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ObjectiveTo describe the development and validation of a novel patient reported outcome measure for symptom burden from long covid, the symptom burden questionnaire for long covid (SBQ-LC).DesignMultiphase, prospective mixed methods study.SettingRemote data collection and social media channels in the United Kingdom, 14 April to 1 August 2021.Participants13 adults (aged ≥18 years) with self-reported long covid and 10 clinicians evaluated content validity. 274 adults with long covid field tested the draft questionnaire.Main outcome measuresPublished systematic reviews informed development of SBQ-LC’s conceptual framework and initial item pool. Thematic analysis of transcripts from cognitive debriefing interviews and online clinician surveys established content validity. Consensus discussions with the patient and public involvement group of the Therapies for Long COVID in non-hospitalised individuals: From symptoms, patient reported outcomes and immunology to targeted therapies (TLC Study) confirmed face validity. Rasch analysis of field test data guided item and scale refinement and provided initial evidence of the SBQ-LC’s measurement properties.ResultsSBQ-LC (version 1.0) is a modular instrument measuring patient reported outcomes and is composed of 17 independent scales with promising psychometric properties. Respondents rate their symptom burden during the past seven days using a dichotomous response or 4 point rating scale. Each scale provides coverage of a different symptom domain and returns a summed raw score that can be transformed to a linear (0-100) score. Higher scores represent higher symptom burden. After rating scale refinement and item reduction, all scales satisfied the Rasch model requirements for unidimensionality (principal component analysis of residuals: first residual contrast values 0.4). Across the 17 scales, person reliability ranged from 0.34 to 0.87, person separation ranged from 0.71 to 2.56, item separation ranged from 1.34 to 13.86, and internal consistency reliability (Cronbach’s alpha) ranged from 0.56 to 0.91.ConclusionsSBQ-LC (version 1.0) is a comprehensive patient reported outcome instrument developed using modern psychometric methods. It measures symptoms of long covid important to people with lived experience of the condition and may be used to evaluate the impact of interventions and inform best practice in clinical management.

ObjectiveTo describe the development and initial validation of a novel patient-reported outcome measure of Long COVID symptom burden, the Symptom-Burden Questionnaire for Long COVID (SBQ™-LC).Method and FindingsThis multi-phase, prospective mixed-methods study took place between April and August 2021 in the United Kingdom (UK). A conceptual framework and initial item pool were developed from published systematic reviews. Further concept elicitation and content validation was undertaken with adults with lived experience (n = 13) and clinicians (n = 10), and face validity was confirmed by the Therapies for Long COVID Study Patient and Public Involvement group (n = 25). The draft SBQ™-LC was field tested by adults with self-reported Long COVID recruited via social media and international Long COVID support groups (n = 274). Thematic analysis of interview and survey transcripts established content validity and informed construction of the draft questionnaire. Rasch analysis of field test data guided item and scale refinement and provided evidence of the final SBQ™-LC’s measurement properties. The Rasch-derived SBQ™-LC is composed of 17 independent scales with promising psychometric properties. Respondents rate symptom burden during the past 7-days using a dichotomous response or 4-point rating scale. Each scale provides coverage of a different symptom domain and returns a summed raw score that may be converted to a linear (0 – 100) score. Higher scores represent higher symptom burden.ConclusionsThe SBQ™-LC is a comprehensive patient-reported assessment of Long COVID symptom burden developed using modern psychometric methods. It measures symptoms of Long COVID important to individuals with lived experience and may be used to evaluate the impact of interventions and inform best practice in clinical management.

