Understanding Pathways into Care-homes using Data (UnPiCD study): a two-part model to estimate inpatient and care-home costs using national linked health and social care data.

BACKGROUND: Pathways into care-homes have been under-researched. Individuals who move-in to a care-home from hospital are clinically distinct from those moving-in from the community. However, it remains unclear whether the source of care-home admission has any implications in term of costs. Our aim was to quantify hospital and care-home costs for individuals newly moving-in to care homes to compare those moving-in from hospital to those moving-in from the community. METHODS: Using routinely-collected national social care and health data we constructed a cohort including people moving into care-homes from hospital and community settings between 01/04/2013-31/03/2015 based on records from the Scottish Care-Home Census (SCHC). Individual-level data were obtained from Scottish Morbidity Records (SMR01/04/50) and death records from National Records of Scotland (NRS). Unit costs were identified from NHS Scotland costs data and care-home costs from the SCHC. We used a two-part model to estimate costs conditional on having incurred positive costs. Additional analyses estimated differences in costs for the one-year period preceding and following care-home admission. RESULTS: We included 14,877 individuals moving-in to a care-home, 8,472 (57%) from hospital, and 6,405 (43%) from the community. Individuals moving-in to care-homes from the community incurred higher costs at £27,117 (95% CI £ 26,641 to £ 27,594) than those moving-in from hospital with £24,426 (95% CI £ 24,037 to £ 24,814). Hospital costs incurred during the year preceding care-home admission were substantially higher (£8,323 (95% CI£8,168 to £8,477) compared to those incurred after moving-in to care-home (£1,670 (95% CI£1,591 to £1,750). CONCLUSION: Individuals moving-in from hospital and community have different needs, and this is reflected in the difference in costs incurred. The reduction in hospital costs in the year after moving-in to a care-home indicates the positive contribution of care-home residency in supporting those with complex needs. These data provide an important contribution to inform capacity planning on care provision for adults with complex needs and the costs of care provision.

Increased care at discharge from COVID-19: The association between pre-admission frailty and increased care needs after hospital discharge; a multicentre European observational cohort study.

BACKGROUND: The COVID-19 pandemic has placed significant pressure on health and social care. Survivors of COVID-19 may be left with substantial functional deficits requiring ongoing care. We aimed to determine whether pre-admission frailty was associated with increased care needs at discharge for patients admitted to hospital with COVID-19. METHODS: Patients were included if aged over 18 years old and admitted to hospital with COVID-19 between 27 February and 10 June 2020. The Clinical Frailty Scale (CFS) was used to assess pre-admission frailty status. Admission and discharge care levels were recorded. Data were analysed using a mixed-effects logistic regression adjusted for age, sex, smoking status, comorbidities, and admission CRP as a marker of severity of disease. RESULTS: Thirteen hospitals included patients: 1671 patients were screened, and 840 were excluded including, 521 patients who died before discharge (31.1%). Of the 831 patients who were discharged, the median age was 71 years (IQR, 58-81 years) and 369 (44.4%) were women. The median length of hospital stay was 12 days (IQR 6-24). Using the CFS, 438 (47.0%) were living with frailty (≥ CFS 5), and 193 (23.2%) required an increase in the level of care provided. Multivariable analysis showed that frailty was associated with an increase in care needs compared to patients without frailty (CFS 1-3). The adjusted odds ratios (aOR) were as follows: CFS 4, 1.99 (0.97-4.11); CFS 5, 3.77 (1.94-7.32); CFS 6, 4.04 (2.09-7.82); CFS 7, 2.16 (1.12-4.20); and CFS 8, 3.19 (1.06-9.56). CONCLUSIONS: Around a quarter of patients admitted with COVID-19 had increased care needs at discharge. Pre-admission frailty was strongly associated with the need for an increased level of care at discharge. Our results have implications for service planning and public health policy as well as a person's functional outcome, suggesting that frailty screening should be utilised for predictive modelling and early individualised discharge planning.

Systematic review and meta-analysis of risk factors for postoperative delirium among older patients undergoing gastrointestinal surgery.

