The impact of frailty in major trauma in older patients.

As our population ages and increasing numbers of older patients experience major trauma it is important to understand factors that influence outcomes in this patient cohort. The aim of this study is to assess the impact of frailty in older patients who experience major trauma (Injury Severity Score (ISS) greater than 15). A retrospective cohort review using the national trauma registry data (Trauma Audit and Research Network) and an institutional database was carried out on all patients aged 60 years or older with an ISS> 15 who were treated at the regional Major Trauma Centre from 2014 to 2017 following major trauma. Frailty was assessed using the modified frailty index (mFI). Outcomes assessed included mortality, complications, hospital stay, functional outcome and discharge destination. 819 patients were included in the study. The most common mechanism of injury was fall from a height less than 2m (57.4%). 412 (51.3%) patients had a low frailty score, 280 (35%) had an intermediate frailty score and 110 (14%) had high frailty score. Increased frailty was associated with increased mortality at discharge (18.7%, 14.6% and 26.4% for low, intermediate and high frailty groups) and at one year (26.2%, 35.2% and 51%, respectively). Other predictors of mortality included male sex, age >90 years and the occurrence of a serious complication. Increasing frailty was also associated with an increased risk of serious complications including unplanned intubation, infection and progressive renal failure, and discharge to a destination other than home. This is the first study that has delineated the impact of frailty in older patients who experience major trauma and provides important information for patients, their families and healthcare providers. Future studies should focus on identifying care pathways that counteract the impact of frailty in this setting.

Management of invasive candidiasis and candidaemia in critically ill adults: expert opinion of the European Society of Anaesthesia Intensive Care Scientific Subcommittee.

OBJECTIVE: The global burden of invasive fungal disease is increasing. Candida albicans remains the leading cause of fungal bloodstream infections, although non-albicans candidal infections are emerging. Areas of controversy regarding diagnosis and management are hampering our ability to respond effectively to this evolving threat. The purpose of this narrative review is to address current controversies and provide recommendations to supplement guidelines. DIAGNOSIS OF INVASIVE CANDIDIASIS: Diagnosis of invasive candidiasis requires a combination of diagnostic tests and patient risk factors. Beta-D glucan and Candida albicans germ tube antibody are both used as biomarkers as adjuncts to diagnosis, although direct culture remains the gold standard. Scoring systems are available to help distinguish between colonization and invasive disease. TREATMENT OF INVASIVE CANDIDIASIS: Echinocandins are recommended as first-line therapy in candidaemia, with de-escalation to fluconazole when clinical stability is achieved. Empirical therapy is highly recommended in high-risk patients, but a more targeted pre-emptive approach is now being favoured. The evidence for prophylactic therapy remains weak. SUMMARY: Mortality attributable to invasive candidiasis may be as high as 70%. Prompt diagnosis and treatment, in conjunction with source control, are the key to improving outcomes.

Cost implications for the NHS of using the Alere™ i Influenza A & B near patient test with nasal swabs.

BACKGROUND: Influenza is an acute viral infection of the respiratory tract. A rapid confirmatory diagnosis of influenza is important, since it is highly transmissible and outbreaks of influenza within the hospital setting increase morbidity and mortality. The objective of this study was to evaluate the cost implications, from the perspective of the UK NHS, of using on-label nasal swabs with the Alere™ i Influenza A & B test in a near patient setting. METHODS: A cost consequence model was developed. The time horizon of the model was from hospital admission on suspicion of influenza until the end of treatment (following a diagnosis of influenza or discharge from hospital). Data on the prevalence of influenza and the sensitivity and specificity of the Alere™ i Influenza A & B test came from two prospective observational diagnostic accuracy studies. Costs were obtained from published resources. Uncertainties in the model data were investigated using deterministic, one-way sensitivity analyses. RESULTS: Using the Alere™ i Influenza A & B point of care test with nasal swabs (on label) in NHS medical assessment units and emergency departments could save approximately £242,730 per 1000 adults presenting with influenza-like symptoms. The main cause for this was reduced times to availability of the result compared with the laboratory RT-PCR test. Other key drivers of savings were the cost of isolation, the prevalence of influenza, the specificity of the test, and the availability of isolation resources. CONCLUSIONS: The Alere™ i Influenza A & B point of care test would have greatest impact in hospitals that have extensive delays in the time to receive a result. Sensitivity analyses identified the model parameters which would have greatest effect on the result and confirmed that assumptions were conservative, i.e. did not change key results.

