A customizable, open-source Winston-Lutz system for multi-target, single isocentre radiotherapy.

Objective. To present and share an open-source system (phantom and software) for verifying the targeting accuracy of linac-based, single-isocenter, multi-target radiotherapy. This quality assurance test extends the traditional Winston-Lutz test, which considers a single target located at isocentre.Approach. Plans for a 3D-printed phantom are provided, which can be customized to accommodate various target (BB) positions. Given BB positions and gantry/collimator/couch combinations, the software generates multi-leaf collimator positions to facilitate multi-target Winston-Lutz (MTWL) plan creation. The software determines deviations between detected and expected BB positions on MV images resulting from MTWL plan delivery. BBs are located using a Hough circle detection algorithm, which is modified to favour the detection of circles: (1) having a reasonable size, (2) that are contained within the radiation field, and (3) having reasonable pixel intensities. Validation was performed in two ways: (1) using synthetic data with zero targeting errors and (2) by measuring real linac targeting errors and comparing against results obtained using a commercial system.Main results. Validation using the synthetic data yielded a mean (maximum) absolute discrepancy of 0.11 mm (0.21 mm), which is comparable to the synthetic phantom resolution (0.2 mm). The mean (maximum) absolute discrepancy compared to the commercial system is 0.13 mm (0.43 mm). These values are similar to results obtained with repeated deliveries of the same MTWL plan with the same phantom setup. Both validation tests yield reasonable results and are therefore considered successful. The MTWL test was performed independently by three physicists on two linacs to investigate repeatability, resulting in a mean (maximum) absolute discrepancy of 0.14 mm (0.51 mm) among the various attempts.Significance. Successful completion of this quality assurance test, using our customizable and open-source system, provides confidence that multi-target, single isocentre radiotherapy treatments can be delivered with sufficient geometric accuracy according to the chosen tolerance level.

Management of COVID-19 ICU-survivors in primary care: - a narrative review.

Many survivors of critical illness suffer from long-lasting physical, cognitive, and mental health sequelae. The number of affected patients is expected to markedly increase due to the COVID-19 pandemic. Many ICU survivors receive long-term care from a primary care physician. Hence, awareness and appropriate management of these sequelae is crucial. An interdisciplinary authorship team participated in a narrative literature review to identify key issues in managing COVID-19 ICU-survivors in primary care. The aim of this perspective paper is to synthesize important literature to understand and manage sequelae of critical illness due to COVID-19 in the primary care setting.

A site-specific standard for comparing dynamic solar ultraviolet protection characteristics of established tree canopies.

A standardised procedure for making fair and comparable assessments of the ultraviolet protection of an established tree canopy that takes into account canopy movement and the changing position of the sun is presented for use by government, planning, and environmental health authorities. The technique utilises video image capture and replaces the need for measurement by ultraviolet radiometers for surveying shade quality characteristics of trees growing in public parks, playgrounds and urban settings. The technique improves upon tree shade assessments that may be based upon single measurements of the ultraviolet irradiance observed from a fixed point of view. The presented technique demonstrates how intelligent shade audits can be conducted without the need for specialist equipment, enabling the calculation of the Shade Protection Index (SPI) and Ultraviolet Protection Factor (UPF) for any discreet time interval and over a full calendar year. •Tree shade UPF measurements are presented using video capture analysis of moving canopies•A standard method for making accurate assessments of tree shade has been developed•Tree shade comparisons are made without the need for specialist equipment.

Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy.

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin-FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.

An exploration of the experience of mental health service users when they decide they would like to change or withdraw from prescribed medications.

This paper reports on a collaborative research project initiated by service user representatives and led by clinicians from the mental health service in Derbyshire. The study explored the experiences of mental health service users when they either changed or terminated their use of mental health-related medications. Three focus groups were conducted with mental health service users from across the county. An inductive thematic analysis identified six key themes, three of which are reported here: the 'two faces' of service provision, describing the positive and negative experiences of services; the general practice/mental health divide, relating to the lack of continuity between the two services; and becoming an informed service user, where participants discussed the importance of seeking information. It is important that mental health professionals always consider presenting their 'best face' to service users, and facilitate the prescribing process with general practitioners. The findings also highlight the potential for supporting service users in using different sources of information to become more informed about medication.

