From online banking to biobanking: designing and implementing a data delivery platform for researchers of the China Kadoorie Biobank

Introduction As a large prospective cohort study of 512,891 participants, we routinely integrate data via linkage to population health outcomes to deliver up-to-date research datasets. Building on experience from the private sector, we have implemented a platform that supports the delivery and audit of secure datasets to internal and external researchers. Objectives and Approach We aimed to create a platform that delivers secure research datasets for preliminary analyses and fieldwork with dynamic censor dates. It must also provide multiple static versions of an analysis-ready database with fixed censor dates. Individual participant outcome data from population health sources (death and disease registries and health insurance agencies) can be integrated and linked regularly to other health-related data, e.g., genetic, bioinformatics, and medical device. With knowledge of data management strategies used in major financial institutions, we have produced systems that successfully implement the techniques of data warehousing, multiple concurrent environments and secure dataset access and delivery. Results As at the end of 2017, we had over 300 registered and approved researchers eligible to request datasets. Using our platform, we have recorded over 150 requests and successfully delivered over 100 de-personalised and encrypted datasets to external researchers around the world. In addition, we have supplied secure datasets to over 20 Global Health MSc and DPhil students studying at The University. The platform currently hosts 4 completed analysis-ready databases with censor dates ranging from 31st December 2013 to 11 years of follow-up as of 31st December 2016. A 5th analysis-ready database (with the most recent outcome data from participants’ death, disease and hospitalisations) is already under development. We plan during 2018 to make available more data sources and outcome data to our external researchers. Conclusion/Implications We have developed a versatile platform that delivers secure datasets for researchers from a selection of analysis-ready databases, each with differing censor dates and available data sources. This platform is scalable and can accommodate regular integration of known follow-up data sources along with new and emerging data sources

End-of-Life Preferences of the 'Very Old'

Background: Despite increasing longevity and numbers of ‘very old’ people (aged ≥85 years) and certainty of death, there is limited literature on end-of-life (EOL) preferences of ‘very old’ people, especially in Australia. This study has explored cardio-pulmonary resuscitation (CPR), life-prolonging treatment (LPT) and place of death (POD) preferences of ‘very old’ people in Queensland (Qld), with a Statement of Choices (SoC) (completed 2015-2021) and hospital use and POD of ‘very old’ decedents, with and without a SoC. Methods: CPR, LPT and POD preferences were extracted from 9555 SoCs. Hospital use and POD data of SoC decedents and matched controls were obtained from Qld Health Statistical Branch and analysed with IBM-SPSS v26 using tests and multinomial regressions (p<0.01). Results: Those who preferred no CPR or LPTs (81.9% and 84.5% respectively) were more likely to be female (CPR:2(2)=22.2;LPT:2(2)=24.7), older (CPR:2(6)=71.6;LPT:2(6)=47.6), live in residential aged care facilities (RACFs) (CPR:2(6)=268.1;LPT:2(6)=142.8) and to have lost decision-making capacity (CPR:2(2)=85.6;LPT:2(2)=36.7) (p<0.001). Increasing age reduced odds (0.931) of these collinear characteristics (p<.001,OR.911-.952,CI99%). RACF was the most preferred POD ((12)=2414.1,p<.001,N=8986). Thematic review of preferences focussed on maximising quality of life and a comfortable death. 100% with no SoC and 60% with SoC had ≥1 hospital admission in last 6 months of life (5- and 2- day median cumulative length of stay) while 60% and 32% of ‘very old’ decedents died in hospital respectively (2(1),=436.2,p<.001,N=5890). Conclusion: While unique preferences should be respected, this research demonstrated that most ‘very old’ people would prefer to forgo interventions that prolong life, particularly if they negatively impact quality of life. They preferred EOL care in their home or RACF. A SoC reduced hospital use and hospital death in this cohort

Production of monoclonal antibodies reactive with ovine eosinophils

<p>Abstract</p> <p>Background</p> <p>There is strong evidence implicating eosinophils in host defence against parasites as well as allergic disease pathologies. However, a lack of reagents such as monoclonal antibodies (mAbs) specific for eosinophils has made it difficult to confirm the functional role of eosinophils in such disease conditions. Using an established mammary model of allergic inflammation in sheep, large numbers of inflammatory cells enriched for eosinophils were collected from parasite-stimulated mammary glands and used for the generation of mAbs against ovine eosinophils.</p> <p>Results</p> <p>A panel of mAbs was raised against ovine eosinophils of which two were shown to be highly specific for eosinophils. The reactivity of mAbs 3.252 and 1.2 identified eosinophils from various cell and tissue preparations with no detectable reactivity on cells of myeloid or lymphoid lineage, tissue mast cells, dendritic cells, epithelial cells or other connective tissues. Two other mAbs generated in this study (mAbs 4.4 and 4.10) were found to have reactivity for both eosinophils and neutrophils.</p> <p>Conclusion</p> <p>This study describes the production of new reagents to identify eosinophils (as well as granulocytes) in sheep that will be useful in studying the role of eosinophils in disease pathologies in parasite and allergy models.</p

Automatic coding of nearly 2 million hospitalisation events to ICD-10 in the China Kadoorie Biobank