Objectives: The Remote Diet Intervention to Reduce Long COVID Symptoms Trial (ReDIRECT) evaluates whether the digitally delivered, evidence-based, cost-effective Counterweight-Plus weight management programme improves symptoms of Long COVID in people with overweight/obesity. Methods: Baseline randomised, non-blinded design with 240 participants allocated in a 1:1 ratio either to continue usual care or to add the remotely delivered Counterweight-Plus weight management programme, which includes a Counterweight dietitian supported delivery of 12 weeks total diet replacement, food reintroduction, and long-term weight loss maintenance. Randomisation is achieved by accessing a web-based randomisation system incorporated into the study web portal developed by a registered Clinical Trials Unit. We are using an innovative approach to outcome personalisation, with each participant selecting their most dominant Long COVID symptom as their primary outcome assessed at six months. Participants in the control arm enter the weight management programme after six months. We are recruiting participants from social media and existing networks (e.g., Long COVID Scotland groups), through newspaper advertisements and from primary care. Main inclusion criteria: people with Long COVID symptoms persisting > three months, aged 18 years or above, body mass index (BMI) above 27kg/m2 (>25kg/m2 for South Asians). The trial includes a process evaluation (involving qualitative interviews with participants and analysis of data on dose, fidelity and reach of the intervention) and economic evaluation (within-trial and long-term cost-utility analyses). Anticipated results: The recruitment for this study started in December 2021 and ended in July 2022. Project results are not yet available and will be shared via peer-reviewed publication once the six-months outcomes have been analysed. Trial registration: Current Controlled Trials ISRCTN12595520

There has been a major focus on the recruitment and retention of nursing and midwifery staff in the health service over the past five years in order to deliver and develop an effective service to meet changing health care needs (Scottish Executive Health Department, 2001). A number of initiatives have been used to tackle the problem, among them encouraging staff, primarily managers, to consider a variety of ways to recruit and retain employees more flexibly. In Scotland this has been approached nationally through the ‘Balancing Working Lives: Celebrating a “Can Do” Approach’, initiative steered by the Centre for Change and Innovation (Scottish Executive Health Department, 2003). This initiative involved a number of individual local projects that were supported by the centre and then publicized in a number of conference days in Scotland. Copyright © 2005 Whurr Publishers Ltd.

Accountability has assumed a higher profile in these changing times and clearly this multifaceted concept is inextricably linked to professionalization. In addition, major changes have taken place in nurse education, resulting in role changes for the nurse teacher. Consequently, nurse teachers will have to examine more closely the many facets of accountability.

Background Nitric oxide (NO) is an important endogenous paracrine vasodilator. The nitrite anion represents an alternate humoural source of NO under hypoxic and/or acidotic conditions. During hypoxia and ischaemia, the usual production of NO by NO synthase enzymes, is markedly reduced. Recently it has emerged that nitrite serves as a biological reservoir for NO under hypoxic conditions. Animal studies have shown that exogenous treatment with nitrite has important hypoxia-specific vasodilator and cytoprotective effects. Our group demonstrated that when administered intra-arterially under normoxic conditions, nitrite substantially vasodilated the venous capacitance bed, but only modestly dilated resistance human forearm vessels. In contrast during hypoxia, potent vasodilation was also observed in resistance vessels. Therefore, in this study we assessed the effects of nitrite on cardiac and peripheral haemodynamics in humans. We hypothesised that an intravenous infusion of sodium nitrite would cause a significant reduction in blood pressure during hypoxia compared to normoxia. Methods Thirty-three healthy subjects (mean age 32±10 years) were recruited. An intravenous infusion of sodium nitrite was administered at incremental doses (3, 8, 30 and 60 μmol/min) during normoxic or hypoxic conditions in random order. Hypoxia was administered by asking subjects to inspire 12% oxygen via a facemask until oxygen saturations of 83–88% were achieved. Haemodynamic measurements were determined non-invasively through the use of impedance cardiography (Taskforce ® ). Aplanation tonometry (SphygmoCor) was used to delineate central (aortic) blood pressure (CBP). Results To allow for the time-dependent effect of hypoxia all measurements in this group were placebo-corrected. During hypoxia, systolic blood pressure (SBP) fell by a mean of 11 mmHg (123±19 mmHg to 112±15 mmHg, p≤0.05) from baseline during peak nitrite dose. There was a non-significant reduction in SBP during normoxia of 6 mmHg (120±13 mmHg to 114±22 mmHg, p=NS). No significant changes were observed in stroke volume or cardiac output in either group. In the hypoxia group, total peripheral resistance mirrored changes in SBP. CBP fell in both groups (9 vs13 mmHg, normoxia vs hypoxia, p=NS) from baseline. No significant changes were observed in parameters between the normoxia and hypoxia group. Conclusion An acute intravenous infusion of nitrite was safe and well tolerated in healthy volunteers. A significant decrease in blood pressure was observed during hypoxia, but not during normoxia, thus supporting the role of nitrite as a hypoxia-specific vasodilator.

