The uptake of soluble and nanoparticulate imaging isotope in model liver tumours after intra-venous and intra-arterial administration

Delivery of chemotherapeutic drugs to tumours by reformulation as nanoparticles has often been proposed as a means of facilitating increased selective uptake, exploiting the increased permeability of the tumour vasculature. However realisation of this improvement in drug delivery in cancer patients has met with limited success. We have compared tumour uptake of soluble Tc99m-pertechnetate and a colloid of nanoparticles with a Tc99m core, using both intra-venous and intra-arterial routes of administration in a rabbit liver VX2 tumour model. The radiolabelled nanoparticles were tested both in untreated and cationised form. The results from this tumour model in an internal organ show a marked advantage in intra-arterial administration over the intra-venous route, even for the soluble isotope. Tumour accumulation of nanoparticles from arterial administration was augmented by cationisation of the nanoparticle surface with histone proteins, which consistently facilitated selective accumulation within microvessels at the periphery of tumours.Sources of support for this research: Sirtex Medical Ltd, Sydney Australia

Observed intra-cluster correlation coefficients in a cluster survey sample of patient encounters in general practice in Australia

BACKGROUND: Cluster sample study designs are cost effective, however cluster samples violate the simple random sample assumption of independence of observations. Failure to account for the intra-cluster correlation of observations when sampling through clusters may lead to an under-powered study. Researchers therefore need estimates of intra-cluster correlation for a range of outcomes to calculate sample size. We report intra-cluster correlation coefficients observed within a large-scale cross-sectional study of general practice in Australia, where the general practitioner (GP) was the primary sampling unit and the patient encounter was the unit of inference. METHODS: Each year the Bettering the Evaluation and Care of Health (BEACH) study recruits a random sample of approximately 1,000 GPs across Australia. Each GP completes details of 100 consecutive patient encounters. Intra-cluster correlation coefficients were estimated for patient demographics, morbidity managed and treatments received. Intra-cluster correlation coefficients were estimated for descriptive outcomes and for associations between outcomes and predictors and were compared across two independent samples of GPs drawn three years apart. RESULTS: Between April 1999 and March 2000, a random sample of 1,047 Australian general practitioners recorded details of 104,700 patient encounters. Intra-cluster correlation coefficients for patient demographics ranged from 0.055 for patient sex to 0.451 for language spoken at home. Intra-cluster correlations for morbidity variables ranged from 0.005 for the management of eye problems to 0.059 for management of psychological problems. Intra-cluster correlation for the association between two variables was smaller than the descriptive intra-cluster correlation of each variable. When compared with the April 2002 to March 2003 sample (1,008 GPs) the estimated intra-cluster correlation coefficients were found to be consistent across samples. CONCLUSIONS: The demonstrated precision and reliability of the estimated intra-cluster correlations indicate that these coefficients will be useful for calculating sample sizes in future general practice surveys that use the GP as the primary sampling unit

Experiences Applying Technology to Overcome Common Challenges in Pharmacy Practice-Based Research in the United States

Despite the importance of pharmacy practice-based research in generating knowledge that results in better outcomes for patients, health systems and society alike, common challenges to PPBR persist. Herein, we authors describe PPBR challenges our research teams have encountered, and our experiences using technology-driven solutions to overcome such challenges. Notably, limited financial resources reduce the time available for clinicians and researchers to participate in study activities; therefore, resource allocation must be optimized. We authors have also encountered primary data collection challenges due to unique data needs and data access/ownership issues. Moreover, we have experienced a wide geographic dispersion of study practices and collaborating researchers; a lack of trained, on-site research personnel; and the identification and enrollment of participants meeting study eligibility criteria. To address these PPBR challenges, we authors have begun to turn to technology-driven solutions, as described here

In vivo tumour imaging employing regional delivery of novel gallium radiolabelled polymer composites

