Scope and mortality of adult medical ICU patients in an Eastern Cape tertiary hospital.

Background: The characteristics and mortality outcomes of patients admitted to South African intensive care units (ICUs) owing to medical conditions are unknown. Available literature is derived from studies based on data from high-income countries. Objectives: To determine ICU utilisation by medical patients and evaluate the scope of admissions and clinical associations with hospital mortality in ICU patients 12 years and older admitted to an Eastern Cape tertiary ICU, particularly in the subset with HIV disease. Methods: A retrospective descriptive one-year cohort study. Data were obtained from the LivAKI study database and demographic data, comorbidities, diagnosis, and mortality outcomes and associations were determined. Results: There were 261 (29.8%) medical ICU admissions. The mean age of the cohort was 40.2 years; 51.7% were female. When compared with the surgical emergencies, the medical subgroup had higher sequential organ failure assessment (SOFA) scores (median score 5 v. 4, respectively) and simplified acute physiology score III (SAPS 3) scores (median 52.7 v. 48.5), a higher incidence of acute respiratory distress syndrome (ARDS) (7.7% v. 2.9%) and required more frequent dialysis (20.3% v. 5.5%). Of the medical admissions, sepsis accounted for 32.4% of admission diagnoses. The HIV seroprevalence rate was 34.0%, of whom 57.4% were on antiretroviral therapy. ICU and hospital mortality rates were 11.1% and 21.5% respectively, while only acute kidney injury (AKI) and sepsis were independently associated with mortality. The HIV-positive subgroup had a higher burden of tuberculosis (TB), higher admission SOFA and SAPS 3 scores and required more organ support. Conclusion: Among medical patients admitted to ICU, there was a high HIV seroprevalence with low uptake of antiretroviral therapy. Sepsis was the most frequently identified ICU admission diagnosis. Sepsis and AKI (not HIV) were independent predictors of mortality. Co-infection with HIV and TB was associated with increased mortality. Contributions of the study: The epidemiology and outcomes of adults who are critically ill from medical conditions in South African intensive care units was previously unknown but has been described in this study. The association of sepsis, TB, HIV and acute kidney injury with mortality is discussed.

Primary cutaneous anaplastic large-cell lymphoma: a review of the SEER database from 2005 to 2016.

INTRODUCTION: Primary cutaneous anaplastic large-cell lymphoma (PC-ALCL) is a rare T-cell lymphoma. A prior analysis of the Surveillance, Epidemiology, and End Results (SEER) database reported only 157 cases of localized primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-ALCL and lymphomatoid papulosis) from 1973 to 2004. Our analysis of the SEER database since 2004 is the largest to date and our results improve our understanding of this disease and their potential prognostic factors. METHODS: We used the SEER database to retrospectively identify patients. Survival was analysed using the Kaplan-Meier method, and log-rank tests were used to compare survival distributions. RESULTS: There were 501 cases of PC-ALCL recorded from 2005 to 2016. Overall survival rates at 5 and 10 years were found to be 80.6% (95% CI 76.3%-84.3%) and 61.5% (95% CI 54.1%-68.1%) respectively. Age ≥ 60 years [hazard ratio (HR) = 1.09, P = 0.001 and use of chemotherapy (HR = 1.86, P = 0.01)] were associated with lower overall survival. In contrast to the 1973-2004 cohort, the head and neck site was not significantly associated with prognosis on multivariate analysis. CONCLUSION: PC-ALCL has been increasingly recognized over the past decade. Age > 60 years and use of chemotherapy are associated with a worse outcome. Contrary to prior studies, location was not associated with poor survival.

The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population.

BACKGROUND: Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. OBJECTIVES: To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. METHODS: All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. RESULTS: There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125). CONCLUSIONS: Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.

Meta-analysis of test accuracy studies using imputation for partial reporting of multiple thresholds.

INTRODUCTION: For tests reporting continuous results, primary studies usually provide test performance at multiple but often different thresholds. This creates missing data when performing a meta-analysis at each threshold. A standard meta-analysis (no imputation [NI]) ignores such missing data. A single imputation (SI) approach was recently proposed to recover missing threshold results. Here, we propose a new method that performs multiple imputation of the missing threshold results using discrete combinations (MIDC). METHODS: The new MIDC method imputes missing threshold results by randomly selecting from the set of all possible discrete combinations which lie between the results for 2 known bounding thresholds. Imputed and observed results are then synthesised at each threshold. This is repeated multiple times, and the multiple pooled results at each threshold are combined using Rubin's rules to give final estimates. We compared the NI, SI, and MIDC approaches via simulation. RESULTS: Both imputation methods outperform the NI method in simulations. There was generally little difference in the SI and MIDC methods, but the latter was noticeably better in terms of estimating the between-study variances and generally gave better coverage, due to slightly larger standard errors of pooled estimates. Given selective reporting of thresholds, the imputation methods also reduced bias in the summary receiver operating characteristic curve. Simulations demonstrate the imputation methods rely on an equal threshold spacing assumption. A real example is presented. CONCLUSIONS: The SI and, in particular, MIDC methods can be used to examine the impact of missing threshold results in meta-analysis of test accuracy studies.