BACKGROUND: Postoperative delirium (POD) is common after surgery. As age is a known risk factor, the increased ageing of the population undergoing surgery emphasizes the importance of the subject. Knowledge of other potential risk factors in older patients with surgical gastrointestinal diseases is lacking. The aim here was to collate and synthesize the published literature on risk factors for delirium in this group. METHODS: Five databases were searched (MEDLINE, Web of Science, Embase, CINAHL(®) and PSYCinfo(®) ) between January 1987 and November 2014. The Newcastle-Ottawa Scale was used to rate study quality. Pooled odds ratios or mean differences for individual risk factors were estimated using the Mantel-Haenszel and inverse-variance methods. RESULTS: Eleven studies met the inclusion criteria; they provided a total of 1427 patients (318 with delirium and 1109 without), and predominantly included patients undergoing elective colorectal surgery. The incidence of POD ranged from 8·2 to 54·4 per cent. A total of 95 risk factors were investigated, illustrating wide heterogeneity in study design. Seven statistically significant risk factors were identified in pooled analysis: old age, American Society of Anesthesiologists (ASA) physical status grade at least III, body mass index, lower serum level of albumin, intraoperative hypotension, perioperative blood transfusion and history of alcohol excess. Patients with POD had a significantly increased duration of hospital stay and a higher mortality rate compared with those without delirium. CONCLUSION: Delirium is common in older patients undergoing gastrointestinal surgery. Several risk factors were consistently associated with POD.

Readability and Writing Quality in Radiation Oncology Journal Articles from 2004-2024.

PURPOSE: Scientific literature is a vital tool which we rely upon to communicate the findings of our studies; however, we rarely direct our study to the writing itself. METHODS AND MATERIALS: Here, we make use of modern natural language processing algorithms coupled with the large, open access PubMed Central corpus to analyze trends in writing complexity within the field of radiation oncology from 2004-2024. Changes in 1) required grade-level to comprehend, 2) lexical complexity, and 3) information content were assessed. Articles were also classified-and then analyzed-by disease subsite. RESULTS: We found significant increases in the three domains over the twenty-year collection period. Genitourinary literature had the greatest readability while gastrointestinal literature was the most complex. CONCLUSIONS: This analysis reveals broad increases in the complexity of our writing. This study demonstrates metrics to use, and benchmark values to refer to, to evaluate the complexity of radiation oncology journal articles.

Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Interstitial Brachytherapy Is Safe: First Results From the Tri-fraction Radiation Therapy Used to Minimize Patient Hospital Trips (TRIUMPH-T) Trial.

PURPOSE: Shorter courses of breast radiotherapy are offered as an alternative to 4 weeks of whole-breast irradiation after lumpectomy, including brachytherapy. A prospective phase 2multi-institution clinical trial to study 3-fraction accelerated partial breast irradiation delivered by brachytherapy was conducted. METHODS AND MATERIALS: The trial treated selected breast cancers after breast-conserving surgery with brachytherapy applicators that delivered 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 2 cm beyond the surgical cavity. Eligible women were age ≥45 years with unicentric invasive or in situ tumors ≤3 cm excised with negative margins and with positive estrogen or progesterone receptors and no metastases to axillary nodes. Strict dosimetric parameters were required to be met and follow up information was collected from the participating sites. RESULTS: Two hundred patients were prospectively enrolled; however, a total of 185 patients who were enrolled were followed for a median of 3.63 years. Three-fraction brachytherapy was associated with low chronic toxicity. There was excellent or good cosmesis in 94% of patients. There were no grade 4 toxicities. Grade 3 fibrosis at the treatment site was present in 1.7% and 32% percent had grades 1 or 2 fibrosis at the treatment site. There was 1 rib fracture. Other late toxicities included 7.4% grade 1 hyperpigmentation, 2% grade 1 telangiectasias, 1.7% symptomatic seromas, 1.7% abscessed cavities, and 1.1% symptomatic fat necrosis. There were 2 (1.1%) ipsilateral local recurrences, 2 (1.1%) nodal recurrences and no distant recurrences. Other incidents included one contralateral breast cancer and 2 second malignancies (lung). CONCLUSIONS: Ultra-short breast brachytherapy is feasible and has excellent toxicity and could be an alternative to standard 5-day, 10 fraction accelerated partial breast irradiation in eligible patients. Patients from this prospective trial will continue to be followed to evaluate long-term outcomes.