A silver-alginate-coated dressing to reduce peripherally inserted central catheter (PICC) infections in NICU patients: a pilot randomized controlled trial.

OBJECTIVE: Our aim was to evaluate the safety of a silver-alginate-containing dressing to reduce peripherally inserted central catheter (PICC) infections in neonatal intensive care unit (NICU) patients. STUDY DESIGN: Patients were randomized 3:1 to receive a patch containing silver, alginate and maltodextrin or standard of care. Patches were placed under the regular transparent retention dressing at the PICC exit site at insertion and were replaced with every dressing change at least every 2 weeks until PICC discontinuation. All study infants were monitored for adverse skin reactions. RESULT: A total of 100 infants were followed up for 1922 person-days, including 75 subjects with 89 PICCs who received the patch. The median birth weight (1330 g) and median gestational age (30 weeks) was lower in the patch group when compared with the controls (P=0.001 and 0.005, respectively). Study patients received the patch with their PICC at a median age of 5 days; the patch stayed in place for a median of 13 days. We noted no adverse skin reactions and found no evidence that the patch alters the microbiology of PICC-associated infections. CONCLUSION: This pilot trial suggests that silver-alginate-coated dressings are skin safe and their inclusion in future trials aimed at reduction of PICC-associated bloodstream infections in the NICU should be considered.

Panton-Valentine Leukocidin associated with community acquired methicillin resistant Staphylococcus aureus: a case report and review of interim guidelines.

We report a case of community acquired methicillin resistant Staphylococcus aureus pneumonia. The causative organism was positive for the toxin Panton-Valentine Leukocidin. This resulted in a severe pneumonia requiring a prolonged stay on our intensive care unit. This infection is becoming more common in the United Kingdom. It can cause a far more aggressive illness than the hospital acquired infection with a high mortality if it becomes an invasive infection. The Department of Health has recently produced interim guidelines for its treatment which we have also reviewed.

The in vivo cytokine release profile following implantation.

There has been no comprehensive study that maps the production of the range of inflammatory cytokines following implantation of a material. There is an urgent requirement for specific data on the real time production of biological markers in order to study their effects in vitro and more accurately predict the in vivo response. This study determined the production of IL-1beta, IL-2, IL-4, IL-6, IL-10, IFNgamma and TNF-alpha in response to a synthetic material implanted in a rat soft tissue model for up to 90 days. IL-1 beta and TNF-alpha were elevated over the total experimental time course with values in the order of 500 pg/ml for IL-1beta and 40 pg/ml for TNF-alpha. The cytokines IL-2, IL-4, IL-6 and IL-10 were also detected and their production reduced with increasing time.

Sci-Fri AM: YIS-01: Comprehensive MR distortion correction: Phantom validation and in-vivo application.

MR images provide excellent diagnostic information; however, their treatment planning utility is limited due to geometric uncertainties from both system and patient related sources. Despite this concern, interest in developing MR-based treatment planning protocols is on the rise because of the ease with which clinically relevant structures can be identified in MR. Here we present our systematic approach to quantifying both machine (gradient non-linearity and B0 inhomogeneity) and patient (susceptibility and chemical shift) distortions. Gradient non-linearities were previously measured using a 3D grid phantom while the remaining types of distortion were measured using a double gradient echo scan to obtain a B0 distortion map specific to each object/patient. Distortion measurement and correction were validated on phantoms and then implemented on a volunteer. B0 inhomogeneity and susceptibility distortions were simulated by offsetting the x2 -y2 shims; maximum absolute distortion was reduced from 5.4 mm to 1.0 mm and mean (± standard deviation) was reduced from 1.7 ± 1.4 mm to 0.4 ± 0.2 mm. Chemical shift distortion was qualitatively evaluated using a phantom containing fat and water inserts; displacement of the fat signal was much improved following distortion correction. Intensity correction was validated using a uniformity phantom and undistorted image profiles were compared to distorted image profiles and to profiles corrected for geometric and geometric/intensity distortion; the need for intensity correction was clearly demonstrated. Once all types of distortion correction were validated on phantoms, the technique was implemented on a volunteer brain image. Both GE and multi-shot EPI images were corrected.