Economic evaluation of strategies for restarting anticoagulation therapy after a first event of unprovoked venous thromboembolism.

Essentials Correct duration of treatment after a first unprovoked venous thromboembolism (VTE) is unknown. We assessed when restarting anticoagulation was worthwhile based on patient risk of recurrent VTE. When the risk over a one-year period is 17.5%, restarting is cost-effective. However, sensitivity analyses indicate large uncertainty in the estimates. SUMMARY: Background Following at least 3 months of anticoagulation therapy after a first unprovoked venous thromboembolism (VTE), there is uncertainty about the duration of therapy. Further anticoagulation therapy reduces the risk of having a potentially fatal recurrent VTE but at the expense of a higher risk of bleeding, which can also be fatal. Objective An economic evaluation sought to estimate the long-term cost-effectiveness of using a decision rule for restarting anticoagulation therapy vs. no extension of therapy in patients based on their risk of a further unprovoked VTE. Methods A Markov patient-level simulation model was developed, which adopted a lifetime time horizon with monthly time cycles and was from a UK National Health Service (NHS)/Personal Social Services (PSS) perspective. Results Base-case model results suggest that treating patients with a predicted 1 year VTE risk of 17.5% or higher may be cost-effective if decision makers are willing to pay up to £20 000 per quality adjusted life year (QALY) gained. However, probabilistic sensitivity analysis shows that the model was highly sensitive to overall parameter uncertainty and caution is warranted in selecting the optimal decision rule on cost-effectiveness grounds. Univariate sensitivity analyses indicate variables such as anticoagulation therapy disutility and mortality risks were very influential in driving model results. Conclusion This represents the first economic model to consider the use of a decision rule for restarting therapy for unprovoked VTE patients. Better data are required to predict long-term bleeding risks during therapy in this patient group.

Erratum to: Methods for evaluating medical tests and biomarkers.

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Validation of histomolecular classification utilizing histological subtype, MUC1, and CDX2 for prognostication of resected ampullary adenocarcinoma.

BACKGROUND: Outcomes for ampullary adenocarcinomas are heterogeneous, and numerous methods of categorisation exist. A histomolecular phenotype based on histology, caudal-type homeodomain transcription factor 2 (CDX2) staining and Mucin 1 (MUC1) staining has recently been tested and validated in two cohorts. We attempt to validate this classification in a large patient population. METHODS: Tissue samples from 163 patients with resected ampullary adenocarcinoma were classified based on histology and immunohistochemical expression of CDX2 and MUC1. A pancreaticobiliary histomolecular classification (PB) was defined as a sample with pancreaticobiliary histology, positive MUC1 and negative CDX2 expression. RESULTS: There were 82 deaths; median follow-up of 32.4 months; and median overall survival of 87.7 (95% CI 42.9-109.5) months. PB comprised 28.2% of the cases. Factors associated with overall survival were histological subtype (P=0.0340); T1/2 vs T3/4 (P=0.001); perineural (P<0.0001) and lymphovascular (P=0.0203) invasion; and histomolecular intestinal histomolecular phenotype (INT) vs PB phenotype (106.4 vs 21.2 months, P<0.0001). Neither MUC1 nor CDX2 was statistically significant, although MUC1 positivity defined as ⩾10% staining was significant (P=0.0023). In multivariate analysis, age (HR 1.03), PB phenotype (HR 2.26) and perineural invasion (PNI; HR 2.26) were associated with poor survival. CONCLUSIONS: The prognostic ability of histomolecular phenotype has been validated in an independent cohort of ampullary adenocarcinoma patients.

Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a poorly understood complication of transplantation carrying a high mortality. Patients commonly deteriorate and require intensive care unit (ICU) admission. Treatment with high-dose steroids and aminocaproic acid (ACA) has been suggested. The current study examined 119 critically ill adult hematopoietic transplant patients treated for DAH. Patients were subdivided into low-, medium- and high-dose steroid groups with or without ACA. All groups had similar baseline characteristics and severity of illness scores. Primary objectives were 30, 60, 100 day, ICU and hospital mortality. Overall mortality (n=119) on day 100 was high at 85%. In the steroids and ACA cohort (n=82), there were no significant differences in 30, 60, 100, day, ICU and hospital mortality between the dosing groups. In the steroids only cohort (n=37), the low-dose steroid group had a lower ICU and hospital mortality (P=0.02). Adjunctive treatment with ACA did not produce differences in outcomes. In the multivariate analysis, medium- and high-dose steroids were associated with a higher ICU mortality (P=0.01) as compared with the low-dose group. Our data suggest that treatment strategies may need to be reanalyzed to avoid potentially unnecessary and potentially harmful therapies.

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).

BACKGROUND: The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC). PATIENTS AND METHODS: A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. RESULTS: Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = <0.001) and patients who initially presented as stage IV disease had improved OS (HR 0.27; P = 0.003). CONCLUSIONS: Patients with MSI-H metastatic CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.

Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer.

BACKGROUND: Insulin/insulin-like growth factor-I (IGF-I) signaling is a mechanism mediating the promoting effect of type 2 diabetes (DM2) on cancer. Human epidermal growth factor receptor (HER2), insulin receptor and IGF-I receptor involve the same PI3K/AKT/mTOR signaling, and different antidiabetic pharmacotherapy may differentially affect this pathway, leading to different prognoses of HER2+ breast cancer. METHODS: We reviewed 1983 consecutive patients with HER2+ breast cancer treated between 1 January 1998 and 30 September 2010. The overall survival, breast cancer-specific death rate, age, race, nuclear grade, stage, menopausal status, estrogen and progesterone receptor status, body mass index and classes of antidiabetic pharmacotherapy were analyzed. RESULTS: A Cox regression analysis showed that DM2 [P=0.026, hazard ratio (HR)=1.42, 95 % confidence interval (95 % CI) 1.04-1.94] predicted poor survival of stage≥2 HER2+ breast cancer. In Kaplan-Meier analysis, metformin predicted lengthened survival and so did thiazolidinediones. Analyzing only the diabetics, Cox regression showed that metformin (P=0.041, HR=0.52, 95 % CI 0.28-0.97) and thiazolidinediones (P=0.036; HR=0.41, 95% CI 0.18-0.93) predicted lengthened survival, and competing risk analysis showed that metformin and thiazolidinediones were associated with decreased breast cancer-specific mortality (P=0.023, HR=0.47, 95% CI 0.24-0.90 and P=0.044, HR=0.42, 95 % CI 0.18-0.98, respectively). CONCLUSIONS: Thiazolidinediones and metformin users are associated with better clinical outcomes than nonusers in diabetics with stage≥2 HER2+ breast cancer. The choice of antidiabetic pharmacotherapy may influence prognosis of this group.

Survival differences among women with de novo stage IV and relapsed breast cancer.

BACKGROUND: The objective of this retrospective study was to determine whether differences in survival exist between women with de novo stage IV and relapsed breast cancer. PATIENTS AND METHODS: Three thousand five hundred and twenty-four women with de novo stage IV or relapsed breast cancer diagnosed from 1992 to 2007 were identified. Disease-free interval (DFI) was defined as the time from the diagnosis of primary nonmetastatic breast cancer to the date of the first distant metastases. Kaplan-Meier product limit method was used to estimate overall survival (OS). Cox proportional hazards model was fitted to determine the association between metastatic disease (relapsed versus de novo) and OS after controlling for other patient/tumor characteristics. RESULTS: Six hundred and forty-three (18.2%) women had de novo stage IV disease and 2881 (81.8%) had relapsed disease. Median follow-up was 19 months. Median OS among patients with de novo stage IV and relapsed disease was 39.2 and 27.2 months, respectively (P < 0.0001). In the multivariable model, women with relapsed disease had an increased risk of death compared with patients with de novo disease (HR = 1.75, 95% confidence interval 1.47-2.08, P < 0.0001). When the multivariable model was stratified by DFI, women with relapsed disease with DFI <6 months, ≥6 months to <2 years, or ≥2 to <5 years each had a significantly higher risk of death compared with women with de novo stage IV disease. The risk of death was not statistically different among patients with relapsed disease with DFI >5 years compared with those with de novo disease. CONCLUSIONS: This large cohort study provides further insight into the natural history of relapsed and de novo stage IV breast cancer. DFI plays an important role in the prognosis for patients with relapsed breast cancer.

A pilot study evaluating predictors of postoperative outcomes after major abdominal surgery: Physiological capacity compared with the ASA physical status classification system.