Prestroke modified rankin stroke scale has moderate interobserver reliability and validity in an acute stroke setting.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is the recommended functional outcome assessment in stroke trials. Utility of mRS may be limited by interobserver variability. prestroke function, described using mRS, is often used as trial entry criterion. We assessed the reliability and validity of prestroke mRS in acute stroke. METHODS: We present two complementary analyses of the properties of prestroke mRS: (1) Paired interviewers (trained in mRS) performed independently a blinded assessment of mRS and prestroke mRS. Interobserver variability was described using percentage agreement and weighted (kw) κ statistics with 95% confidence interval (95% CI). Validity was assessed by comparing prestroke mRS with other markers of function (comorbidity; medication count; need for carers). (2) We further assessed validity using a larger retrospective dataset. We compared prestroke mRS with Charlson comorbidity index (CCI) and the Rockwood frailty index. Rank correlation coefficient or Fisher exact test were used as appropriate. RESULTS: Paired interviewers assessed 74 stroke survivors. Median standard mRS was 4 (interquartile range [IQR], 2-4), median prestroke mRS was 1 (IQR, 0-3; range, 0-4). Reliability for standard mRS interview was 56% agreement, kw=0.55 (95% CI, 0.39-0.71). Reliability for prestroke mRS was 70%, kw=0.70 (95% CI, 0.53-0.87). The retrospective dataset described 231 subjects. In this data set, Spearman Rho for prestroke mRS and frailty index was J. 0.82 (95% CI, 0.78-0.86); CCI 0.50 (95% CI, 0.40-0.59); patient age 0.45 (95% CI, 0.34-0.54); medication count 0.28 (95% CI, 0.15-0.40). There was no association between need for carers and prestroke mRS (p=0.10). CONCLUSIONS: Interobserver reliability of prestroke mRS is limited but comparable with standard mRS. Poor correlation of prestroke mRS with certain markers of function suggests limited validity. Our data would suggest that relying on mRS alone may be a suboptimal measure of prestroke function and could potentially bias trial samples.

The effect of krill oil supplementation on skeletal muscle function and size in older adults: A randomised controlled trial.

BACKGROUND & AIMS: The aim of this study was to determine the effect of krill oil supplementation, on muscle function and size in healthy older adults. METHODS: Men and women, aged above 65 years, with a BMI less than 35kg/m2, who participated in less than 1h per week of structured self-reported exercise, were enrolled in the study (NCT04048096) between March 2018 and March 2020. Participants were randomised to either control or krill oil supplements (4g/day) for 6 months in this double blind randomised controlled trial. At baseline, 6 weeks and 6 months, knee extensor maximal torque was measured as the primary outcome of the study. Secondary outcomes measured were grip strength, vastus lateralis muscle thickness, short performance physical battery test, body fat, muscle mass, blood lipids, glucose, insulin, and C-Reactive Protein, neuromuscular (M-Wave, RMS and voluntary activation), and erythrocyte fatty acid composition. RESULTS: A total of 102 men and women were enrolled in the study. Ninety-four participants (krill group (26 women and 23 men) and placebo group (27 women and 18 men)) completed the study (mean (SD): age 71.2 (5.1) years and weight 71.8 (12.3) kg). Six months supplementation with krill oil resulted in, an increase in knee extensor maximal torque, grip strength and vastus lateralis muscle thickness, relative to control (p<0.05). The 6-month treatment effects were 9.3% (95%CI: 2.8, 15.8%), 10.9% (95%CI: 8.3, 13.6%) and 3.5% (95%CI: 2.1, 4.9%) respectively. Increases in erythrocyte fatty acid profile were seen with krill oil for EPA 214% (95%CI: 166, 262%), DHA 36% (95%CI: 24, 48%) and the omega-3 index 61% (95%CI: 49, 73%), relative to control (p < 0.05). Krill oil resulted in an increased, relative to control (p < 0.05), M-Wave of 17% (95%CI: 12.7, 38.1%) but there was no effect of krill oil on RMS, voluntary activation, or on any other secondary outcomes such as performance of the short performance physical battery test or quality of life. CONCLUSION: Krill oil supplementation for 6 months results in statistically and clinically significant increases in muscle function and size in healthy older adults. GOV IDENTIFIER: NCT04048096.

The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland.

In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer's disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom - cognitive decline - is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland's clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.

Patient-reported outcome measures (PROMs) use in post-stroke patient care and clinical practice: a realist synthesis protocol.