Diagnostic accuracy and cost analysis of the Alere™ i Influenza A&B near-patient test using throat swabs.

BACKGROUND: Clinical diagnostic sensitivity alone is inadequate in the diagnosis of influenza. Polymerase chain reaction (PCR) testing is sensitive but the inherent delays in result availability potentially prolong time to isolation and treatment. Until recently no near-patient test (NPT) has demonstrated adequate sensitivity for routine clinical use. AIM: To evaluate diagnostic accuracy, time to result availability, clinical impact, and cost consequences of Alere™ i Influenza A&B NPT (Alere Inc., Waltham, MA, USA) using off-label throat swabs. METHODS: Prospective, multi-centre [four UK National Health Service (NHS) hospitals], diagnostic accuracy cohort study with cost modelling. Throat swab samples from suspected influenza patients were tested for influenza using the reference standard of PCR; a second throat swab was tested using NPT. FINDINGS: A total of 827 participants were recruited; 589 were suitable for analysis: sensitivity was 75.8% [95% confidence interval (CI): 67.0-84.6]; specificity was 96.8% (95% CI: 95.2-98.3). Sensitivity varied between Sheffield (Northern General Hospital: 82.1%; Royal Hallamshire Hospital: 83.3%) and other sites (Doncaster Royal Infirmary: 71.4%; Newcastle's Royal Victoria Infirmary: 50.0%) whereas specificity was high (92-100%). Positive predictive value (PPV) was 81.2% (95% CI: 72.9-89.5) with negative predictive value 95.6% (95% CI: 93.9-97.4) with observed prevalence of 15.4%. Median time to result for PCR was 1.1 days (on-site laboratories) and 5.2 days (remote laboratories). Isolation findings: 75% influenza positive not isolated; 69% of isolated participants did not have influenza. For a cohort of 1000 participants, annual estimated non-diagnostic cost savings with NPT are £215,040. CONCLUSION: This first prospective study of the Alere i NPT using throat swabs demonstrates high specificity, high PPV during seasonal epidemics, and rapid result availability which could lead to substantial cost savings.

Multiple intra-hospital transports during relocation to a new critical care unit.

OBJECTIVE: Intra-hospital transport (IHT) of critically ill patients is associated with morbidity and mortality. Mass transfer of patients, as happens with unit relocation, is poorly described. We outline the process and adverse events associated with the relocation of a critical care unit. DESIGN: Extensive planning of the relocation targeted patient and equipment transfer, reduction in clinical pressure prior to the event and patient care during the relocation phase. SETTING: The setting was a 30-bed, tertiary referral, combined medical and surgical critical care unit, located in a 570-bed hospital that serves as the national referral centre for cardiothoracic surgery and spinal injuries. PARTICIPANTS: All stakeholders relevant to the critical care unit relocation were involved, including nursing and medical staff, porters, information technology services, laboratory staff, project development managers, pharmacy staff and building contractors. MAIN OUTCOME MEASURES: Mortality at discharge from critical care unit and discharge from hospital were the main outcome measures. A wide range of adverse events were prospectively recorded, as were transfer times. RESULTS: Twenty-one patients underwent IHT, with a median transfer time of 10 min. Two transfers were complicated by equipment failure and three patients experienced an episode of hypotension requiring intervention. There were no cases of central venous or arterial catheter or endotracheal tube dislodgement, and hospital mortality at 30 days was 14%. CONCLUSION: Although IHT is associated with morbidity and mortality, careful logistical planning allows for efficient transfer with low complication rates.

Ultrasound-guided infraclavicular axillary vein cannulation: a useful alternative to the internal jugular vein.

BACKGROUND: Ultrasound (US) guidance reduces complications and increases accuracy during internal jugular vein (IJV) cannulation. The subclavian vein (SCV) is popular but is less amenable to US guidance. The axillary vein (AxV), a direct continuation of the SCV, is an alternative, but to date, experience with US is limited to small case series. METHODS: Retrospective procedural data were collected on 2586 sequential patients referred for insertion of tunnelled central venous access at a UK tertiary centre from 2004 to 2011. RESULTS: A total of 99.8% of patients tolerated the procedure with local anaesthesia ± sedation; six patients had general anaesthesia. Twenty-six (1%) patients had uncorrected coagulopathy or thrombocytopenia. A total of 2572 (99.5%) of patients were cannulated successfully: right AxV 1644 cases, left AxV 279, right IJV 547, left IJV 89, other techniques 13, and 14 (0.5%) cases failed. The initial site chosen was successful in 96%. In patients who previously underwent long-term cannulation, 93.3% of lines were sited easily. Forty-eight (1.9%) procedural complications occurred. CONCLUSIONS: In this large analysis of US-guided central venous access in a complex patient group, the majority of patients were cannulated successfully and safely. The subset of patients undergoing AxV cannulation demonstrated a low rate of complications. The AxV route of access appears to be a safe and effective alternative to the IJV.

Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction.

Gastrointestinal carcinomas frequently disseminate within the abdominal cavity to form secondary peritoneal metastases. Invasion of the peritoneal mesothelium is fundamental to this process, yet the underlying invasive mechanisms remain unclear. Preliminary in vitro work suggested that tumour cells can induce mesothelial apoptosis, representing a novel mechanism of peritoneal invasion. We examined the role of tumour cell-induced mesothelial apoptosis and explored the role of the death ligand/receptor system, Fas Ligand/Fas, as mediators of the apoptotic process. Cultured human mesothelial cells were used to establish in vitro co-culture models with the SW480 colonic cancer cell line. Tumour-induced mesothelial apoptosis was confirmed by phase-contrast microscopy and apoptotic detection assays. Human mesothelial cells and SW480 tumour cells constitutively expressed Fas and Fas Ligand mRNA and protein as determined by RT-PCR and confocal fluorescent microscopy. Stimulation of human mesothelial cells with anti-Fas monoclonal antibody or crosslinked soluble Fas Ligand-induced apoptosis, confirming the functional status of the Fas receptor. Pretreatment of SW480 cells with a blocking recombinant anti-Fas Ligand monoclonal antibody significantly reduced mesothelial apoptosis, indicating that tumour-induced mesothelial apoptosis may, in part, be mediated via a Fas-dependent mechanism. This represents a novel mechanism of mesothelial invasion and offers several new targets for therapeutic intervention.

Agreement between preoperative core needle biopsy and postoperative invasive breast cancer histopathology is not dependent on the amount of clinical material obtained.

AIMS: To establish the relation between the amount of breast core needle biopsy (CNB) material examined and agreement between preoperative and postoperative histopathology parameters in invasive breast cancer. METHODS: The CNB and surgical specimen histopathology reports of 113 patients with invasive breast carcinoma were reviewed and the total amount of CNB material examined for each case was determined. Agreement was calculated for tumour type, grade, mitoses, nuclear pleomorphism, and tubule formation. Associations between the amount of CNB material and histopathology agreement before and after surgery were explored using binary logistic regression. RESULTS: Tumour type and grade agreed in 65.4% and 61.6% of cases, respectively. The components used to calculate grade--nuclear pleomorphism (57.4%), mitoses (59.4%), and tubule formation (55.6%)--agreed slightly less frequently. The proportion of cases with preoperative and postoperative assessments that agreed did not depend on the number of cores collected or the total amount of material examined. CONCLUSION: Neither tumour type and grade, nor the individual components used to calculate grade agreed consistently between the CNB and surgical specimen. The number of cores collected and the total amount of material reviewed by the pathologist does not influence the likelihood of agreement between preoperative and postoperative histopathology reports.

A novel in vitro dermal wound-healing model incorporating a response to mechanical wounding and repopulation of a fibrin provisional matrix.

Previously our laboratory, and others, described an in vitro model for the study of fibroblast wound repopulation. The so-called punch-wounded, fibroblast-populated collagen lattice has been used extensively in tissue repair research. We now identify certain shortcomings with this model, which have led to its enhancement by the introduction of a provisional matrix fabricated in situ from fibrinogen and alpha-thrombin. In the previous model, fibroblasts repopulate the wound defect (WD) as a monolayer of cells and on reaching confluence, a process reminiscent of fibroplasia fills the wound space. The enhanced model, with fibrin acting as a provisional matrix, allowed fibroblasts to repopulate the WD as a three-dimensional network of cells that were morphologically different from cells migrating over the collagen substratum of the previous model. Fibroblast repopulation of the fibrin matrix was typically around double the rate of repopulation of the empty wound space. We propose this model as an enhanced, yet sufficiently reproducible, model for the study of fibroblast responses to tissue damage. It can be further enhanced by the addition of other cell types and matrix components.

Pathological scarring: strategic interventions.