BACKGROUND: This pilot study compared the risk predictive value of preoperative physiological capacity (PC: defined by gas exchange measured during cardiopulmonary exercise testing) with the ASA physical status classification in the same patients (n=32) undergoing major abdominal cancer surgery. METHODS: Uni- and multivariate logistic regression models were fitted to measurements of PC and ASA rank data determining their predictive value for postoperative morbidity. Receiver operating characteristic (ROC) curves were used to discriminate between the predictive abilities, exploring trade-offs between sensitivity and specificity. RESULTS: Individual statistically significant predictors of postoperative morbidity included the ASA rank [P=0.038, area under the curve (AUC)=0.688, sensitivity=0.630, specificity=0.750] and three newly identified measures of PC: PAT (% predicted anaerobic threshold achieved, <75% vs > or =75%), DeltaHR1 (heart rate response from rest to the anaerobic threshold), and HR3 (heart rate at the anaerobic threshold). A two-variable model of PC measurements (DeltaHR1+PAT) was also shown to be statistically significant in the prediction of postoperative morbidity (P=0.023, AUC=0.826, sensitivity=0.813, specificity=0.688). CONCLUSIONS: Three newly identified PC measures and the ASA rank were significantly associated with postoperative morbidity; none showed a statistically greater association compared with the others. PC appeared to improve predictive sensitivity. The potential for new unidentified measures of PC to predict postoperative outcomes remains unexplored.

MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers.

Suppression of annexin A1 (ANXA1), a mediator of apoptosis and inhibitor of cell proliferation, is well documented in various cancers but the underlying mechanism remains unknown. We investigated whether decreased ANXA1 expression was mediated by microRNAs (miRNAs), which are small, non-coding RNAs that negatively regulate gene expression. Using Sanger miRBase, we identified miR-584, miR-196a and miR-196b as potential miRNAs targeting ANXA1. Only miRNA-196a showed significant inverse correlation with ANXA1 mRNA levels in 12 cancer cell lines of esophageal, breast and endometrial origin (Pearson's correlation -0.66, P=0.019), identifying this as the candidate miRNA targeting ANXA1. Inverse correlation was also observed in 10 esophageal adenocarcinomas (Pearson's correlation -0.64, P=0.047). Analysis of paired normal/tumor tissues from additional 10 patients revealed an increase in miR-196a in the cancers (P=0.003), accompanied by a decrease in ANXA1 mRNA (P=0.004). Increasing miR-196a levels in cells by miR-196a mimics resulted in decreased ANXA1 mRNA and protein. In addition, miR-196a mimics inhibited luciferase expression in luciferase plasmid reporter that included predicted miR-196a recognition sequence from ANXA1 3'-untranslated region confirming that miR-196a directly targets ANXA1. miR-196a promoted cell proliferation, anchorage-independent growth and suppressed apoptosis, suggesting its oncogenic potential. This study demonstrated a novel mechanism of post-transcriptional regulation of ANXA1 expression and identified miR-196a as a marker of esophageal cancer.

Long-term complications of platinum-based chemotherapy in testicular cancer survivors.

The purpose of this study was to describe the rates of cardiovascular and other medical complications related to the use of platinum-based chemotherapy in American testicular cancer survivors. The study sample consisted of 143 eligible long-term testicular cancer survivors. Participants were interviewed, their medical records were reviewed, and blood was obtained for cholesterol measurement during their follow-up visit. The mean follow-up time was 8.4 yr, and their mean age at follow-up was 41.2 yr; 72.7% had had non-seminoma, and 82.5% had received platinum-based chemotherapy. Hypertension rates in the platinum-treated group increased significantly from baseline to follow-up; however, once adjusted for blood pressure measurement (undiagnosed hypertension), no such increase was seen, and hypertension rates were already higher than national estimates at baseline in all groups. At the follow-up visit, the rates of hyperlipidemia (adjusted for measured cholesterol level) in both platinum- and non-platinum-treated groups (28.4% and 37.5%, respectively) were higher than national estimates (16.9%). Rates of coronary artery disease were higher in those who had received platinum and radiation (11.1%) than in those who had received platinum alone (4.3%), but this difference was not statistically significant. As suggested by previous studies, platinum-based chemotherapy may be associated with hypertension, hyperlipidemia, and coronary artery disease. However, our data suggest that undiagnosed hypertension and hyperlipidemia may be significant confounders, and we also observed a trend toward lower testosterone levels in participants who experienced cardiovascular complications.

Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis.