BACKGROUND: There is growing interest in the use of routine patient-reported outcome measures (PROMs) to influence the care of individual patients with stroke. However, there are significant gaps in our understanding as to how PROMs influence post-stroke patient care and clinical practice. This is due to factors including the number of purported uses for PROMs and that PROMs are complex interventions, which attempt to stimulate varied actions or behaviours. Therefore, the objective of this realist synthesis is to offer theory-based explanations as to how PROMs influence post-stroke clinical practice and patient care. METHODS: This is a protocol for a realist synthesis, which involves three distinct phases: theory building (phase 1), theory testing and refinement (phase 2) and synthesis (phase 3). Phase 1 will develop initial rough programme theories (IRPTs), through literature searches (from January 2000 onwards) of MEDLINE, EMBASE, PsycINFO, CINAHL, Cochrane Library and the grey literature. Only secondary sources will be included that contribute to the development of IRPTs. Only two IRPTs, prioritised by the stakeholder group, will be taken forward to be tested and refined during phase 2. Further novel searches will be employed in phase 2, utilising the same criteria as phase 1; however, phase 2 searches will not utilise grey literature searches, and only primary research studies that contribute to the refinement of programme theories under investigation will be included. Two independent reviewers will screen and select all returned results. The reviewers will code and annotate relevant sources, resulting in 'fragments' to be extracted and graded based on the richness of their contribution to explanation and causal insight. Further, these fragments will be organised into 'Context-Mechanism-Outcome' configurations. Phase 3 of the review will involve the synthesis of context-mechanism-outcome configurations to form middle-range theory-based explanations and developed logic models for stakeholders to understand how PROMs in post-stroke clinical practice and patient care work for whom, how and under what circumstances. DISCUSSION: The resulting realist synthesis will provide guidance on the implementation of PROMs within routine post-stroke clinical practice and patient care and act as a touchstone for further testing and refinement of PROMs programmes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020138649 .

Closing the UK care home data gap - methodological challenges and solutions.

UK care home residents are invisible in national datasets. The COVID-19 pandemic has exposed data failings that have hindered service development and research for years. Fundamental gaps, in terms of population and service demographics coupled with difficulties identifying the population in routine data are a significant limitation. These challenges are a key factor underpinning the failure to provide timely and responsive policy decisions to support care homes. In this commentary we propose changes that could address this data gap, priorities include: (1) Reliable identification of care home residents and their tenure; (2) Common identifiers to facilitate linkage between data sources from different sectors; (3) Individual-level, anonymised data inclusive of mortality irrespective of where death occurs; (4) Investment in capacity for large-scale, anonymised linked data analysis within social care working in partnership with academics; (5) Recognition of the need for collaborative working to use novel data sources, working to understand their meaning and ensure correct interpretation; (6) Better integration of information governance, enabling safe access for legitimate analyses from all relevant sectors; (7) A core national dataset for care homes developed in collaboration with key stakeholders to support integrated care delivery, service planning, commissioning, policy and research. Our suggestions are immediately actionable with political will and investment. We should seize this opportunity to capitalise on the spotlight the pandemic has thrown on the vulnerable populations living in care homes to invest in data-informed approaches to support care, evidence-based policy making and research.

Equality of access to "fast-track" stroke services in an older, socio-economically deprived Scottish population.

BACKGROUND AND AIMS: Unequal access to specialist stroke services may contribute to the disproportionate stroke burden in certain populations. We evaluated the relationship between access to TIA services, deprivation and age. METHODS: We prospectively recorded referral pattern data on consecutive TIA service patients. Socio-economic deprivation was derived from postcode and census data. Associations were described using Kruskal-Wallis statistics. RESULTS: Of 3,462 patients assessed, there was no association between time to clinic referral or attendance and increasing deprivation or age. CONCLUSION: Inequality of access to TIA services for older, deprived patients was not evident. However, delay to assessment and prevalence of risk factors was substantial for all patients.

Nosocomial COVID-19 infection: examining the risk of mortality. The COPE-Nosocomial Study (COVID in Older PEople).