Aberrant cutaneous scar formation is a substantial cause of postoperative morbidity. There is at present no clear consensus on the best way to prevent or treat such scarring, although recently there has been considerable progress in developing an understanding of the mechanisms of tissue repair and scarring. We carried out a literature review using Medline to establish the current understanding of the key events occurring during tissue repair and to identify potential causes of scarring. We now review the key events during tissue repair and the pathogenesis of fibroproliferative disease. Tissue repair is achieved through a multistranded, elegantly coordinated process within which the balance between synthesis and breakdown of matrix is upset during fibrotic disease. Scars form because the signals directing tissue repair are not correctly terminated, and while the initiation and propagation of repair is well understood the signals that direct its cessation have yet to be elucidated.

Use of pilot plant facilities to aid validation programs.

According to the FDA guidelines (1), pilot plant facilities may be used to generate material to support process validation studies. The guidelines also state that process modifications are an inevitable part of process development and scale-up. However, if such modifications are made, there is a need to demonstrate that the products from both the old and new processes are comparable (2). Both of these guidelines were combined and applied during a recent development of a product at Genentech. In order to implement the process modifications and demonstrate product comparability, the pilot plant facilities were used for these production runs. As the process had changed and the product was being prepared for BLA submission, in process samples from the new manufacturing process were also required to support the process validation studies. By using pilot plant facilities to implement the process modifications, test product comparability, and produce material for process validation, we were able to minimize the impact of such work on the large-scale manufacturing facility.

Cardiotrophin-1 can protect cardiac myocytes from injury when added both prior to simulated ischaemia and at reoxygenation.

OBJECTIVE: The cytokine cardiotrophin-1 (CT-1) has previously been shown to protect cultured cardiocytes from cell death induced by serum removal or hypoxia when administered prior to the damaging stimulus. We wished to test whether a similar protective effect could be observed if CT-1 was added after the ischaemic period and to investigate the signalling pathways involved in the protective effect when CT-1 is given prior to or after ischaemia. METHODS: We therefore examined the protective effect of CT-1 in cultured rat cardiocytes exposed to simulated ischaemia followed by reoxygenation when CT-1 was administered either prior to simulated ischaemia or at reoxygenation. RESULTS: We show that CT-1 can exert a protective effect against the damaging effects of simulated ischaemia/reoxygenation both when added after the simulated ischaemia at reoxygenation (P<0.05 in trypan blue, TUNEL and annexin V assays) or when added prior to the simulated ischaemia (P<0.05). In both cases, these protective effects are blocked by an inhibitor of the p42/p44 MAPK pathway (P<0.05 in all assays). CONCLUSION: CT-1 can protect cardiac cells when added either prior to simulated ischaemia or at the time of reoxygenation following simulated ischaemia and these effects are dependent upon its ability to activate the p42/p44 MAPK pathway. Hence CT-1 may have therapeutic potential when added at the time of reperfusion following ischaemic damage.

Effects of cardiotrophin-1 (CT-1) in a mouse motor neuron disease.

Cardiotrophin-1 (CT-1) has potent survival-promoting effects on motor neurons in vitro and in vivo and may be effective in treating motor neuron diseases (MND). We investigated the effects of CT-1 treatment in wobbler mouse MND. Wobbler mice were randomly assigned to receive subcutaneously injected CT-1 (1 mg/kg, n = 18, in two experiments) or vehicle (n = 18, in two experiments) daily, 6 times/week for 4 weeks after clinical diagnosis at age 3 to 4 weeks. Cardiotrophin-1 treatment prevented deterioration in paw position and walking pattern abnormalities. Grip strength declined steadily in the vehicle group, whereas in the CT-1 group it declined at week 1 but increased thereafter to exceed baseline strength by 5% (P = 0.0002) at week 4. Running speed was faster with CT-1 (P = 0.007). Biceps muscle twitch tension, muscle weight, mean muscle fiber diameter, and intramuscular axonal sprouting were significantly greater with CT-1 treatment than with vehicle treatment. Histometry revealed a trend that indicated CT-1 modestly increased the number of immunoreactive motor neurons, as determined by both choline acetyltransferase and c-Ret antibodies, and reduced the number of phosphorylated neurofilament immunoreactive perikarya (P = 0.05). The number of large myelinated motor axons significantly increased with treatment (206 versus 113, P = 0.01). We conclude that CT-1 exerts myotrophic effects as well as neurotrophic effects in a mouse model of spontaneous MND, a finding that has potential therapeutic implications for human MND.

Modernization and religious intermarriage in the Republic of Ireland.