We conducted a meta-analysis to examine the effect of intraoperative monitoring of neuromuscular function on the incidence of postoperative residual curarisation (PORC). PORC has been considered present when a patient has a train-of-four (TOF) ratio of < 0.7 or < 0.9. We analysed data from 24 trials (3375 patients) that were published between 1979 and 2005. We excluded data on mivacurium from this meta-analysis because only three studies had examined the incidence of PORC associated with its use. Long- and intermediate-acting neuromuscular blocking drugs had been given to 662 and 2713 patients, respectively. Neuromuscular function was monitored in 823 patients (24.4%). A simple peripheral nerve stimulator was used in 543 patients, and an objective monitor was used in 280. The incidence of PORC was found to be significantly lower after the use of intermediate neuromuscular blocking drugs. We could not demonstrate that the use of an intraoperative neuromuscular function monitor decreased the incidence of PORC.

Evaluation and attributional analysis of an aromatherapy service for older adults with physical health problems and carers using the service.

OBJECTIVE: To evaluate an aromatherapy service for older adults with physical health problems and their carers. The aromatherapy service was based in a carer support unit at a hospital in Birmingham. The research question was, 'What types of benefits do clients/carers report from aromatherapy?' DESIGN: Qualitative analysis of interview scripts and written descriptions. SETTING: The interviews were carried out either at the carer support unit, at a connected day centre or at the client/carer's home. PARTICIPANTS: The participants were six clients and four carers who were in contact with the carer support unit and had received aromatherapy from the aromatherapist in the past year. MAIN OUTCOME MEASURES: The participants were interviewed using a semi-structured questionnaire to explore which part of a session they liked best, perceived benefits of aromatherapy and a smell attribution to certain essential oils. The aromatherapist was also asked to write descriptions of her perceived benefits for the clients and carers. The interviews were analysed qualitatively and compared to the aromatherapist's written descriptions. RESULTS: All clients and carers said they benefited from the aromatherapy and felt more relaxed after a session. The qualitative analysis revealed a 70% area of overlap and a 30% 'hidden' area of congruence. The smell analysis revealed individual differences in attribution depending on past experience and expectation of oil presented. CONCLUSION: The findings of this evaluation suggest the aromatherapy service offered was valuable to clients and carers and their perception of its benefits for them were largely congruent with those of the aromatherapist.

The role of 3' poly(A) tail metabolism in tumor necrosis factor-alpha regulation.

In unstimulated RAW 264.7 macrophage-like cells, tumor necrosis factor-alpha (TNF-alpha) mRNA was transcribed and accumulated in the cytoplasm, but the TNF-alpha transcripts failed to associate with polysomes, and TNF-alpha protein was not detected. Stimulation with lipopolysaccharide (LPS) induced an increase in TNF-alpha transcription, cytoplasmic TNF-alpha mRNA accumulation, polysome association, and secretion of TNF-alpha protein. This process was associated with a 200-nucleotide increase in the apparent length of the TNF-alpha mRNA. The difference in TNF-alpha mRNA size was caused by marked truncation of the 3' poly(A) tail in unstimulated cells. Fully adenylated TNF-alpha mRNA appeared within 15 min of LPS stimulation. We speculate that removal of the poly(A) tail blocks initiation of TNF-alpha translation in unstimulated macrophages. LPS inactivates this process, allowing synthesis of translatable polyadenylated TNF-alpha mRNA.

Warming macrophages to febrile range destabilizes tumor necrosis factor-alpha mRNA without inducing heat shock.

We have previously reported that sustained tumor necrosis factor (TNF)-alpha expression is suppressed by temperatures in the febrile range in human macrophages. In this study, we examined the mechanisms of high-temperature-induced macrophage TNF suppression in the RAW 264.7 macrophage cell line. Incubating lipopolysaccharide (LPS)-stimulated RAW 264.7 cells at 40 degrees C reduced TNF secretion by 92% and peak TNF mRNA levels by 43% compared with cells incubated at 37 degrees C (P < 0.05) but did not affect levels of glyceraldehyde-3-phosphate dehydrogenase, beta-actin, or interleukin-6 mRNA. TNF mRNA half-life, measured after transcriptional arrest with actinomycin D, was reduced from 21.8 +/- 3.6 min in LPS-stimulated RAW 264.7 cells at 37 degrees C to 16.0 +/- 1.8 min at 40 degrees C (P < 0.03), but these cells at 40 degrees C did not alter transcription rate or TNF mRNA polysome association. TNF mRNA destabilization occurred at temperatures below the threshold (43 degrees C) for the generalized heat shock response in these cells. We conclude that heating macrophages to febrile-range temperatures attenuates sustained TNF expression by modulating posttranscriptional processing, including acceleration of TNF mRNA decay.