Rat mammary ducts, free of buds, can alone regenerate complete mammary trees when transplanted into the interscapular fat pads of syngeneic host rats. All the main mammary cell types are identified within such outgrowths. Epithelial cells, which show the presence of milk fat globule membrane antigens and microvilli on their luminal surfaces, line the ducts. Basal cells surrounding the ducts show characteristic features of myoepithelial cells: immunoreactive actin and keratin within the cytoplasm, myofilaments, pinocytotic vesicles and hemidesmosomal attachments to the basement membrane. Cells within the end buds and lateral buds, however, show few if any cytoplasmic myofilaments and are relatively undifferentiated in appearance. Intermediate morphologies between these cells and myoepithelial cells are seen nearer the ducts. In this respect they exactly resemble the cap cells found in terminal end buds (TEBs) of normal mammary glands. Occasional epithelial cells within alveolar buds show the presence of immunoreactive casein, which is a product of secretory alveolar cells in the normal rat mammary gland. Dissected terminal end buds can regenerate similar ductal outgrowths. Thus, ductal tissue alone can generate all the major mammary cell types seen in the normal gland, including the cap cells.

Human melanoma variants of low and high experimental metastatic activity, which had been derived from the same parental line, showed markedly different growth responses to agents which elevated intracellular cAMP. The high metastatic line had a significant decrease in in vitro proliferation following treatment with cholera toxin (10(-9) M) and forskolin (100 microM), with both agents causing virtual cessation of cell growth after 3-5 days incubation. Pre-treatment with 10(-9) M cholera toxin reduced colony forming ability to 11-15 per cent of control values, saturation densities were decreased to 10-25 per cent of controls and these cytostatic responses were accompanied by changes in cellular morphology. Lung colonising capacity of this cell line after i.v. injection into athymic mice was reduced significantly by prior exposure to cholera toxin (a median of 2 lung nodules versus 26 lung nodules for untreated, control cells). In contrast, low metastatic cell lines showed no significant growth inhibition in the presence of these agents. Cholera toxin (10(-9) M) reduced colony forming ability of these cells to only 74 per cent of control values and there were no significant decreases in growth rate nor any morphological changes in response to either cholera toxin or forskolin. The variable response obtained in the cell lines appeared neither to be a consequence of variation in induced levels of intracellular cAMP nor in differences between the cell lines in response to the same agent; forskolin (100 microM) induced a maximal 25-fold elevation and cholera toxin (10(-9) M) a 2.5-fold elevation increase in cAMP. These data show that highly metastatic variants of a human melanoma cell line differ from their less metastatic counterparts in the way they respond to agents which elevate the second messenger molecule cAMP.

A mammary epithelial cell line, Rama 25, growing on plastic, deposits fibronectin, type IV collagen, and laminin in punctate structures located beneath the basal surface of the cells. When grown on the surface of collagen gels, Rama 25 cells deposit these basement membrane proteins in a continuous layer between the basal surface of the cells and the surface of the collagen matrix. Rama 25 cells also penetrate the collagen matrix forming rudimentary duct-like structures. These structures are surrounded by a discontinuous layer of basement membrane proteins. The ducts of fetal and neonatal rat mammary glands contain few mature myoepithelial cells and our results suggest that some mammary epithelial cells, in contact with a collagenous stroma, are capable of synthesizing a basal lamina-like structure.

