An electronic healthcare record server implemented in PostgreSQL

This paper describes the implementation of an Electronic Healthcare Record server inside a PostgreSQL relational database without dependency on any further middleware infrastructure. The five-part international standard for communicating healthcare records (ISO EN 13606) is used as the information basis for the design of the server. We describe some of the features that this standard demands that are provided by the server, and other areas where assumptions about the durability of communications or the presence of middleware lead to a poor fit. Finally, we discuss the use of the server in two real-world scenarios including a commercial application

PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) is considered a non‐immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD‐L1 expression in a JAK/Stat1‐dependent manner. In vitro, PD‐L1 inhibition did not alter radio‐ and chemosensitivity. In vivo, addition of anti‐PD‐L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD‐L1 blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced CD45+CD8+ T‐cell infiltration with concomitant upregulation of T‐cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radiosensitization by anti‐PD‐L1. Blockade of PD‐L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti‐PD‐L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC

Interferon Signaling Is Frequently Downregulated in Melanoma

Immune checkpoint inhibitors that block the programmed cell death protein 1/PD-L1 pathway have significantly improved the survival of patients with advanced melanoma. Immunotherapies are only effective in 15–40% of melanoma patients and resistance is associated with defects in antigen presentation and interferon signaling pathways. In this study, we examined interferon-γ (IFNγ) responses in a large panel of immune checkpoint inhibitor-naïve melanoma cells with defined genetic drivers; BRAF-mutant (n = 11), NRAS-mutant (n = 10), BRAF/NRAS wild type (n = 10), and GNAQ/GNA11-mutant uveal melanomas (UVMs) (n = 8). Cell surface expression of established IFNγ downstream targets PD-L1, PD-L2, HLA-A, -B, and -C, HLA-DR, and nerve growth factor receptor (NGFR) were analyzed by flow cytometry. Basal cellular expression levels of HLA-A, -B, -C, HLA-DR, NGFR, and PD-L2 predicted the levels of IFNγ-stimulation, whereas PD-L1 induction was independent of basal expression levels. Only 13/39 (33%) of the melanoma cell lines tested responded to IFNγ with potent induction of all targets, indicating that downregulation of IFNγ signaling is common in melanoma. In addition, we identified two well-recognized mechanisms of immunotherapy resistance, the loss of β-2-microglobulin and interferon gamma receptor 1 expression. We also examined the influence of melanoma driver oncogenes on IFNγ signaling and our data suggest that UVM have diminished capacity to respond to IFNγ, with lower induced expression of several targets, consistent with the disappointing response of UVM to immunotherapies. Our results demonstrate that melanoma responses to IFNγ are heterogeneous, frequently downregulated in immune checkpoint inhibitor-naïve melanoma and potentially predictive of response to immunotherapy

Is chronic kidney disease associated with diabetic retinopathy in Asian adults?

Background: Diabetic nephropathy (DN) is commonly associated with diabetic retinopathy (DR). Few studies have demonstrated that chronic kidney disease (CKD) is associated with DR. However, it is not clear if CKD in the absence of albuminuria is associated with DR. Methods: We included 301 participants with diabetes (Chinese, Malay and Indian ethnicity aged ≥24 years who participated in the Singapore Prospective Study Program (2003-2007). Retinal photographs taken from both eyes were graded for DR using the modified Airlie House Classification. We examined the association of CKD defined by low estimated glomerular filtration rate (eGFR) (&lt;60mL/min per 1.73m2, n=54), and albuminuria (urinary albumin-to-creatinine ratio ≥30, n = 116) with any-DR (n=99) in logistic regression models. We replicated this analysis in another independent population-based sample of Malay adults (n=265) with similar methodology in Singapore. Results: 41% of those with low-eGFR had normoalbuminuria. In separate models, while albuminuria was significantly associated with any-DR, low-eGFR was not significantly associated with any-DR. In a model combining both markers, compared to the referent group (normal-eGFR+normoalbuminuria), the odds ratio (OR) (95% confidence interval [CI]) of any-DR were: 2.33 (1.27-4.27) for normal-eGFR+albuminuria, 1.38 (0.49-3.91) for low-eGFR + normoalbuminuria, and 2.64 (1.05-6.63) for low-eGFR+albuminuria. Similar findings for any-DR were observed in the replication cohort of Malay persons (3.56 [1.49-8.54] for normal-eGFR+albuminuria, 1.69 (0.52-5.55) for low-eGFR+normoalbuminuria, 4.34 [1.68-11.24] for low-eGFR+albuminuria.Conclusion: We demonstrated that CKD is associated with DR only in the presence of albuminuria suggesting that CKD is more likely related to diabetes in the presence of albuminuria.</p

IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects

Longitudinal clinical study of patients with iron rim lesions in multiple sclerosis

