Search

The fictive temperature of vitreous silica containing approximately 900 wt ppm of hydroxyl groups was monitored with small angle x-ray scattering. The measurements were carried out during annealing and while scanning the temperature, with annealing temperatures ranging between 930 and 1330 K. Fitting the data to the Adam-Gibbs-Fulcher equation by using the Tool-Narayanaswamy method yields a particularly simple thermorheological behavior for type-III vitreous silica. Unlike the general case for glass kinetics, including vitreous silica with low hydroxyl content, the relaxation time constant is nearly decoupled from the fictive temperature. This high degree of decoupling of the state of the glass and the relaxation rate agrees with the results of viscosity measurements. By improving the data analysis procedure, we have significantly increased the precision of the results, and it was possible to resolve changes of the activation energy of the relaxation processes to within 0.5%. This has made sample aging effects that had previously been undetectable visible. [ABSTRACT FROM AUTHOR]

Discusses several options for the beneficial reuse of biosolids in Victoria. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on sludge management for the 21st century.

This case study reflects on the care of a diabetic patient with an extensive pressure ulcer on the heel. It addresses the issue of the limitations of scope of practice and expertise of the tissue viability nurse with regard to effective treatment of the diabetic foot. Methods of autolytic, sharp and surgical debridement are all attempted with varying degrees of success, together with one application of larval therapy. The importance of collaboration with members of the multidisciplinary team is addressed. Unfortunately, the final patient outcome is not yet known but this has provided a valuable reflective learning experience for myself as a tissue viability nurse. [ABSTRACT FROM AUTHOR]

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR - which was leukocyte-associated (FDR = 4.9 ×10 -7 ). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 × 10 -8 ), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 × 10 -5 ). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo . Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways.

Rationale: In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4-8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung). Objectives: We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry. Measurements and Main Results: Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection ( P  < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).

Introduction: First Episode Rapid Early Intervention for Eating Disorders (FREED) is the leading eating disorder (ED) early intervention model for young people. Research has shown that it reduces the duration of untreated illness, improves clinical outcomes, and has cost savings. However, less is known about the experience of implementing FREED. This study aimed to investigate the views and experiences of adopting, implementing, and sustaining FREED from the perspective of clinical staff., Methods: Seven focus groups were conducted involving 26 clinicians. Thematic analysis was used, with the Non-Adoption, Abandonment and Challenges to Scale-up, Spread and Sustainability (The NASSS framework) framework being applied to organise subthemes and determine facilitators and barriers. The NASSS framework was also used to rate the complexity of themes as either simple (straightforward, predictable, few components), complicated (multiple interrelating components), or complex (dynamic, unpredictable, not easily divisible into constituent components)., Results: There were 16 subthemes identified under seven broader themes representing each domain of the NASSS framework. Key barriers and areas of complexity included factors related to EDs as an illness (e.g., high acuity and prevalence), and organisational complexity (e.g., staffing shortages, lack of managerial/team support). Key facilitators included positive clinician/adopter attitudes, a supportive national network, and the ability for FREED to be flexible/adaptable over time., Conclusion: The FREED model appears to be desirable to clinical staff. Wider team and managerial support was perceived to be particularly important to its successful implementation, as were the national network and supervision. Key areas of complexity include staffing issues and high ED acuity/prevalence. These barriers to implementation need to be managed and investment continued to expand and improve early intervention for EDs further., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hyam, Yeadon-Ray, Richards, Semple, Allen, Owens, Jackson, Semple, Glennon, Di Clemente, Griffiths, Mills and Schmidt.)

Introduction: The First Episode Rapid Early Intervention for Eating Disorders (FREED) service has shown promising outcomes for young people with an eating disorder, leading to national scaling and implementation across England. Between 2020 and 2023, the national implementation of FREED was supported by the Academic Health Science Networks (AHSNs), which are publicly funded organisations with the mission to spread innovations at scale and pace. This study aimed to investigate the views and experiences of AHSN programme leads on the national roll-out of FREED and the perceived sustainability of the model., Methods and Results: Semi-structured interviews were conducted with 13 programme leads across the AHSNs with direct experience supporting the national implementation of FREED. Thematic analysis was adopted using a critical realist approach. Initial sub-themes were inductively generated and then organised under seven larger themes representing the domains of the Non-adoption, Abandonment, and Challenges to Scale-Up, Spread and Sustainability (NASSS) framework. Each sub-theme was classified as a facilitator and/or barrier and then each larger theme/domain was assessed for its complexity (simple, complicated, complex). Data analysis revealed 28 sub-themes, 10 identified as facilitators, 13 as barriers, and five as both. Two domains were classed as simple, three as complicated, and two as complex. Sub-themes ranged from illness-related complexities to organisational pressures. Key facilitators included a high-value proposition for FREED and a supportive network. Key barriers included staffing issues and illness-related factors that challenge early intervention., Discussion: Participants described broad support for FREED but desired sustained investment for continued provision and improving implementation fidelity. Future development areas raised by participants included enlarging the evidence base for early intervention, increasing associated training opportunities, and widening the reach of FREED. Results offer learning for early intervention in eating disorders and the scaling of new health initiatives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Hyam, Torkelson, Richards, Semple, Allen, Owens, Jackson, Semple, Glennon, Di Clemente and Schmidt.)