The three-dimensional growth in vitro of cloned rat mammary cell lines on floating type I collagen gels has been investigated. Multicellular outgrowths formed by the various cell types show morphological differences on serial histological sectioning and electron microscopy. One cell line, Rama 25, an epithelial cell line derived from a dimethylbenz( a )anthracene (DMBA)-induced mammary adenocarcinoma can form branched tubules within the matrix. The amount of collagen in the matrix modified the structure of the predominant outgrowths formed by this cell line. High-concentration (0.6% w/v) collagen gels support the growth of tubules up to 0.5 mm in length which have an extensive lumen surrounded by rings of up to 26 cells. Absence of differentiated myoepithelial elements around the ring suggests a resemblence to primitive ducts found in the mammary glands of neonatal rats. The spectrum of cellular polarity toward the lumen seen throughout the tubules and the occasional irregular arrangement of epithelial cells are features of adenocarcinoma. Lumen formation occurs by central cell necrosis and separation of the external layers of initially solid cords. The tubules branch either dichotomously, by bifurcation at the distal ends or monopodially, by budding at the sides of the outgrowths. Rama 25 grown on gels containing lower concentrations of collagen (0.1 or 0.3% w/v) produce narrow branching structures with incomplete lumina and spikes of elongated cells. Tubular structures are not formed by Rama 25 grown on nonfloating gels. At the light microscopic level the layer of spindle cells formed beneath the surface monolayer on nonfloated gels resembles the sarcomatous regions of tumors, however at the ultrastructural level the spindle cells show some evidence of being myoepithelial-like rather than fibroblast-like. Sandwiching the epithelial cell sheet between two layers of collagen gel results in loss of contact with the media and the formation of spindle cells. The myoepithelial-like cell lines Rama 29 and Rama 401 form spiked branches of elongated cells and solid branching cords of cells, respectively. However, no lumen formation is observed. The fibroblast-like cell line Rama 27 shows extensive migration of either single cells or chains of cells into the gel. Thus only one cell type (Rama 25) is necessary to form branched tubules in vitro and the structure of the tubules can be modified by collagen, a component of the extracellular matrix.

A series of WF rat mammary tumors comprising one transplantable nonmetastasizing line (MT-W9), two predominantly lymphatic (SMT-2A and SMT-077) and one lymphatic and hematogenous (MT-450) metastasizing transplantable lines, and 7,12-dimethylbenz[a]anthracene (DMBA)-induced nonmetastasizing primary tumors was examined for the presence of epithelial and myoepithelial cell characteristics with the use of immunocytochemical techniques. Tumor cells staining for myosin were only occasionally observed in a basal orientation in glandular structures in sections of DMBA-induced and MT-W9 tumors; anti-laminin serum stained the peripheries of the glandular structures in the DMBA-induced and MT-W9 tumors but failed to stain the SMT-2A and SMT-077 tumor cells. In the nonmetastasizing tumors immunologically detectable keratin occurred mainly in the outer cellular layer of glandlike structures, whereas milk fat globule membrane immunoreactivity occurred primarily in the luminal cells. Both these types of immunoreactivity were observed in MT-450 tumor cells, but the pattern of keratin staining was random. No such immunoreactivity occurred in SMT-2A or SMT-077 tumors. No tumor cell-associated staining for fibronectin was seen in any of the tumors examined, although host stromal components stained intensely. The nonmetastasizing tumors contained cuboidal epithelial cells with lumen formation, surface microvilli, and intercellular junctional complexes, together with a relatively undifferentiated elongated cell component. Other elongated cells showed hemidesmosomes, pinocytotic vesicles, tonofilaments, and small bundles of cytoplasmic filaments, suggesting gradations toward a myoepithelial phenotype. The MT-450 tumors were ultrastructurally similar to the nonmetastasizing tumors, but no features of myoepithelial cells were seen, although some cuboidal epithelial cells exhibited prominent tonofilaments. The SMT-2A and SMT-077 tumors consisted of nests of cuboidal-like cells with highly pleomorphic nuclei and much intercellular collagen. The results indicate a progressive loss of cellular differentiation characteristics, particularly those of the myoepithelial cell with increasing malignancy in this system.