,469 pg/ml vs. 1,511 +/- 488 pg/ml). In 10 patients (38%) the TNF-alpha levels from stimulated whole blood cultures were greater than the 95% confidence interval of the control group. TNF-alpha levels in patients were not significantly altered by antiretroviral therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Rural physicians need access to digital health sciences libraries (DHSLs) that is easy and reasonably rapid. The goal of this project was to study rural hospitals' access to a DHSL on the Internet, by comparing differing access speeds with differing costs and their acceptability for retrieving text, image, and video information in a DHSL. METHODS: DHSL system response time was measured at three different times during the day over three different types of network connections (T1, Frame Relay, Modem). Text, image, and video information was retrieved. Costs were determined for installation and operation of the different types of network connections. RESULTS: System response times were consistent at the three different testing times for each media type retrieved by each of the three network connection types. System response times for text retrieval met literature standards for all connections. Image retrieval met literature standards for T1 and Frame relay connections. No connection met literature standards for video retrieval. CONCLUSIONS: High speed access to DHSLs is preferable; Frame relay connections provide substantively similar service as T1 connections at less cost. However, access via modem to a DHSL can provide access to the majority of information--text--in a DHSL with an acceptable system response time.

As the federal administration advances the idea of the "information superhighway," many disciplines are being challenged to find ways to use advanced telecommunications to improve access to information, enhance learning opportunities, and achieve higher levels of international competitiveness. Telemedicine, the use of communications technology in the practice of medicine, may change the way rural health care is provided by improving access to medical information, diagnostic tools, and consultations. The information and health care services required by health care professionals are rapidly changing, and dissemination of this information to isolated practitioners has proven to be difficult. By providing support electronically from a central site, the most current information is more readily available. Using test-bed hospitals in rural and urban settings, the National Library of Medicine-funded National Laboratory for the Study of Rural Telemedicine at the University of Iowa is currently developing the necessary infrastructure to support targeted projects studying how telemedicine applications can be made more effective and readily available.

Pterygia are invasive, proliferative fibrovascular growths, with the matrix metalloproteinase (MMP) family of enzymes strongly implicated in the pathogenesis of these lesions. The purpose of this study was to determine the cellular distribution and activation status of matrilysin (MMP-7) in pterygia.Resected pterygia (n = 8) and normal conjunctiva (n = 8) were sectioned and analyzed immunohistochemically with two different epitope-specific anti-MMP-7 monoclonal antibodies (Abs) which differentiate pro- and active MMP-7. The specificity of each Ab was confirmed by Western blot analysis of p-aminophenylmercuric acetate (APMA)-activated and latent recombinant MMP-7. Pterygia (n = 4) and autologous normal conjunctiva (n = 4) were placed in organ culture to determine the activation status of secreted MMP-7.Precursor and active forms of MMP-7 were detected in epithelial cells from both pterygia and normal conjunctiva. Intense immunoreactivity for pro- and active MMP-7 was also observed in the pterygium vasculature, but was essentially absent from conjunctival vessels. Pro-MMP-7 was also identified in the epithelial basement membrane and associated with matrix components in pterygia. The 141-7B2 Ab reacted with the 30-kDa latent MMP-7, and the IM47L Ab precipitated a 19-kDa active enzyme, thus confirming the differential specificity of each Ab. Pro- and active MMP-7 were increased 1.4- and 2.7-fold, respectively, in the supernatants from organ-cultured pterygia compared with conjunctiva.This study is the first to specifically localize an active MMP species in pterygia and strengthens the hypothesis that these enzymes are involved in the pathogenesis of this disease. The data also suggest that MMP-7 may play a significant role in the angiogenesis that characterizes this lesion. Future studies will be directed at determining whether targeting MMP activity may be useful for treatment of pterygia.

Pterygia are a common, benign, fibrovascular, and infiltrative process of the corneal-conjunctival junction of unknown pathogenesis. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes active against all components of the extracellular matrix, whose activity is specifically neutralized by tissue inhibitors of MMPs (TIMPs). In the current study the hypothesis was that MMPs and TIMPs may actively participate in the formation and progression of pterygia.In this study, 25 pterygium specimens and 15 normal conjunctival biopsies obtained from subjects undergoing surgery for glaucoma and cataract, were processed for immunohistochemistry or in situ hybridization. Pterygium epithelial cells (PECs) were cultured under serum-free conditions and exposed to proinflammatory cytokines to determine both the mRNA and protein expression profiles of MMPs and TIMPs.Collagenase-1 and gelatinase A were expressed in all pterygia examined, specifically localized to the epithelium (directly adjacent to collagen type III), with gelatinase B expression exclusively associated with neutrophils. No collagenase-1 or gelatinase A was detected in normal conjunctiva. TIMP-1 and -3 were localized to epithelial cells with additional TIMP-3 immunoreactivity detected in the extracellular matrix, endothelial cells and leukocytes of all diseased tissue. TIMP-3 protein was evident in 4 of 15 normal conjunctiva. Induction of collagenase-1, gelatinase A, and TIMP-1 mRNA and protein was demonstrated in epithelial cells treated with tumor necrosis factor-alpha and interleukin-1alpha, whereas TIMP-3 expression was unaltered.This is the first study to document the cellular expression of MMPs and TIMPs in pterygia and cultured human PECs. MMPs and TIMPs may contribute to the inflammation, tissue remodeling, and angiogenesis that characterize pterygia. Understanding the role these proteins play may lead to novel therapies intended to reduce the progressive nature of pterygia.