BACKGROUND: Hospital admissions for non-coronavirus disease 2019 (COVID-19) pathology have decreased significantly. It is believed that this may be due to public anxiety about acquiring COVID-19 infection in hospital and the subsequent risk of mortality. AIM: To identify patients who acquire COVID-19 in hospital (nosocomial COVID-19 infection (NC)) and their risk of mortality compared to those with community-acquired COVID-19 (CAC) infection. METHODS: The COPE-Nosocomial Study was an observational cohort study. The primary outcome was the time to all-cause mortality (estimated with an adjusted hazard ratio (aHR)), and secondary outcomes were day 7 mortality and the time-to-discharge. A mixed-effects multivariable Cox's proportional hazards model was used, adjusted for demographics and comorbidities. FINDINGS: The study included 1564 patients from 10 hospital sites throughout the UK, and one in Italy, and collected outcomes on patients admitted up to April 28th, 2020. In all, 12.5% of COVID-19 infections were acquired in hospital; 425 (27.2%) patients with COVID died. The median survival time in NC patients was 14 days compared with 10 days in CAC patients. In the primary analysis, NC infection was associated with lower mortality rate (aHR: 0.71; 95% confidence interval (CI): 0.51-0.98). Secondary outcomes found no difference in day 7 mortality (adjusted odds ratio: 0.79; 95% CI: 0.47-1.31), but NC patients required longer time in hospital during convalescence (aHR: 0.49, 95% CI: 0.37-0.66). CONCLUSION: The minority of COVID-19 cases were the result of NC transmission. No COVID-19 infection comes without risk, but patients with NC had a lower risk of mortality compared to CAC infection; however, caution should be taken when interpreting this finding.

Hyperglycaemia in acute stroke--to treat or not to treat.

Diabetes is common amongst patients with stroke and is associated with poorer outcome. Post-stroke hyperglycaemia is also recognised in up to half of the patients, and is independently associated with adverse sequelae: both increased mortality and poorer functional outcomes. Neither the aetiology nor the pathophysiology of such hyperglycaemia is fully understood. Both direct neurological toxicity and systemic consequences are postulated to occur. A distinction between occult diabetes and non-diabetic hyperglycaemia seems important as prognosis and effect of intervention differ in these two groups. The optimal management of the milder forms of hyperglycaemia associated with acute stroke is unknown. Randomised trial data remain limited but presently offer no strong support for aggressive intervention in stroke, though in other critical illness settings tight control of blood sugar appears beneficial. Studies based in coronary care and high dependency units have shown a possible beneficial effect of insulin, but evidence for intervention in acute stroke is at best limited. However, if glucose management is to be undertaken, this should be instituted while there is still salvageable tissue and the glucose reduction must be substantial. Intravenous insulin may be more effective than glucose-potassium-insulin infusion. Both interventions carry a risk of hypoglycaemia and any proposed intervention must balance safety, convenience and glycaemic control. Until further trial data are available, consensus guidelines may be followed, which are generally conservative for blood glucose levels below 10 mM (180 mg/dl).

Dr John Rankin; his life, legacy and the 50th anniversary of the Rankin Stroke Scale.

Dr John Rankin (1923-1981) is one of the many distinguished alumni of the former University Department of Materia Medica and Therapeutics, Stobhill Hospital Glasgow. While his varied international career encompassed pulmonary physiology, occupational medicine and public health, he remains best remembered in the United Kingdom for his early stroke publications. In a series of articles published 50 years ago in the Scottish Medical Journal he described early rehabilitative stroke medicine using a novel grading system. Half a century on Rankin's eponymous stroke scale has become the endpoint of choice in acute stroke trials. This paper describes Rankin's remarkable career and the legacy of his work, with a particular focus on his stroke research and grading system.

CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract.