Background: Iron rims (IRs) surrounding white matter lesions (WMLs) are suggested to predict a more severe disease course. Only small longitudinal cohorts of patients with and without iron rim lesions (IRLs) have been reported so far. Objective: To assess whether the presence and number of IRLs in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) are associated with long-term disability or progressive disease. Methods: Ninety-one CIS/MS patients were recruited between 2008 and 2013 and scanned with 7 T magnetic resonance imaging (MRI). Expanded Disability Status Scale (EDSS) was used to calculate Age-related Multiple Sclerosis Severity Score (ARMSS) at the time of scan and at the latest clinical follow-up after 9 years. WMLs were assessed for the presence of IRL using Susceptibility weighted imaging (SWI)-filtered phase images. Results: In all, 132 IRLs were detected in 42 patients (46%); 9% of WMLs had IRs; 54% of the cohort had no rims, 30% had 1–3 rims and 16% had ⩾4. Patients with IRL had a higher EDSS and ARMSS. Presence of IRL was also a predictor of long-term disability, especially in patients with ⩾4 IRLs. IRLs have a greater impact on disability compared to the WML number and volume. Conclusion: The presence and number of perilesional IR on MRI hold prognostic value for long-term clinical disability in MS

Interleukin-10 Promoter Polymorphism is Associated with the Predisposition to the Development of IgA Nephropathy and Focal Segmental Glomerulosclerosis in Korea

The roles of interleukin-10 (IL-10) have been emphasized in several models of glomerulonephritis (GN). Three biallelic polymorphisms within the IL-10 promoter region, at positions -1,082, -819, and -592 from the transcription initiation site, were shown to affect the level of IL-10 production. To investigate the effect of IL-10 promoter polymorphisms on the predisposition to development of GN in Korea, IL-10 promoter polymorphisms were assayed by polymerase chain reaction followed by restriction fragment length polymorphism in 108 patients with IgA nephropathy (IgAN), 49 focal segmental glomerulosclerosis (FSGS), and 100 healthy controls. In comparison with the control, the frequency of -1,082*G alleles were lower in IgAN and the frequencies of -592*C and -819*C were lower in FSGS, respectively. As for the haplotype, GCC haplotype was less frequent among IgAN than the control and ATA haplotype was more frequent among FSGS than the control (p<0.05). The frequency of intermediate producer genotypes (GCC/ACC and GCC/ATA) were lower among IgAN or FSGS than the control. Our findings suggested that IL-10 promoter polymorphism predisposed to the development of IgAN and FSGS in Korean patients

Multivariate Neural Representations of Value during Reward Anticipation and Consummation in the Human Orbitofrontal Cortex

The role of the orbitofrontal cortex (OFC) in value processing is a focus of research. Conventional imaging analysis, where smoothing and averaging are employed, may not be sufficiently sensitive in studying the OFC, which has heterogeneous anatomical structures and functions. In this study, we employed representational similarity analysis (RSA) to reveal the multi-voxel fMRI patterns in the OFC associated with value processing during the anticipatory and the consummatory phases. We found that multi-voxel activation patterns in the OFC encoded magnitude and partial valence information (win vs. loss) but not outcome (favourable vs. unfavourable) during reward consummation. Furthermore, the lateral OFC rather than the medial OFC encoded loss information. Also, we found that OFC encoded values in a similar way to the ventral striatum (VS) or the anterior insula (AI) during reward anticipation regardless of motivated response and to the medial prefrontal cortex (MPFC) and the VS in reward consummation. In contrast, univariate analysis did not show changes of activation in the OFC. These findings suggest an important role of the OFC in value processing during reward anticipation and consummation.This study was supported by grants from the National Science Fund China (81088001, 31500894 and 91132701), the Strategic Priority Research Programme (B) of the Chinese Academy of Science (XDB02030002), the Beijing Training Project for the Leading Talents in S & T (Z151100000315020), the Beijing Municipal Science & Technology Commission Grant, and a grant from the initiation fund of the CAS/SAFEA International Partnership Programme for Creative Research Team (Y2CX131003). LS is funded by the NIHR Biomedical Research Centre and Biomedical Research Unit in Dementia based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge

Fluorescent nanoparticles for sensing

Nanoparticle-based fluorescent sensors have emerged as a competitive alternative to small molecule sensors, due to their excellent fluorescence-based sensing capabilities. The tailorability of design, architecture, and photophysical properties has attracted the attention of many research groups, resulting in numerous reports related to novel nanosensors applied in sensing a vast variety of biological analytes. Although semiconducting quantum dots have been the best-known representative of fluorescent nanoparticles for a long time, the increasing popularity of new classes of organic nanoparticle-based sensors, such as carbon dots and polymeric nanoparticles, is due to their biocompatibility, ease of synthesis, and biofunctionalization capabilities. For instance, fluorescent gold and silver nanoclusters have emerged as a less cytotoxic replacement for semiconducting quantum dot sensors. This chapter provides an overview of recent developments in nanoparticle-based sensors for chemical and biological sensing and includes a discussion on unique properties of nanoparticles of different composition, along with their basic mechanism of fluorescence, route of synthesis, and their advantages and limitations