Objective: To determine how distinct combinations of resistance training prescription (RTx) variables (load, sets and frequency) affect muscle strength and hypertrophy., Data Sources: MEDLINE, Embase, Emcare, SPORTDiscus, CINAHL, and Web of Science were searched until February 2022., Eligibility Criteria: Randomised trials that included healthy adults, compared at least 2 predefined conditions (non-exercise control (CTRL) and 12 RTx, differentiated by load, sets and/or weekly frequency), and reported muscle strength and/or hypertrophy were included., Analyses: Systematic review and Bayesian network meta-analysis methodology was used to compare RTxs and CTRL. Surface under the cumulative ranking curve values were used to rank conditions. Confidence was assessed with threshold analysis., Results: The strength network included 178 studies (n=5097; women=45%). The hypertrophy network included 119 studies (n=3364; women=47%). All RTxs were superior to CTRL for muscle strength and hypertrophy. Higher-load (>80% of single repetition maximum) prescriptions maximised strength gains, and all prescriptions comparably promoted muscle hypertrophy. While the calculated effects of many prescriptions were similar, higher-load, multiset, thrice-weekly training (standardised mean difference (95% credible interval); 1.60 (1.38 to 1.82) vs CTRL) was the highest-ranked RTx for strength, and higher-load, multiset, twice-weekly training (0.66 (0.47 to 0.85) vs CTRL) was the highest-ranked RTx for hypertrophy. Threshold analysis demonstrated these results were extremely robust., Conclusion: All RTx promoted strength and hypertrophy compared with no exercise. The highest-ranked prescriptions for strength involved higher loads, whereas the highest-ranked prescriptions for hypertrophy included multiple sets., Prospero Registration Number: CRD42021259663 and CRD42021258902., Competing Interests: Competing interests: SMP reports grants or research contracts from the US National Dairy Council, Canadian Institutes for Health Research, Dairy Farmers of Canada, Roquette Freres, Ontario Centre of Innovation, Nestle Health Sciences, Myos, National Science and Engineering Research Council and the US NIH during the conduct of the study; personal fees from Nestle Health Sciences, non-financial support from Enhanced Recovery, outside the submitted work. SMP has patents licensed to Exerkine but reports no financial gains from any patent or related work. The remaining authors report no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We performed a systematic review, meta-analysis, and meta-regression to determine if increasing daily protein ingestion contributes to gaining lean body mass (LBM), muscle strength, and physical/functional test performance in healthy subjects. A protocol for the present study was registered (PROSPERO, CRD42020159001), and a systematic search of Medline, Embase, CINAHL, and Web of Sciences databases was undertaken. Only randomized controlled trials (RCT) where participants increased their daily protein intake and were healthy and non-obese adults were included. Research questions focused on the main effects on the outcomes of interest and subgroup analysis, splitting the studies by participation in a resistance exercise (RE), age (<65 or ≥65 years old), and levels of daily protein ingestion. Three-level random-effects meta-analyses and meta-regressions were conducted on data from 74 RCT. Most of the selected studies tested the effects of additional protein ingestion during RE training. The evidence suggests that increasing daily protein ingestion may enhance gains in LBM in studies enrolling subjects in RE (SMD [standardized mean difference] = 0.22, 95% CI [95% confidence interval] 0.14:0.30, P < 0.01, 62 studies, moderate level of evidence). The effect on LBM was significant in subjects ≥65 years old ingesting 1.2-1.59 g of protein/kg/day and for younger subjects (<65 years old) ingesting ≥1.6 g of protein/kg/day submitted to RE. Lower-body strength gain was slightly higher by additional protein ingestion at ≥1.6 g of protein/kg/day during RE training (SMD = 0.40, 95% CI 0.09:0.35, P < 0.01, 19 studies, low level of evidence). Bench press strength is slightly increased by ingesting more protein in <65 years old subjects during RE training (SMD = 0.18, 95% CI 0.03:0.33, P = 0.01, 32 studies, low level of evidence). The effects of ingesting more protein are unclear when assessing handgrip strength and only marginal for performance in physical function tests. In conclusion, increasing daily protein ingestion results in small additional gains in LBM and lower body muscle strength gains in healthy adults enrolled in resistance exercise training. There is a slight effect on bench press strength and minimal effect performance in physical function tests. The effect on handgrip strength is unclear., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Three south-London hospital trusts undertook a feasibility study, comparing data from 93 patients who received the 14-day adhesive ambulatory electrocardiography (ECG) patch Zio XT with retrospective data from 125 patients referred for 24-hour Holter for cryptogenic stroke and transient ischaemic attack following negative 12-lead ECG. As the ECG patch was fitted the same day as the clinical decision for ambulatory ECG monitoring was made, median time to the patient having the monitor fitted was significantly reduced in all three hospital trusts compared with 24-hour Holter being ordered and fitted. Hospital visits reduced by a median of two for patients receiving Zio XT. This project supports that it is feasible to use a patch as part of routine clinical care with a positive impact on care pathways., (© Royal College of Physicians 2022. All rights reserved.)