Since unmethylated CpG motifs are more frequent in DNA from bacteria than vertebrates, and the unmethylated CpG motif has recently been reported to have stimulatory effects on lymphocytes, we speculated that bacterial DNA may induce inflammation in the lower respiratory tract through its content of unmethylated CpG motifs. To determine the role of bacterial DNA in lower airway inflammation, we intratracheally instilled prokaryotic and eukaryotic DNA in C3H/HeBFEJ mice and performed whole lung lavage 4 h after the exposure. Heat denatured, single stranded Escherichia coli genomic DNA (0.06 ng endotoxin/microg DNA) was compared to heat denatured, single stranded calf thymus DNA (0.007 endotoxin/microg DNA). 10 microg of bacterial DNA, in comparison to 10 microg of calf thymus DNA, resulted in a fourfold increase in the concentration of cells (P = 0.0002), a fivefold increase in the concentration of neutrophils (P = 0.0002), a 50-fold increase in the concentration of TNF-alpha (P = 0.001), and a fourfold increase in the concentration of both IL-6 (P = 0.0003) and macrophage inflammatory protein-2 (P = 0.0001) in the lavage fluid. Importantly, instillation of 0.60 ng of E. coli LPS resulted in a negligible inflammatory response. To test whether the stimulatory effects of bacterial DNA are due to its unmethylated CpG dinucleotides, we methylated the bacterial DNA and also prepared 20 base pair oligonucleotides with and without CpG motifs. In comparison to instillation of untreated bacterial DNA, methylation of the bacterial DNA resulted in a significant reduction in the concentration of cells and cytokines in the lower respiratory tract. Moreover, oligonucleotides containing embedded unmethylated CpG motifs resulted in inflammation in the lower respiratory tract that was indistinguishable from that observed with untreated bacterial DNA. In contrast, oligonucleotides without the embedded CpG motifs or with embedded but methylated CpG motifs resulted in significantly less inflammation in the lower respiratory tract. The possible relevance of these data to human disease was shown by extracting and analyzing DNA in sputum from patients with cystic fibrosis (CF). Approximately 0.1 to 1% of this sputum DNA was bacterial. Intratracheal instillation of highly purified CF sputum DNA caused acute inflammation similar to that induced by bacterial DNA. These findings suggest that bacterial DNA, and unmethylated CpG motifs in particular, may play an important pathogenic role in inflammatory lung disease.

Preclinical evaluation of radiation and systemic, RGD-targeted, adeno-associated virus phage-TNF gene therapy in a mouse model of spontaneously metastatic melanoma.

The incidence of melanoma in the United States continues to rise, with metastatic lesions notoriously recalcitrant to therapy. There are limited effective treatment options available and a great need for more effective therapies that can be rapidly integrated in the clinic. In this study, we demonstrate that the combination of RGD-targeted adeno-associated virus phage (RGD-AAVP-TNF) with hypofractionated radiation therapy results in synergistic inhibition of primary syngeneic B16 melanoma in a C57 mouse model. Furthermore, this combination appeared to modify the tumor microenvironment, resulting in decreased Tregs in the draining LN and increased tumor-associated macrophages within the primary tumor. Finally, there appeared to be a reduction in metastatic potential and a prolongation of overall survival in the combined treatment group. These results indicate the use of targeted TNF gene therapy vector with radiation treatment could be a valuable treatment option for patients with metastatic melanoma.

Very low density lipoproteins (VLDL) trigger the release of histamine from human basophils.

Circulating basophils are well established sources of the granule-associated mediator, histamine. The physiological control, however, of histamine release from human basophils is poorly understood. Because histamine may play a role in the transendothelial transport of various compounds, including very low density lipoprotein (VLDL) and its hydrolysis products, we investigated the possibility that VLDL regulates mediator release from basophils. The incubation of VLDL (at physiological concentrations) with basophils (isolated as mixed leukocyte preparations) resulted in a significant release of histamine. Histamine release was dependent on VLDL concentration (half-maximal stimulation occurring at VLDL-protein concentration of 15-20 micrograms/ml), length of incubation (half-maximal release at 5-12 min), temperature (37 degrees C optimum) and required calcium (concentration 0.5-2.0 mM). Furthermore, VLDL-induced histamine release was inhibited by three different mediator-release inhibitors: dimaprit, dibutyryl cAMP and nordihydroguaiaretic acid. Incubation of basophils with LDL or HDL under the same experimental conditions did not result in significant histamine release from basophils. The histamine-secretory response of basophils obtained from different donors varied considerably. Basophils isolated from 28 donors and challenged with 100 micrograms/ml VLDL released 23 +/- 5% of their cellular histamine (mean +/- S.E.; with a range of 0-94%). Desensitization of VLDL-induced histamine release could be accomplished by preincubation of basophils with either VLDL or anti-IgE but not with N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Through the secretion of histamine, a potent vasoactive mediator (and also possibly through granule-associated glycosaminoglycans, stimulants of the enzyme lipoprotein lipase), this novel effect of VLDL may be part of a physiological loop for the regulation of VLDL hydrolysis and lipid transport. This effect of VLDL may also have deleterious consequences, because of the atherogenic properties of histamine.