There are strong theoretical reasons for hypothesizing that those sections of the population who are most exposed to modernization processes are more likely to marry outside their own religious group. We examine this for Catholic-Protestant intermarriage in the Republic of Ireland. We use a multivariate analysis on survey data to test the hypotheses that urban dwellers, persons of non-farming parents, persons with higher levels of education and the young are more likely to be religiously intermarried. While the odds of being in an intermarriage are greater for urban dwellers, this is in large part due to their being non-farmers. The farming effect is not necessarily related to religiosity. The odds of being in an intermarriage do not increase significantly for persons with third level education and this can be explained in terms of the marriage market for minority groups. It is shown that the historical context and the minority position of religious group should be taken into account in explanations which relate modernization to the pattern of religious intermarriage.

Curative radiotherapy for anterior commissure laryngeal carcinoma.

There is continuing controversy surrounding the most effective treatment of glottic carcinoma involving the anterior commissure (AC). Surgery has been the preferred method of treatment, since studies previously indicated early tumor invasion of the thyroid cartilage at the AC, thereby assuming less curability by radiotherapy (RT). Subsequent laryngeal anatomic studies and refinement of RT techniques have brought into question the ineffectiveness of curative irradiation. A retrospective review of 174 patients with early-stage glottic carcinoma treated with standard fractionation curative RT revealed 34 patients with T1 and T2 lesions involving the AC. Allowing for a follow-up of at least 3 years, we observed only a 12% (4 of 34 patients) local recurrence rate after RT alone, with excellent voice quality and no major complications related to the irradiation. The 4 local recurrences were controlled by total laryngectomy, although 2 patients developed distant metastatic disease. Radiotherapy represents an effective method of treating T1 squamous cell carcinoma of the glottis with AC involvement. The small number of T2 glottic carcinomas in this study prevents a meaningful conclusion concerning treatment of these lesions.

Brain-derived neurotrophic factor induces excitotoxic sensitivity in cultured embryonic rat spinal motor neurons through activation of the phosphatidylinositol 3-kinase pathway.

Neurotrophic factors (NTFs) can protect against or sensitize neurons to excitotoxicity. We studied the role played by various NTFs in the excitotoxic death of purified embryonic rat motor neurons. Motor neurons cultured in brain-derived neurotrophic factor, but not neurotrophin 3, glial-derived neurotrophic factor, or cardiotrophin 1, were sensitive to excitotoxic insult. BDNF also induces excitotoxic sensitivity (ES) in motor neurons when BDNF is combined with these other NTFs. The effect of BDNF depends on de novo protein and mRNA synthesis. Reagents that either activate or inhibit the 75-kDa NTF receptor p75NTR do not affect BDNF-induced ES. The low EC50 for BDNF-induced survival and ES suggests that TrkB mediates both of these biological activities. BDNF does not alter glutamate-evoked rises of intracellular Ca2+, suggesting BDNF acts downstream. Both wortmannin and LY294002, which specifically block the phosphatidylinositol 3-kinase (PI3K) intracellular signaling pathway in motor neurons, inhibit BDNF-induced ES. We confirm this finding using a herpes simplex virus (HSV) that expresses the dominant negative p85 subunit of PI3K. Infecting motor neurons with this HSV, but not a control HSV, blocks activation of the PI3K pathway and BDNF-induced ES. Through the activation of TrkB and the PI3K signaling pathway, BDNF renders developing motor neurons susceptible to glutamate receptor-mediated cell death.

Cardiotrophin-1 attenuates endotoxin-induced acute lung injury.

Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokine family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Recent evidence suggests that, like other members of this family, CT-1 may possess anti-inflammatory properties. We hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)-induced acute lung injury. We studied the effects of CT-1 (100 microgram/kg ip, 10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were harvested for determination of neutrophil accumulation (myeloperoxidase, MPO, assay) and lung edema (wet-to-dry weight ratio). Mechanisms of pulmonary vasorelaxation were examined in isolated pulmonary artery rings at 6 h by interrogating endothelium-dependent (response to acetylcholine) and endothelium-independent (response to sodium nitroprusside) relaxation following alpha-adrenergic (phenylephrine)-stimulated preconstriction. CT-1 abrogated the endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0.2 units MPO/g wet lung (gwl) vs 6. 3 +/- 0.3 units MPO/gwl in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Similarly, CT-1 prevented ETX-induced lung edema: wet-to-dry-weight ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Endotoxin caused significant impairment of both endothelium-dependent and -independent pulmonary vasorelaxation, and CT-1 attenuated this injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties in a model of endotoxin-induced acute lung injury.