Males seeking to improve body composition may ingest thermogenic dietary supplements with the goal of elevating resting metabolic rate. The purpose of this study was to examine the effects of a commercially available dietary supplement (containing ingredients that promote thermogenesis) on resting metabolic rate (RMR) in a randomized, double-blind, placebo-controlled cross-over study. Ten healthy, physically active males (age: 26.5 ± 6.4 years; height: 177.6 ± 7.2 cm; body weight: 80.5 ± 10.8 kg) underwent two testing sessions separated by approximately 7 days. Following baseline assessments of RMR, heart rate (HR), and blood pressure (BP), each participant ingested a thermogenic dietary supplement or a placebo. Assessments were repeated at 60, 120, and 180 minutes postingestion. Approximately 1 week later, participants ingested the alternative supplement and the assessments were repeated. Post hoc analyses revealed that the dietary supplement treatment demonstrated significant elevations in RMR during the postingestion period ( p < 0.05) from 1,859 ± 266 kcal to 2,027 ± 288 kcal (increase of 9%) to 2,072 ± 292 kcal (increase of 11.5%) and to 2,040 ± 271 kcal (increase of 9.7%) at 60, 120, and 180 minutes postingestion, respectfully. No significant elevations were observed in the placebo treatment at any time point. HR and BP measures were within normal clinical values throughout the intervention.

Background: The effects of the widely used progestin-only injectable contraceptives, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A), on host susceptibility to Mycobacterium tuberculosis (Mtb) are unknown., Methods: We recruited human immunodeficiency virus-uninfected females, not taking any contraceptives, from Cape Town, South Africa, to evaluate the effect of MPA, NET-A, and dexamethasone on Mtb containment in monocyte-derived macrophages co-incubated with purified protein derivative (PPD)-driven peripheral blood-derived effector cells., Results: MPA (P < .005) and dexamethasone (P < .01), but not NET-A, significantly attenuated Mtb containment in Mtb-infected macrophages co-cultured with PPD-driven effector cells at physiologically relevant concentrations and in a dose-dependent manner. Antagonizing the glucocorticoid receptor with mifepristone (RU486) abrogated the reduction in Mtb containment. In PPD-stimulated peripheral blood mononuclear cells, MPA and dexamethasone, but not NET-A, upregulated (median [interquartile range]) regulatory T cells (5.3% [3.1%-18.2%]; P < .05), reduced CD4+ T-cell interferon-γ (21% [0.5%-28%]; P < .05) and granzyme B production (12.6% [7%-13.5%]; P < .05), and reduced CD8+ perforin activity (2.2% [0.1%-7%]; P < .05). RU486 reversed regulatory T-cell up-regulation and the inhibitory effect on Th1 and granzyme/perforin-related pathways., Conclusions: MPA, but not NET-A, subverts mycobacterial containment in vitro and downregulates pathways associated with protective CD8+- and CD4+-related host immunity via the glucocorticoid receptor. These data potentially inform the selection and use of injectable contraceptives in tuberculosis-endemic countries., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Breast cancer remains one of the leading causes of cancer-associated death worldwide. Conventional treatment is associated with substantial toxicity and suboptimal efficacy. We, therefore, developed and evaluated the in vitro efficacy of an autologous dendritic cell (DC) vaccine to treat breast cancer. We recruited 12 female patients with stage 1, 2, or 3 breast cancer and matured their DCs with autologous tumour-specific lysate, a toll-like receptor (TLR)-3 and 7/8 agonist, and an interferon-containing cocktail. The efficacy of the vaccine was evaluated by its ability to elicit a cytotoxic T-lymphocyte response to autologous breast cancer cells in vitro. Matured DCs (≥ 60% upregulation of CD80, CD86, CD83, and CCR7) produced high levels of the Th1 effector cytokine, IL12-p70 (1.2 ng/ml; p < 0.0001), compared to DCs pulsed with tumour lysate, or matured with an interferon-containing cocktail alone. We further showed that matured DCs enhance antigen-specific CD8 + T-cell responses to HER-2 (4.5%; p < 0.005) and MUC-1 (19%; p < 0.05) tetramers. The mature DCs could elicit a robust and dose-dependent antigen-specific cytotoxic T-lymphocyte response (65%) which was tumoricidal to autologous breast cancer cells in vitro compared to T-lymphocytes that were primed with autologous lysate loaded-DCs (p < 0.005). Lastly, we showed that the mature DCs post-cryopreservation maintained high viability, maintained their mature phenotype, and remained free of endotoxins or mycoplasma. We have developed a DC vaccine that is cytotoxic to autologous breast cancer cells in vitro. The tools and technology generated here will now be applied to a phase I/IIa clinical trial.