Introduction Using linkage to the Chinese National Health Insurance (HI) system, we identified disease outcomes from a prospective cohort study of 512,000 middle-aged Chinese adults. Mandarin free-text diagnosis data were supplied by over 30 different agencies across 10 areas, often without an accompanying International Classification of Diseases 10th revision (ICD-10) code. Objectives and Approach To facilitate a genome-wide association study (GWAS) of all our genotyped participants, we needed to code as many of our 2.02 million hospitalisation events as possible. We developed software to assign ICD-10 codes to unique disease descriptions and stored the coded diagnoses in an internal corpus. The software used an interface which allowed clinicians to select and code disease descriptions individually, or collectively using Chinese keywords. All coded disease descriptions were subsequently validated by an independent Mandarin-speaking clinician. All new events with descriptions which matched exactly those already in the corpus were automatically coded to ICD-10. Results By the end of 2016, there were 2,021,352 hospitalisation events coded to ICD-10. 436,702 (21.6%) were automatically assigned codes where disease descriptions corresponded to those in the Chinese version of the ICD-10 codebook. A further 1,084,197 (53.6%) were coded by a clinician using our standardisation software; all disease descriptions linked to 200 or more events were included. Finally, a remaining 454,237 (22.5%) events were given the ICD-10 codes supplied by the health insurance agency (after cleaning). In total, 97.7% of all health insurance events were coded to ICD-10. Overall, over 17,000 unique disease descriptions have been clinically classified. Conclusion/Implications Automatic coding of hospitalisation events to ICD-10 has enabled our study to investigate a greater range of diseases and use GWAS to detect novel genetic variants. We are now well positioned to test semantic matching and machine learning strategies for coding of the remaining 46,216 (2.3%) uncoded events

ΔNp73, A Dominant-Negative Inhibitor of Wild-type p53 and TAp73, Is Up-regulated in Human Tumors

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH2 terminally truncated isoform. ΔNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. ΔNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. ΔNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. ΔNp73 efficiently counteracts transactivation function, apoptosis, and growth suppression mediated by wild-type p53 and TAp73, and confers drug resistance to wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous ΔNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. ΔNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, ΔNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of ΔNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73. This trait might be selected for in human cancers

Smartphone-based remote monitoring of vision in macular disease enables early detection of worsening pathology and need for intravitreal therapy

BACKGROUND/AIMS: To assess the outcomes of home monitoring of distortion caused by macular diseases using a smartphone-based application (app), and to examine them with hospital-based assessments of visual acuity (VA), optical coherence tomography-derived central macular thickness (CMT) and the requirement of intravitreal injection therapy. DESIGN: Observational study with retrospective analysis of data. METHODS: Participants were trained in the correct use of the app (Alleye, Oculocare, Zurich, Switzerland) in person or by using video and telephone consultations. Automated threshold-based alerts were communicated based on a traffic light system. A ‘threshold alarm’ was defined as three consecutive ‘red’ scores, and turned into a ‘persistent alarm’ if present for greater than a 7-day period. Changes of VA and CMT, and the requirement for intravitreal therapy after an alarm were examined. RESULTS: 245 patients performing a total of 11 592 tests (mean 46.9 tests per user) were included and 85 eyes (164 alarms) examined. Mean drop in VA from baseline was −4.23 letters (95% CI: −6.24 to −2.22; p<0.001) and mean increase in CMT was 29.5 µm (95% CI: −0.08 to 59.13; p=0.051). Sixty-six eyes (78.5%) producing alarms either had a drop in VA, increase in CMT or both and 60.0% received an injection. Eyes with persistent alarms had a greater loss of VA, −4.79 letters (95% CI: −6.73 to −2.85; p<0.001) or greater increase in CMT, +87.8 µm (95% CI: 5.2 to 170.4; p=0.038). CONCLUSION: Smartphone-based self-tests for macular disease may serve as reliable indicators for the worsening of pathology and the need for treatment

Lethal and mutagenic effects of ultraviolet radiation on Glomerella conidia

1. 1) The survival curves of ultraviolet irradiated Glomerella conidia have a sigmoid shape. The sigmoid survival curve may be described as a 7 hit curve (approximately) or as indicating radiation-produced toxic substances with a threshold for lethal action.2. 2) At high doses of radiation the survival curve levels off to form a long plateau. This plateau in the curve indicates the presence of a small proportion of resistant spores among the sensitive population. The resistant spores may be observed under the microscope and are characterized by the presence of melanin pigment in the spore in contrast to the great majority of Glomerella conidia which appear colorless. The proportion of resistant spores increases with increasing age of the spore culture.3. 3) With increasing dose of ultraviolet radiation the mutation curve rises to a peak and then declines at higher doses of radiation. This decline in the frequency of mutants among the surviving spores is due to an increasing proportion of resistant pigmented spores among the surviving population at high doses. The mutation curve for sensitive spores alone does not decline at the higher doses of radiation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32538/1/0000647.pd

p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents

Of less known literary work of Ivan Golub before the 1990s

Kronologija objavljivanja književnih djela svećenika, književnika i znanstvenika Ivana Goluba sugerira da se, osim rijetkih izuzetaka iz ranijeg razdoblja, književnim stvaralaštvom intenzivnije počeo baviti tek 1990-ih godina. No, kada u obzir uzmemo do danas uglavnom nepoznata njegova djela koja su nastala znatno prije, ali su objavljena tek 1990-ih godina, i to vjerojatno prije svega zahvaljujući slomu komunističkog društveno-političkog poretka koji je do tada proskribirao književnost kršćanskog nadahnuća, postaje jasno da se Golub književnim stvaralaštvom u kontinuitetu i otprilike jednakim intenzitetom ustvari bavio još od 1970-ih pa sve do danas.The order in which literary works by Ivan Golub, a Croatian priest, author and scientist, were published suggests, with some rare exceptions early on, that he started writing intensely only after the 1990s. However, we should take into consideration his works that are mostly unknown today and were created well before, but published only in the 1990s. That is probably because of the collapse of the communist socio-political order, which had prohibited literature of Christian inspiration up until then. It then becomes clear that Golub has been writing with the same intensity ever since the 1970s and to this day