Semi-automatic cone beam CT segmentation of in vivo pre-clinical subcutaneous tumours provides an efficient non-invasive alternative for tumour volume measurements.

OBJECTIVE: To evaluate the feasibility and accuracy of using cone beam CT (CBCT) scans obtained in radiation studies using the small-animal radiation research platform to perform semi-automatic tumour segmentation of pre-clinical tumour volumes. METHODS: Volume measurements were evaluated for different anatomical tumour sites, the flank, thigh and dorsum of the hind foot, for a variety of tumour cell lines. The estimated tumour volumes from CBCT and manual calliper measurements using different volume equations were compared with the "gold standard", measured by weighing the tumours following euthanasia and tumour resection. The correlation between tumour volumes estimated with the different methods, compared with the gold standard, was estimated by the Spearman's rank correlation coefficient, root-mean-square deviation and the coefficient of determination. RESULTS: The semi-automatic CBCT volume segmentation performed favourably compared with manual calliper measures for flank tumours ≤2 cm(3) and thigh tumours ≤1 cm(3). For tumours >2 cm(3) or foot tumours, the CBCT method was not able to accurately segment the tumour volumes and manual calliper measures were superior. CONCLUSION: We demonstrated that tumour volumes of flank and thigh tumours, obtained as a part of radiation studies using image-guided small-animal irradiators, can be estimated more efficiently and accurately using semi-automatic segmentation from CBCT scans. ADVANCES IN KNOWLEDGE: This is the first study evaluating tumour volume assessment of pre-clinical subcutaneous tumours in different anatomical sites using on-board CBCT imaging. We also compared the accuracy of the CBCT method to manual calliper measures, using various volume calculation equations.

Continual trending of Fick variables in the critically ill patient.

We continually monitored components of the Fick equation (oxygen consumption, arterial and mixed venous oxygen saturation) simultaneously in ten hemodynamically stable, mechanically ventilated postoperative patients in order to evaluate our ability to continually calculate cardiac output (Qc) from its Fick determinants. Qc underestimated (p less than 0.001) cardiac output calculated from intermittent CO-oximeter measurements (6.2 vs 6.4 L/min) with good correlation (r = .96), while it consistently overestimated (p less than 0.05) thermodilution cardiac output (Qtd) (6.2 vs 5.9 L/min, r = .84). Measured oxygen consumption correlated with Qtd (r = .78) nearly as well as did Qc, while mixed venous oxygen saturation correlated poorly with Qtd (r = -.10). Trends of multiple Fick variables were helpful in interpreting changes in a single parameter. We conclude that continual trending of Fick variables in critically ill patients is both feasible and useful and that Qc agrees well with both traditional Fick cardiac output computed from CO-oximetry data and thermodilution measurements. Finally, measured oxygen consumption, available continuously, correlates well with changes in cardiac output in this subset of critically-ill patients.

Pentoxifylline does not alter the response to inhaled grain dust.

Pentoxifylline (PTX) has been shown to reduce sepsis-induced neutrophil sequestration in the lung and inhibit endotoxin-mediated release of tumor necrosis factor-alpha (TNF-alpha). Previously, we have shown that endotoxin appears to be the principal agent in grain dust causing airway inflammation and airflow obstruction following grain dust inhalation. To determine whether PTX affects the physiologic and inflammatory events following acute grain dust inhalation, 10 healthy, nonsmoking subjects with normal airway reactivity were treated with PTX or placebo (PL) followed by corn dust extract (CDE) inhalation (0.08 mL/kg), using a single-blinded, crossover design. Subjects received PTX (1,200 mg/d) or PL for 4 days prior to CDE inhalation and 400 mg PTX or PL on the exposure day. Both respiratory symptoms and declines in FEV1 and FVC occurred following CDE exposure in both groups, but there were no significant differences in the frequency of symptoms or percent declines from baseline in the FEV1 and FVC at any of the time points measured in the study. Elevations in peripheral blood leukocyte and neutrophil concentrations and BAL total cell, neutrophil, TNF-alpha, and interleukin-8 concentrations were measured 4 h following exposure to CDE in both the PTX- and PL-treated subjects, but no significant differences were found between treatment groups. These results suggest that pretreatment with PTX prior to inhalation of CDE, in the doses used in this study, does not alter the acute physiologic or inflammatory events following exposure to inhaled CDE.