Purpose: Children who are living with chronic conditions may be supported in self-care through enjoyable active learning and family social processes. This research focused on development and evaluation of "Don't Push Your Luck!", an educational board game designed to inspire family discussion about chronic conditions, and help affected children learn about self-care choices and consequences., Design and Methods: Mixed-method research was conducted with families from one outpatient Cystic Fibrosis Clinic and four Hemophilia Treatment Centres in Canada and United States (N=72). In phase I, board game prototype and questionnaires were refined with affected boys, siblings, and parents living with hemophilia (n=11), compared with families living with cystic fibrosis (n=11). In phase II, final board game was evaluated with families living with hemophilia (n=50). Data collection included pre-post-game questionnaires on decision-making and Haemo-QoL Index©, and post-game enjoyment. Analysis included descriptive statistics, inferential statistics (non-parametric), and qualitative themes., Results: Findings revealed this game was an enjoyable and effective resource to engage families in self-care discussions. Key themes included communication, being involved, knowing, decisions and consequences, and being connected. Qualitative and quantitative findings aligned. Statistical significance suggests the game enhanced family engagement to support decision-making skills, as parents identified that the game helped them talk about important topics, and children gained insight regarding family supports and self-care responsibility., Conclusions: This board game was an effective, developmentally appropriate family resource to facilitate engagement and conversation about everyday life experiences in preparation for self-care., Practice Implications: There is promising potential to extend this educational family board game intervention with a greater range of school-age children and families living with chronic conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Test the psychometric properties and cut-off scores for the Canadian Little Developmental Coordination Disorder Questionnaire (Little DCDQ), which screens for coordination difficulties in children aged 3 to 4 years., Methods: Parents of children with typical development (n = 108) and children at risk for motor problems (n = 245) completed the questionnaire. A subgroup (n = 119) of children was tested with the Movement Assessment Battery for Children-2 (MABC-2) and the Beery-Buktenica Developmental Test of visual-motor integration (VMI) to determine motor impairment (MI)., Results: Test-retest reliability (r = 0.956, p < .001) and internal consistency (Cronbach's alpha = 0.94) were high. Construct validity was supported by a factor analysis and significant difference in scores of children who were typically developing and were at risk. Concurrent validity was evaluated for the children who received standardized motor testing, with significant difference between children with and without MI. Discriminant function analysis showed that all 15 items were able to distinguish the two groups. The questionnaire correlated well with the MABC-2 and VMI. Validity as a screening tool was assessed using logistic regression modeling (X(2)(5) = 25.87, p < .001) and receiver operating curves, establishing optimal cut-off values with adequate sensitivity., Conclusions: The Little DCDQ is a reliable, valid instrument for early identification of children with motor difficulties.

Objectives: To identify risk factors for failure of outpatient antibiotic therapy (OPAT) in infective endocarditis (IE)., Patients and Methods: We identified IE cases managed at a single centre over 12 years from a prospectively maintained database. 'OPAT failure' was defined as unplanned readmission or antibiotic switch due to adverse drug reaction or antibiotic resistance. We analysed patient and disease-related risk factors for OPAT failure by univariate and multivariate logistic regression. We also retrospectively collected follow-up data on adverse disease outcome (defined as IE-related death or relapse) and performed Kaplan-Meier survival analysis up to 36 months following OPAT., Results: We identified 80 episodes of OPAT in IE. Failure occurred in 25/80 episodes (31.3%). On multivariate analysis, cardiac or renal failure [pooled OR 7.39 (95% CI 1.84-29.66), P=0.005] and teicoplanin therapy [OR 8.69 (95% CI 2.01-37.47), P=0.004] were independently associated with increased OPAT failure. OPAT failure with teicoplanin occurred despite therapeutic plasma levels. OPAT failure predicted adverse disease outcome up to 36 months (P=0.016 log-rank test)., Conclusions: These data caution against selecting patients with endocarditis for OPAT in the presence of cardiac or renal failure and suggest teicoplanin therapy may be associated with suboptimal OPAT outcomes. Alternative regimens to teicoplanin in the OPAT setting should be further investigated.

On April 1, 2007, Alberta became the first province in Canada to introduce cystic fibrosis (CF) to its newborn screening program. The Alberta protocol involves a two-tier algorithm involving an immunoreactive trypsinogen measurement followed by molecular analysis using a CF panel for 39 mutations. Positive screens are followed up with sweat chloride testing and an assessment by a CF specialist. Of the 99,408 newborns screened in Alberta during the first two years of the program, 221 had a positive CF newborn screen. The program subsequently identified and initiated treatment in 31 newborns with CF. A relatively high frequency of the R117H mutation and the M1101K mutation was noted. The M1101K mutation is common in the Hutterite population. The presence of the R117H mutation has created both counselling and management dilemmas. The ability to offer CF transmembrane regulator full sequencing may help resolve diagnostic dilemmas. Counselling and management challenges are created when mutations are mild or of unknown clinical significance.

Objectives: The long elimination half-life of teicoplanin facilitates outpatient parenteral antibiotic therapy (OPAT) with thrice-weekly dosing. This study aimed to develop teicoplanin dosage guidelines for OPAT use from routine clinical data., Methods: Patients received 15-25 mg/kg/day for 3 days, then 15-25 mg/kg thrice weekly. Trough concentrations were measured weekly and doses adjusted to maintain 20-30 or 10-20 mg/L according to clinical condition. Concentration-time data were analysed using the pharmacokinetic package NONMEM and the final model was used to develop new dosage guidelines., Results: Data from 94 and 36 patients were used for model development and validation, respectively. Patient ages ranged from 15 to 94 years, weights from 43 to 146 kg and estimated CL(CR) from 9 to 195 mL/min. Teicoplanin concentrations (n = 670) ranged from 6.7 to 66.9 mg/L and a one-compartment model adequately described the data. The typical estimate of CL was 0.542 L/h and changed by 10.6% for every 10 mL/min difference from a CL(CR) of 66 mL/min. V was 1.62 L/kg. Dosage guidelines based on body weight and CL(CR) can be expected to lead to a significant improvement in the proportion of concentrations in the range 20-30 mg/L. Alternative doses aimed at lower target concentrations have also been developed., Conclusions: New dosage guidelines have been developed to support thrice-weekly administration of teicoplanin in an OPAT setting.

Genetic defects in the IFN-gamma response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-gamma may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-gamma and IFN-gamma production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-gamma was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-gamma to increase production of TNF-alpha by both autologous and normal donor PBMCs, and recovery of exogenous IFN-gamma from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-gamma-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-gamma. The purified anti-IFN-gamma antibody was shown to be functional first in blocking the upregulation of TNF-alpha production in response to endotoxin; second in blocking induction of IFN-gamma-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-gamma pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.

This case study reflects on the care of a diabetic patient with an extensive pressure ulcer on the heel. It addresses the issue of the limitations of scope of practice and expertise of the tissue viability nurse with regard to effective treatment of the diabetic foot. Methods of autolytic, sharp and surgical debridement are all attempted with varying degrees of success, together with one application of larval therapy. The importance of collaboration with members of the multidisciplinary team is addressed. Unfortunately, the final patient outcome is not yet known but this has provided a valuable reflective learning experience for myself as a tissue viability nurse.