Host inflammatory response to NiCr, CoCr, and Ti in a soft tissue implantation model.

The inflammatory response to nickel chromium (NiCr), cobalt chromium (CoCr), and titanium (Ti) implants at 7 and 28 days was investigated using real-time PCR analysis along with histological and immunohistochemical staining. Contrasting inflammatory profiles were found in response to the different metal compositions. The inflammatory profile induced by CoCr remained consistent and elevated during the 28-day period with high cell counts associated with the implants and a progressive recruitment of T lymphocytes. The response to NiCr was also elevated, but with an initially low T-lymphocyte infiltration that increased by the later time period. Ti indicated an early increased inflammatory response that had reduced by 28 days. Changes in gene expression demonstrated that Ti induced very low levels of expression of the three inflammatory cytokine genes. NiCr initiated a significant upregulation in gene expression for IL-6 and TNF-alpha. CoCr resulted in the highest upregulation of IL-2 indicative of T-lymphocyte activation to this material.

Long-term study of re-infection following successful eradication of Helicobacter pylori infection.

BACKGROUND: 'Re-infection' with Helicobacter pylori after eradication has been estimated to occur in 0-14% of patients, although most so-called 're-infections' occur within the first year following 'eradication' and many may actually be due to recrudescence of a temporarily suppressed infection. AIM: To study the true re-infection rate, we have studied re-infection rates after eradication therapy by excluding the first year's data, minimizing the possible confounding effect of recrudescence. METHODS: All patients tested for H. pylori infection following eradication therapy between 1987 and 2004 were evaluated. Testing was carried out by urea breath test and gastric biopsy. Patients were included if they were found to be negative for H. pylori infection by testing at least 1 year following eradication and underwent at least one further test for H. pylori. RESULTS: 1162 patients met the inclusion criteria with median post-eradication follow-up of 3 years (1.5-14) including 4668 tests; 3319 years of follow-up were analysed. Thirteen cases of re-infection occurred (re-infection rate 0.4% per year). CONCLUSIONS: This large study of H. pylori re-infection avoided cases of recrudescence by excluding the first post-eradication year. True re-infection is probably less common than previously thought.

Flow cytometric measurement of phagocytosis reveals a role for C3b in metal particle uptake by phagocytes.

A methodology for the quick and efficient study of phagocytosis has been developed. It uses the flow cytometer to exploit the change in size and granularity that occurs in cells upon the ingestion of particulate material. The numbers of cells that have phagocytosed particles can be calculated from the distinct shift in regions that occurs. The method also allows the factors governing phagocytosis to be studied in detail through the use of blocking agents or antibodies. Blood-derived monocytes were studied to investigate the role of complement in metal particle phagocytosis to further understand aseptic loosening. Factor C3b was found to be fundamental to the opsonization and phagocytosis of metal particles by monocytes.

Transitional cell carcinoma of the bladder mimicking lobular carcinoma of the breast: a discohesive variant of urothelial carcinoma.

AIMS: To describe a series of 10 cases of transitional cell carcinoma which show morphological features which mimic lobular carcinoma of the breast and diffuse carcinoma of the stomach. METHODS AND RESULTS: Ten cases were identified from the files at Southampton University Hospitals NHS Trust and from the authors' consultation files. Immunostains were performed and clinical information was obtained. Eight of the patients were male and two female. Ages ranged from 52 to 77 years at presentation. All of the tumours showed areas where the tumour was composed of uniform cells with a discohesive single-cell, diffusely invasive growth pattern. In areas the tumour cells were arranged in linear single-cell files and in separate areas solid sheets of discohesive cells. In all of the cases some tumour cells showed prominent intracytoplasmic vacuoles. In addition to this pattern, four cases showed typical transitional cell carcinoma or carcinoma in situ. The majority of the tumours expressed cytokeratin 20 but not oestrogen receptors. CONCLUSION: This study highlights a pattern of diffusely invasive transitional cell carcinoma not previously described and one which is important to recognize in order to avoid misdiagnosis of metastatic lobular carcinoma of the breast, especially in small biopsies.

