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Improving equity in women's health requires gender-specific and empowering approaches. However, health programs often disempower women by adopting a 'one-size-fits-all' approach that emphasizes diet, exercise and weight loss over other important aspects like sleep and mental wellbeing. This article reports on the design of Next Level Health (NLH), a program that aims to empower women through developing a wide range of health behaviors to support their holistic wellbeing. NLH is grounded by ethics, theory and evidence to support women to make achievable, sustainable changes that are relevant to their everyday lives. Women utilized the NLH framework to develop an integrative health routine across six domains: physical activity, sleep, nutrition, eating behavior, self-care and stress management. The framework guided them to set small, incremental goals that were adaptive to their needs and built from their existing circumstances. Participants reflected on their progress with a facilitator during monthly meetings, accessed a social media support page and received monthly text messages. Health programs remain an essential approach to improving women's health alongside community- and policy-level strategies. The development of NLH exemplifies how evidence may partner with modern health promotion values to inform relevant and ethical program design for women., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The development of brain metastases (BM) is one of the most feared complications of cancer due to the substantial neurocognitive morbidity and a grim prognosis. In the past decade, targeted therapies and checkpoint inhibitors have demonstrated promising intracranial response rates for tumors of multiple histologies. As overall survival for these patients improves, there is a growing need to identify issues surrounding patient survivorship and to standardize physician practice patterns for these patients. To date, there has not been an adequate study to specifically explore these questions of survivorship and practice standardization for patients with advanced cancer and BM., Methods: Here, we present results from a cross-sectional survey in which we analyze responses from 237 patients, 209 caregivers, and 239 physicians to identify areas of improvement in the clinical care of BM., Results: In comparing physician and patient/caregiver responses, we found a disparity in the perceived discussion of topics pertaining to important aspects of BM clinical care. We identified variability in practice patterns for this patient population between private practice and academic physicians. Many physicians continue to have patients with BM excluded from clinical trials. Finally, we obtained patient/physician recommendations on high-yield areas for federal funding to improve patient quality of life., Conclusion: By identifying potential areas of unmet need, we anticipate this wealth of actionable information will translate into tangible benefits for both patients and caregivers. Future studies are needed to validate our findings., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Motivation: Due to new technology for efficiently generating genome data, machine learning methods are urgently needed to analyze large sets of gene trees over the space of phylogenetic trees. However, the space of phylogenetic trees is not Euclidean, so ordinary machine learning methods cannot be directly applied. In 2019, Yoshida et al. introduced the notion of tropical principal component analysis (PCA), a statistical method for visualization and dimensionality reduction using a tropical polytope with a fixed number of vertices that minimizes the sum of tropical distances between each data point and its tropical projection. However, their work focused on the tropical projective space rather than the space of phylogenetic trees. We focus here on tropical PCA for dimension reduction and visualization over the space of phylogenetic trees., Results: Our main results are 2-fold: (i) theoretical interpretations of the tropical principal components over the space of phylogenetic trees, namely, the existence of a tropical cell decomposition into regions of fixed tree topology; and (ii) the development of a stochastic optimization method to estimate tropical PCs over the space of phylogenetic trees using a Markov Chain Monte Carlo approach. This method performs well with simulation studies, and it is applied to three empirical datasets: Apicomplexa and African coelacanth genomes as well as sequences of hemagglutinin for influenza from New York., Availability and Implementation: Dataset: http://polytopes.net/Data.tar.gz. Code: http://polytopes.net/tropica_MCMC_codes.tar.gz., Supplementary Information: Supplementary data are available at Bioinformatics online., (Published by Oxford University Press 2020. This work is written by US Government employees and is in the public domain in the US.)

Objective: Effective screening for concussion is increasingly important, and medical professionals play a critical role in diagnostic and return-to-play decisions. However, few well-validated measures are available to assist in those decisions. This study aims to determine whether previously validated measures assessing neurocognitive and neurobehavioral abilities can predict Centers for Disease Control (CDC) concussion symptom endorsement in a sample of child or youth athletes., Method: Participants were 113 individuals, aged 6-17, representing 29 consecutive cases undergoing a post-concussion evaluation by a pediatric neurologist and 84 consecutive cases completing standardized baseline assessments (i.e., not being evaluated as a follow-up to a concussion). All participants completed the same standardized battery of tests comprised of the Connors' Continuous Performance Test (CPT 3), the Balance Error Scoring System (BESS), and the NIH 4-Meter Gait Test as well as completing a checklist of CDC concussion symptoms., Results: Regression analyses indicate that the screening battery explained 33% of the variance (d = 1.4) in concussion symptom endorsement, after controlling for age. The neurocognitive test alone (CPT 3) accounts for 21.5% of the variance (d = 1.05) in symptoms after controlling for age, and the neurobehavioral measures (BESS and NIH 4-Meter Gait) then account for an additional 11.5% variance (accounting for 18.6% variance, d = .96, when entered first). These effect sizes are considered large to very large and reflect a marked increase in predictive validity relative to existing measures commonly used in concussion assessments., Conclusions: A relatively brief screening battery can function in medical settings to predict significant and substantial variability in CDC concussion symptoms in a pediatric sample., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