Background: Understanding the regional vascular delivery of particles to tumour sites is a prerequisite for developing new diagnostic and therapeutic composites for treatment of oncology patients. We describe a novel imageable 67Ga-radiolabelled polymer composite that is biocompatible in an animal tumour model and can be used for preclinical imaging investigations of the transit of different sized particles through arterial networks of normal and tumour-bearing organs. Results: Radiolabelling of polymer microspheres with 67Ga was achieved using a simple mix and wash method, with tannic acid as an immobilising agent. Final in vitro binding yields after autoclaving averaged 94.7%. In vivo stability of the composite was demonstrated in New Zealand white rabbits by intravenous administration, and intrahepatic artery instillations were made in normal and VX2 tumour implanted rabbit livers. Stability of radiolabel was sufficient for rabbit lung and liver imaging over at least 3 hours and 1 hour respectively, with lung retention of radiolabel over 91%, and retention in both normal and VX2 implanted livers of over 95%. SPECT-CT imaging of anaesthetised animals and planar imaging of excised livers showed visible accumulation of radiolabel in tumours. Importantly, microsphere administration and complete liver dispersal was more easily achieved with 8 μm diameter MS than with 30 μm MS, and the smaller microspheres provided more distinct and localised tumour imaging. Conclusion: This method of producing 67Ga-radiolabelled polymer microspheres is suitable for SPECT-CT imaging of the regional vascular delivery of microspheres to tumour sites in animal models. Sharper distinction of model tumours from normal liver was obtained with smaller MS, and tumour resolution may be further improved by the use of 68Ga instead of 67Ga, to enable PET imaging.The ANU authors acknowledge the collaborative research project support generously provided to ANU by Sirtex Medical Ltd. (Sydney), including donation of a GE Hawkeye Infinia SPECT/CT scanner and a Xeleris image processing system

The Surgical Nosology In Primary-care Settings (SNIPS): a simple bridging classification for the interface between primary and specialist care

BACKGROUND: The interface between primary care and specialist medical services is an important domain for health services research and policy. Of particular concern is optimising specialist services and the organisation of the specialist workforce to meet the needs and demands for specialist care, particularly those generated by referral from primary care. However, differences in the disease classification and reporting of the work of primary and specialist surgical sectors hamper such research. This paper describes the development of a bridging classification for use in the study of potential surgical problems in primary care settings, and for classifying referrals to surgical specialties. METHODS: A three stage process was undertaken, which involved: (1) defining the categories of surgical disorders from a specialist perspective that were relevant to the specialist-primary care interface; (2) classifying the 'terms' in the International Classification of Primary Care Version 2-Plus (ICPC-2 Plus) to the surgical categories; and (3) using referral data from 303,000 patient encounters in the BEACH study of general practice activity in Australia to define a core set of surgical conditions. Inclusion of terms was based on the probability of specialist referral of patients with such problems, and specialists' perception that they constitute part of normal surgical practice. RESULTS: A four-level hierarchy was developed, containing 8, 27 and 79 categories in the first, second and third levels, respectively. These categories classified 2050 ICPC-2 Plus terms that constituted the fourth level, and which covered the spectrum of problems that were managed in primary care and referred to surgical specialists. CONCLUSION: Our method of classifying terms from a primary care classification system to categories delineated by specialists should be applicable to research addressing the interface between primary and specialist care. By describing the process and putting the bridging classification system in the public domain, we invite comment and application in other settings where similar problems might be faced

The contribution of demographic and morbidity factors to self-reported visit frequency of patients: a cross-sectional study of general practice patients in Australia

BACKGROUND: Understanding the factors that affect patients' utilisation of health services is important for health service provision and effective patient management. This study aimed to investigate the specific morbidity and demographic factors related to the frequency with which general practice patients visit a general practitioner/family physician (GP) in Australia. METHODS: A sub-study was undertaken as part of an ongoing national study of general practice activity in Australia. A cluster sample of 10,755 general practice patients were surveyed through a random sample of 379 general practitioners. The patient reported the number of times he/she had visited a general practitioner in the previous twelve months. The GP recorded all the patient's major health problems, including those managed at the current consultation. RESULTS: Patients reported an average of 8.8 visits to a general practitioner per year. After adjusting for other patient demographics and number of health problems, concession health care card holders made on average 2.6 more visits per year to a general practitioner than did non-card holders (p < .001). After adjustment, patients from remote/very remote locations made 2.3 fewer visits per year than patients from locations where services were highly accessible (p < .001). After adjustment for patient demographics, patients with diagnosed anxiety made on average 2.7 more visits per year (p = 0.003), those with diagnosed depression 2.2 more visits than average (p < .0001), and those with back problems 2.4 more visits (p = 0.009) than patients without the respective disorders. CONCLUSIONS: Anxiety, back pain and depression are associated with greater patient demand for general practice services than other health problems. The effect of sociodemographic factors on patient utilisation of general practice services is complex. Equity of access to general practice services remains an issue for patients from remote areas, while concession health care card holders are attending general practice more frequently than other patients relative to their number of health problems

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study

Background: The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. Methods: We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. Results: Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age \u3e50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections. Conclusions: Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes