Multiple myeloma screening within a fracture liaison service (FLS).

Multiple myeloma (MM) remains incurable. Although early diagnosis improves outcomes, it has been unclear which populations to target for screening with serum electrophoresis, serum free light chains and urine electrophoresis. Here, we assessed the value of MM screening in a Fracture Liaison Service, finding that 1 per 195 fragility fractures has undiagnosed MM, which can be expedited to Haematology Services. PURPOSE: A key role of the Fracture Liaison Service (FLS) is screening for secondary causes of osteoporosis. In 2019, the Royal Osteoporosis Society recommended that all patients attending FLS who are recommended anti-osteoporosis therapy have universal screening for myeloma based on serum electrophoresis, serum free light chains and urine electrophoresis. Here, we examined the impact of universal myeloma screening within an FLS. METHODS: We sampled all patients seen by the Oxfordshire FLS between January and April 2018. The completion rates and outcomes of screening were checked using the hospital and FLS databases. RESULTS: Of 950 patients identified by the FLS, 628 were eligible for MM screening; 473 (75%) of these were female, and the average age was 78.4 years. Overall, 584 had some form of myeloma screening, of which 577 (92%) had serum electrophoresis, 525 (84%) had serum free light chains and 407 (65%) had urine electrophoresis measured. A total of 327 (59%) patients had complete screening. Three patients (0.5%) had newly diagnosed myeloma and were urgently referred to Haematology Services. Furthermore, 46 (8%) patients had a detectable serum paraprotein with a likely diagnosis of monoclonal gammopathy of uncertain significance (MGUS) and referred for community annual surveillance according to local guidelines. CONCLUSION: Addition of universal myeloma screening to laboratory testing identified myeloma in 1 per 195 patients, and its precursor state MGUS in 1 per 13 patients, which may have otherwise been missed. Further analysis with long-term follow-up is needed to clearly define the value of diagnosing MGUS within the FLS setting and establish the benefits vs. costs and methods to improve screening completion rates.

Impaired airway epithelial cell responses from children with asthma to rhinoviral infection.

BACKGROUND: The airway epithelium forms an effective immune and physical barrier that is essential for protecting the lung from potentially harmful inhaled stimuli including viruses. Human rhinovirus (HRV) infection is a known trigger of asthma exacerbations, although the mechanism by which this occurs is not fully understood. OBJECTIVE: To explore the relationship between apoptotic, innate immune and inflammatory responses to HRV infection in airway epithelial cells (AECs) obtained from children with asthma and non-asthmatic controls. In addition, to test the hypothesis that aberrant repair of epithelium from asthmatics is further dysregulated by HRV infection. METHODS: Airway epithelial brushings were obtained from 39 asthmatic and 36 non-asthmatic children. Primary cultures were established and exposed to HRV1b and HRV14. Virus receptor number, virus replication and progeny release were determined. Epithelial cell apoptosis, IFN-ß production, inflammatory cytokine release and epithelial wound repair and proliferation were also measured. RESULTS: Virus proliferation and release was greater in airway epithelial cells from asthmatics but this was not related to the number of virus receptors. In epithelial cells from asthmatic children, virus infection dampened apoptosis, reduced IFN-ß production and increased inflammatory cytokine production. HRV1b infection also inhibited wound repair capacity of epithelial cells isolated from non-asthmatic children and exaggerated the defective repair response seen in epithelial cells from asthmatics. Addition of IFN-ß restored apoptosis, suppressed virus replication and improved repair of airway epithelial cells from asthmatics but did not reduce inflammatory cytokine production. CONCLUSIONS: Collectively, HRV infection delays repair and inhibits apoptotic processes in epithelial cells from non-asthmatic and asthmatic children. The delayed repair is further exaggerated in cells from asthmatic children and is only partially reversed by exogenous IFN-ß.

Gastroschisis in a developing country: poor resuscitation is a more significant predictor of mortality than postnasal transfer time.

BACKGROUND: The time from birth to the first paediatric surgical consultation of neonates with gastroschisis is a predictor of mortality in dveloping countries. This is contrary to findings in the developed world. We set out to document this relationship within our population. METHOD: Neonates with gastroschisis who were transferred to Steve Biko Academic Hospital within the study period were included. The association between mortality and demographic, clinical and biochemical variables was assessed. Significant variables after univariate analysis were subjected to multivariates regression. RESULTS: Sixty patients were included. The mortality rate was 65%. Mean transfer time and distance were 14.9 hours and 225km. Forty-eight per cent of the neonates were either dehydrated or in hypovolaemic shock clinically on arrival. Eight neonates arrived hypothermic. It was shown through univariate analysis that female sex, appropriate weight for gestational age, hydration status, gestation, transfer time, serum urea, base deficit and serum bicarbonate (HCO3) were significant predictors of mortality. Only female sex, appropriate weight for gestational age and serum HC03 were shown to be significant using ultivariate analysis. CONCLUSION: Our high mortality rate was not due to lengthy transfer times. The poor clinical condition of the patients on arrival at our hospital, which relates to deficiencies in the neonatal transfer system, had a direct impact on the survival of neonates with gastroschisis.

The addition of a large caliber needle during endoscopic ultrasound-guided fine needle aspiration of solid and lymph node lesions: any importance?

AIM: The benefits of using multiple gauge needles during EUS-FNA of solid and lymph node lesions are unknown. The purpose of our study was to find out the significance of adding a large caliber needle if small caliber needle fail to achieve diagnostic specimen after few passes. METHODS: It was a retrospective review of all EUS-FNA procedures performed by one of the two experienced endosonographers. A large (22 or 19 gauge) needle was added if on-site cytologic analysis did not reveal adequate specimen after ≥2 passes. The adequacy of the specimen was determined by the Cytopathologist, and categorized as either satisfactory for analysis or unsatisfactory. The cytologic findings were reported as either benign or malignant. RESULTS: Out of total 1200 EUS cases, FNA was performed in 306 cases with different solid and lymph node lesions. Multiple gauge needles were used in 188/306 (39%) cases. There was no statistically significant difference in the diagnostic yield and definitive diagnosis between multiple and single gauge needle groups. The finding was unchanged after controlling the number of needle passes. No complications were noted. CONCLUSION: The addition of a large caliber needle achieved at least the same (or even slightly higher diagnostic yield), and can be a method of rescue in certain cases.

Evidence of endogenous volatile organic compounds as biomarkers of diseases in alveolar breath.

The effect of oxygen on markers of oxidative stress has been partially elucidated. Volatile organic compounds (VOCs) are created during the oxidative burst and excreted in the human alveolar breath, which indeed contains biomarkers. A general concept including collection, separation, detection and clinical biomakers validation is presented in this article: (i) a method for the collection and GC-MS of halogenated VOCs in human alveolar breath is described: a transportable apparatus which sampled specifically alveolar breath; the VOCs were captured in a thermal desorption tube, Carbotrap 200® and each sample was thermally desorbed from the trap in an automated GC-MS apparatus; (ii) the inhibitory effects of halogenated alkanes on mitochondria are suspected likely to fight against oxidative stress deleterious reactions; (iii) two-dimensional gas chromatography occurs by the repeated and re-injection of effluent from one chromatographic column into a second column of orthogonal phase. A new commercial GCxGC system is presented; it is accomplished with a dual-stage, quad-jet thermal modulator positioned between the two columns; (iv) the affinity-based sensors usually used in connection with the GCxGC system face a difficulty to take into account different biases coming from different sources of drifting. Compared to other affinity-based sensing modes like electrical ones, gravimetric sensors enable a better decoupling. Nano Electro Mechanical Systems (NEMS)-based resonators are a particular type of gravimetric gas sensors. They are coated with a sensitive layer of polymer where gases of interest present in the atmosphere adsorb, generating an additional mass load which is measured through a frequency shift; (v) examination of exhaled breath has the potential to change the existing routine approaches in human medicine. Breath sampling to identify volatile biomarkers in diseases has been proposed in several respiratory diseases. Several VOCs have been identified in these patients by GC-MS. However, the use of traditional analytical instruments such as GC-MS to detect biomarkers of diseases has not become a routine for clinical applications. Consequently the electronic nose was the logical instrument of choice for disease diagnosis due to the capability of identifying complex mixtures of VOCs (as a whole) within sampled air using pattern-recognition algorithms.

Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures.

BACKGROUND AND STUDY AIMS: The accurate diagnosis of indeterminate pancreaticobiliary strictures presents a clinical dilemma. Probe-based confocal laser endomicroscopy (pCLE) offers real-time in vivo microscopic tissue examination that may increase sensitivity for the detection of malignancy. the objective of this study was to develop and validate a standard descriptive classification of pcle in the pancreaticobiliary system. PATIENTS AND METHODS: A total of 102 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) with pCLE to assess indeterminate pancreaticobiliary strictures were enrolled in a multicenter registry; 89 of these patients were evaluable. Information and data on the following were collected prospectively: clinical, ERCP, tissue sampling, pCLE, and follow-up. A uniform classification of pCLE findings ("Miami Classification") was developed, consisting of a set of image interpretation criteria. Thereafter, these criteria were tested through blinded consensus review of 112 randomized pCLE videos from 47 patients, and inter-observer variability was assessed in 42 patients . RESULTS: A consensus definition of the specific criteria of biliary and pancreatic pCLE findings for indeterminate strictures was developed. Single-image interpretation criteria did not have a high enough sensitivity for predicting malignancy. However, combining two or more criteria significantly increased the sensitivity and predictive values. The characteristics most suggestive of malignancy included the following: thick white bands (>20 µm), or thick dark bands (>40 µm), or dark clumps or epithelial structures. These provided sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 33%, 80%, and 80% compared with 48%, 100%, 100%, and 41% for standard tissue sampling methods. Inter-observer variability was moderate for most criteria. CONCLUSION: The Miami Classification enables a structured, uniform, and reproducible description of pancreaticobiliary pCLE. Combining individual characteristics improves the sensitivity for the detection of malignancy.

A survey on the current status of laparoscopic training in paediatric surgery in South Africa.

OBJECTIVES: To document the current status of laparoscopic training of paediatric surgical registrars in South Africa. METHODS: An anonymous questionnaire was distributed. Participants were asked to document their involvement in a number of index laparoscopic procedures during the preceding year, as well as additional non-operative training they received and their satisfaction with their training thus far. RESULTS: All registrars (N=16) completed the questionnaire. Registrars were from the Universities of KwaZulu-Natal, Cape Town, Stellenbosch, Pretoria and the Witwatersrand, and Walter Sisulu University. The ratio of consultants proficient in paediatric laparoscopy to registrars was between 0.6 and 1. Junior registrars were more likely to assist with, and senior registrars more likely to perform, procedures. Registrar satisfaction varied greatly across institutions, with 44% of registrars satisfied with their training. CONCLUSIONS: The consultant-to-registrar ratio is favourable, and high patient load provides opportunity for laparoscopic education. However, there are a number of obstacles to adequate training. These include the feasibility of after-hours laparoscopic surgery and the availability and use of training aids. The introduction of a structured training programme across all institutions will improve laparoscopic proficiency and satisfaction among paediatric surgical registrars in South Africa.

Changes in adult home parenteral nutrition practice over 25 years.

BACKGROUND AND AIMS: Home Parenteral Nutrition (HPN) is the established treatment of intestinal failure. This study considers the changes in practice in a single UK centre over the past twenty-five years. METHODS: Data was culled from a database used for clinical care and maintained prospectively. RESULTS: Two hundred and five patients were included from 1993 to 2018. Patient numbers increased from 22 during 1999-2003 to 158 during 2014-2018. The median age at discharge increased from 52 years during 1999-2003 to 59 years during 2014-2018. Thirty percent of patients discharged during 1999-2003 had Crohn's disease, reducing to 14% during 2014-2018. Fifteen percent of patients discharged during 1999-2003 had small bowel fistula or obstruction in comparison to 44% during 2014-2018. Only 18 patients were treated with palliative intent, the majority in recent years. An increasing number of patients required help with HPN care over the years. Survival in non-palliative patients was 85% at 1 year, 67% at 3 years, 53% at 5 years and 42% at 10 years. The majority of deaths were due to underlying disease and only 5 of 55 deaths were attributed to HPN alone. HPN dependence in non-palliative patients was 73% at 1 year, 59% at 3 years, 56% at 5 years and 43% at 10 years. Fifty eight patients stopped HPN after reconstructive surgery. Patients experienced 5.1 admissions/1000 HPN days (64.7 admission days/1000 HPN days). Admission rate did not change over the years though the percentage due to catheter problems fell from 52% to 40% while the percentage due to underlying disease or unrelated cause rose. CONCLUSIONS: The increase in numbers, age and dependency of HPN patients requires increasing resource and consideration of new models of service. Many patients with short bowel syndrome now survive to old age and the care needs of the HPN patient who has become elderly can be complex. A significant proportion of patients are being referred for HPN as a bridge to reconstructive surgery after surgical complication and this requires close involvement of gastrointestinal surgeons in HPN teams. The need for hospital admissions remains a burden for HPN patients and there is scope for changes in service provision to try to reduce hospital days.

Characteristics, cardiovascular comorbidity and medicines management in patients with type 2 diabetes and CKD: results of the IRIDIEM study.

BACKGROUND: Type 2 diabetes is a leading cause of chronic kidney disease (CKD). The purpose of the Individual Risk-Profiling and Treatment in Diabetes Management (IRIDIEM) study was to evaluate the characteristics of CKD and associated comorbidities in patients with type 2 diabetes and CKD. METHODS: IRIDIEM was conducted as a cross-sectional survey in 109 centres in 11 countries and included 1,205 patients aged >or=50 years with type 2 diabetes for >or=5 years and CKD stage 2-4. RESULTS: 50% of patients were in CKD stage 4; 42% had CKD stage 3, and 4% were in CKD stage 2. Concomitant risk factors for cardiovascular disease and/or progression of CKD included hypertension (92% of patients), proteinuria (74%), hypercholesterolaemia (65%), and hypertriglyceridaemia (44%). Only 64% of patients with hypertension had received antihypertensive medication. Anaemia was present in 34% of patients and increased markedly with advanced CKD stages. Of patients with documented anaemia, only 19% had received epoetin and only 7% had received iron treatment. CONCLUSION: IRIDIEM documents the need to improve adherence to current best practice guidelines for management of cardiorenal risk factors including earlier initiation of antihypertensive treatment, lipid and anaemia management in this high-risk patient population.

Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

An alternative real-time PCR method to detect the Bacillus cereus group in naturally contaminated food gelatine: a comparison study.

AIMS: Comparison of an internally controlled real-time PCR assay with the standard plate-based assay (ISO 21871) for the detection of Bacillus cereus group cells in gelatine. METHODS AND RESULTS: A comprehensive TaqMan probe was designed allowing the real-time PCR assay to be fully inclusive and exclusive. An internal amplification control was designed and implemented at 500 copies per reaction without impact on target detection. Specific and selective detection of target cells was achieved with a quick and simple DNA preparation procedure. No significant difference (kappa = 0.99) was observed between the performance of the real-time PCR and the standard plate-based method on naturally contaminated gelatines (n = 197). Relative accuracy, relative sensitivity and relative specificity were > or =99%. CONCLUSIONS: The real-time PCR assay is a valid alternative of the standard plate-based assay. SIGNIFICANCE AND IMPACT OF THE STUDY: The real-time PCR assay decreased the time between sample collection and result from 2 days to 2 h, while analysis cost did not increase. The gelatine-producing industry can ensure gelatine safety and quality in a much faster way.

An alternative real-time PCR method for the detection of thermotolerant Bacillus sensu lato contaminants in naturally-contaminated gelatine.

AIMS: Comparison of an internally-controlled real-time PCR assay with the current plate-based assay for the detection of Bacillus sensu lato contaminants in gelatine. METHODS AND RESULTS: A comprehensive TaqMan probe was designed allowing the real-time PCR assay to be fully inclusive for the gelatine-contaminating Bacillus s.l. species. An internal amplification control was implemented at 500 copies per reaction without impact on target detection. Specific and selective detection of target cells was achieved with a quick and simple DNA preparation procedure. No significant difference (Kappa value = 0.94) was observed between the performance of the real-time PCR and the current plate-based method on naturally contaminated gelatines (n = 162). Relative accuracy, relative sensitivity and relative specificity were 97.5%. CONCLUSIONS: The real-time PCR assay is an adequate alternative of the current plate-based assay. SIGNIFICANCE AND IMPACT OF THE STUDY: The real-time PCR assay decreased the time between sample collection and result from 2 days to 2 h. The gelatine-producing industry can ensure gelatine quality in a much faster way.

Overview of HOMEChem: House Observations of Microbial and Environmental Chemistry.

The House Observations of Microbial and Environmental Chemistry (HOMEChem) study is a collaborative field investigation designed to probe how everyday activities influence the emissions, chemical transformations and removal of trace gases and particles in indoor air. Sequential and layered experiments in a research house included cooking, cleaning, variable occupancy, and window-opening. This paper describes the overall design of HOMEChem and presents preliminary case studies investigating the concentrations of reactive trace gases, aerosol particles, and surface films. Cooking was a large source of VOCs, CO2, NOx, and particles. By number, cooking particles were predominantly in the ultrafine mode. Organic aerosol dominated the submicron mass, and, while variable between meals and throughout the cooking process, was dominated by components of hydrocarbon character and low oxygen content, similar to cooking oil. Air exchange in the house ensured that cooking particles were present for only short periods. During unoccupied background intervals, particle concentrations were lower indoors than outdoors. The cooling coils of the house ventilation system induced cyclic changes in water soluble gases. Even during unoccupied periods, concentrations of many organic trace gases were higher indoors than outdoors, consistent with housing materials being potential sources of these compounds to the outdoor environment. Organic material accumulated on indoor surfaces, and exhibited chemical signatures similar to indoor organic aerosol.

Comparison of techniques for obtaining lower airway epithelial cells from children.

Airway epithelial cells (AECs) are important in asthma as they are the first cells to encounter pathogens/allergens. In children, AECs can be obtained using a "blind" nonbronchoscopic technique through an endotracheal tube. However, due to the increasing use of laryngeal masks the number of children in whom this technique is applicable has become limited. Recently, the present authors began to use a portable "bronchoscope-directed" technique to sample AECs. The current study compares both techniques in both asthmatic and nonasthmatic children. A total of 81 children undergoing elective surgery, were grouped according to atopic status and respiratory symptoms. Cellular yield of blind and bronchoscope-directed brushings were compared and immunocytochemistry performed. AECs were cultured and cytokine analysis of culture supernatant undertaken. Both techniques were equally well-tolerated, with the only adverse effect being a cough in 10% of the subjects. The mean+/-SD cell yield was higher in bronchoscope-directed than blind brushings (5.1+/-2.4 versus 3.1+/-1.4x10(6) cells). Immunocytochemistry confirmed an epithelial cell lineage. Culture supernatant cytokine concentrations were similar regardless of sampling technique with patterns preserved between asthmatic and healthy nonatopic phenotypes. Compared with blind brushing portable bronchoscope-directed brushing is well-tolerated, yields significantly more cells and is a potentially quick and useful technique for obtaining airway epithelial cells for research into childhood respiratory disease, specifically asthma.

Dysregulated repair in asthmatic paediatric airway epithelial cells: the role of plasminogen activator inhibitor-1.

BACKGROUND: Asthma is associated with structural changes to airways such as extracellular matrix deposition and epithelial damage. Evidence suggests that asthmatic airway epithelial repair is abnormal and that elevated plasminogen activator inhibitor-1 levels observed in asthma may be involved in the epithelial repair process and in excessive matrix accumulation. OBJECTIVE: To assess the ability of asthmatic airway epithelial cells (AECs) to repair mechanically induced wounds and to investigate the role that plasminogen activator inhibitor-1 plays in the repair process. METHODS: AECs were isolated from atopic asthmatic and healthy non-atopic children by bronchial brushing, subcultured and wound repair experiments were performed. Plasminogen activator inhibitor-1 gene expression was assessed using real-time PCR while protein activity was measured in cell lysates as well as plasma. The role of plasminogen activator inhibitor-1 in epithelial proliferation and wound repair was investigated using siRNA. RESULTS: Cells from asthmatic children have a significantly longer repair time in comparison with cells from otherwise healthy donors. Plasminogen activator inhibitor-1 mRNA expression was up-regulated 68-fold in freshly isolated asthmatic cells compared with normal cells, and protein levels were also significantly elevated in the asthmatic cell lysates, but plasma levels were similar in both groups. Plasminogen activator inhibitor-1 cells expression increased in both cohorts during culture. Gene silencing substantially reduced the rate of proliferation in asthmatic and healthy cells. Mechanical wounding of epithelial monolayers induced plasminogen activator inhibitor-1 expression in asthmatic and non-asthmatic cohorts, while gene silencing delayed wound repair of healthy cell, with minimal effect on those from asthmatics. CONCLUSION: Asthmatic AECs are inherently dysfunctional in their ability to repair wounds; plasminogen activator inhibitor-1 mRNA and protein activity are constitutively up-regulated in asthmatic epithelium and play functional roles in both proliferation and repair of healthy cells. In asthmatic cells, elevated plasminogen activator inhibitors-1 levels fail to stimulate epithelial repair.

Blind Pew sends a black spot: the current haemoglobin controversy.

Two randomised controlled trials of anaemia management published in the last year have fuelled the current haemoglobin controversy and led the United States Food and Drug Administration to issue a public health advisory warning concerning the use of erythropoiesis-stimulating agents and target haemoglobin levels. There is much more to the haemoglobin controversy than purely target haemoglobin levels. This article seeks to outline some of the current issues involved.

Normal ranges and temporal variation in plasma concentrations of L-lactate and free amino acids in adult sheep.

To determine baseline variation in blood plasma concentrations of free amino acids and l-lactate, samples were collected at a single time point from nine flocks of different breeds of ewes at a common physiological stage and monthly from one flock of crossbred mule ewes over a 12 month period. Significant differences were detected between time points in the concentrations of all plasma metabolites. With few exceptions prion protein genotype had no significant effect on the plasma metabolite concentrations measured.

Effect of scrapie incubation on the concentrations of plasma amino acids and L-lactate in infected lambs.

Three groups of two weeks old growing lambs differing in PrP genotype were orally inoculated with scrapie and maintained under defined conditions until disease endpoint. Plasma concentrations of free alanine and serine, but not L-lactate increased during the final 6 months of the disease. At the same time, plasma concentrations of several essential and non-essential free amino acids decreased linearly, indicating reduced feed intake and are consistent with, but occurring before establishment, of cachexia. These observations are consistent with those reported previously from studies on cattle infected with BSE and with the hypothesis that scrapie may effect peripheral tissue metabolism.

Substrate-Independent Epitaxial Growth of the Metal-Organic Framework MOF-508a.

Plasmachemical deposition is a substrate-independent method for the conformal surface functionalization of solid substrates. Structurally well-defined pulsed plasma deposited poly(1-allylimidazole) layers provide surface imidazole linker groups for the directed liquid-phase epitaxial (layer-by-layer) growth of metal-organic frameworks (MOFs) at room temperature. For the case of microporous [Zn (benzene-1,4-dicarboxylate)-(4,4'-bipyridine)0.5] (MOF-508), the MOF-508a polymorph containing two interpenetrating crystal lattice frameworks undergoes orientated Volmer-Weber growth and displays CO2 gas capture behavior at atmospheric concentrations in proportion to the number of epitaxially grown MOF-508 layers.