Virilisation in a case of transitional cell carcinoma of the ovary.

A 52 year old woman presented with a five month history of emotional changes, voice changes, and of abdominal discomfort. Clinical, biochemical, and radiological examinations showed evidence of virilisation, raised testosterone, and a complex ovarian mass. Microscopy of the resection specimen showed the tumour to be a transitional cell carcinoma of the ovary with luteinisation and hyperplasia of the intervening stromal cells. This is a unique case of virilisation caused by transitional cell carcinoma of the ovary. Theories as to the origin of testosterone production in non-functioning ovarian tumours are discussed.

Reversible watermarking for authentication of DICOM images.

We propose a watermarking scheme that can recover the original image from the watermarked one. The purpose is to verify the integrity and authenticity of DICOM images. We used 800x600x8 bits ultrasound (US) images in our experiment. SHA-256 of the whole image is embedded in the least significant bits of the RONI (Region of Non-Interest). If the image has not been altered, the watermark will be extracted and the original image will be recovered. SHA-256 of the recovered image will be compared with the extracted watermark for authentication.

Defining hormesis.

Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and underlying evolutionary and toxicologically based mechanistic strategies. Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis. Given the limited magnitude of the stimulatory response (i.e., usually 30-60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.

A study of tissue interface membranes from revision accord knee arthroplasty: the role of T lymphocytes.

Despite four decades of advances in the design of orthopaedic devices aseptic loosening remains a major cause for the revision of total joint arthroplasty. This study used the techniques of immunohistochemistry and reverse transcription polymerase chain reaction to identify the inflammatory cell types, cytokines and chemokines within the interface tissue surrounding failed Accord Knee prostheses. Many T cells were identified within the tissue: however, the classical marker of activation, CD25 was expressed on very few cells. Molecular analysis failed to detect the synthesis of either Th1 or Th2 cytokines. These results suggest that the T cells are being actively recruited to the site of inflammation along the chemokine gradients but are not participating in a classical immune response.

Hormesis: a generalizable and unifying hypothesis.

The present article represents a comprehensive effort to assess the hypothesis that hormesis is a highly generalizable biological phenomenon independent of environmental stressor, biological endpoint, and experimental model system. The evaluative methodology and complementary approaches employed to assess this question are (1) evolutionary biology-based theoretical paradigm; (2) evaluation of > 20,000 toxicology articles using a priori entry and evaluative criteria; (3) evaluation of 17 large-scale studies each providing data on numerous agents tested in the same experimental model by the same research team; (4) the assimilation of experimental pharmacological data on 24 receptor systems in which biphasic dose responses have been established reproducibly along with hormetic mechanism elucidation; and (5) assessment of the original hormesis database with 1600 dose-response relationships demonstrating evidence consistent with the hormesis hypothesis. The complementary approaches for assessing hormesis provided strong support for its credibility as a central biological theory based on its high frequency of occurrence and quantitative features of expression within microbe, plant, and invertebrate and vertebrate animal systems. The findings suggest that hormetic effects represent evolutionary-based adaptive responses to environmentally induced disruptions in homeostasis. Such adaptive responses, which are incorporated into organismal integrative physiological systems and now clarified at the mechanistic level for more than two dozen receptor systems, provide a cogent basis for the application of hormetic mechanisms in the elucidation of fundamental evolutionary-based biological processes and in the development of novel clinical modalities.

Agonist concentration gradients as a generalizable regulatory implementation strategy.

This article proposes a general mechanism by which biphasic dose-response relationships occur in pharmacological and toxicological experimental systems. Such biphasic responses are mediated via a strategy of differential binding to stimulatory and inhibitory receptor subtypes based on agonist concentrations. Such a strategy is widely seen in pharmacological systems and has been demonstrated in toxicological-related biphasic dose responses in which the treatment altered levels of endogenous agonists.