In Streptomyces coelicolor, we identified a para-hydroxybenzoate (PHB) hydroxylase, encoded by gene pobA (SCO3084), which is responsible for conversion of PHB into PCA (protocatechuic acid), a substrate of the β-ketoadipate pathway which yields intermediates of the Krebs cycle. We also found that the transcription of pobA is induced by PHB and is negatively regulated by the product of SCO3209, which we named PobR. The product of this gene is highly unusual in that it is the apparent fusion of two IclR family transcription factors. Bioinformatic analyses, in vivo transcriptional assays, electrophoretic mobility shift assays (EMSAs), DNase I footprinting, and isothermal calorimetry (ITC) were used to elucidate the regulatory mechanism of PobR. We found that PobR loses its high affinity for DNA (i.e., the pobA operator) in the presence of PHB, the inducer of pobA transcription. PHB binds to PobR with a KD of 5.8 μM. Size-exclusion chromatography revealed that PobR is a dimer in the absence of PHB and a monomer in the presence of PHB. The crystal structure of PobR in complex with PHB showed that only one of the two IclR ligand binding domains was occupied, and defined how the N-terminal ligand binding domain engages the effector ligand.

Objectives: Wedge resections are frequently performed for small peripheral lesions in patients unfit for a more extensive resection. We aimed to investigate whether patient sex and histology type are important factors determining survival in patients undergoing a wedge resection for stage I lung cancer., Methods: We retrospectively analysed a prospective thoracic database of patients (n = 2859) who had undergone potentially curative wedge resection for stage I non-small-cell lung cancer. Only patients with adenocarcinoma or squamous carcinoma were included (n = 540). We benchmarked our 5-year survival against the sixth International Association for the Study of Lung Cancer results. Kaplan-Meier, Cox multivariate regression analysis and propensity analysis were utilized to assess the effect of sex and histology on survival post-wedge resection with regard to long-term survival., Results: Cox regression of patients who had undergone wedge resection demonstrated that adenocarcinoma (odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.11-4.19), P = 0.02 was the only significant term determining long-term survival. Cox regression of male patients identified adenocarcinoma (OR: 3.29, 95% CI: 1.22-8.86), P = 0.02 as the only significant term determining long-term survival. Cox regression of female patients failed to identify any significant factors that determine long-term survival. Propensity matching based on gender identified that gender had no effect on survival, P = 0.46; however, histology was associated with a difference in survival, P = 0.02. This effect occurred in males, P = 0.02, but not females, P = 0.26. Propensity matching based on histology identified that gender had no effect on survival, P = 0.29; however, histology was associated with a difference in survival, P = 0.01. This effect occurred in males, P = 0.01, but not females, P = 0.26. Differing life expectancy between males and females was adjusted for by the use of the Framingham-predicted life expectancy., Conclusions: Long-term survival of patients with stage I non-small-cell lung cancer who undergo a wedge resection is affected by gender and histological type. Male patients undergoing wedge resections for adenocarcinoma have outcomes inferior to those of patients with squamous carcinoma. Histology type does not affect survival in female patients undergoing wedge resections., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Cold acclimation has been shown to be attenuated by the degradation of the INDUCER OF CBF EXPRESSION1 protein by the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1). However, recent work has suggested that HOS1 may have a wider range of roles in plants than previously appreciated. Here, we show that hos1 mutants are affected in circadian clock function, exhibiting a long-period phenotype in a wide range of temperature and light environments. We demonstrate that hos1 mutants accumulate polyadenylated mRNA in the nucleus and that the circadian defect in hos1 is shared by multiple mutants with aberrant mRNA export, but not in a mutant attenuated in nucleo-cytoplasmic transport of microRNAs. As revealed by RNA sequencing, hos1 exhibits gross changes to the transcriptome with genes in multiple functional categories being affected. In addition, we show that hos1 and other previously described mutants with altered mRNA export affect cold signaling in a similar manner. Our data support a model in which altered mRNA export is important for the manifestation of hos1 circadian clock defects and suggest that HOS1 may indirectly affect cold signaling through disruption of the circadian clock.

Objectives: To determine whether patient sex has a significant effect on long-term outcomes post curative resection of non-small-cell lung cancer., Methods: We retrospectively analysed a prospectively validated thoracic surgery database (n = 4212), from a single institution, from September 2001 to October 2012. Univariate, Cox multivariate and propensity analysis was performed. Long-term follow-up was carried out via the National Strategic Tracing Service that operates in the United Kingdom., Results: One hundred per cent follow-up was achieved. Overall institutional in-hospital mortality was 2.0% for all thoracic resections. Median survival was 2.78 years (range 0-13 years). Two thousand two hundred and thirty-three males and 1979 females were included. Kaplan-Meier survival of all the patients demonstrated superior survival of females for all stages, P = 0.0003, and stage I, P = 0.0006. Female sex conferred no survival advantage in stage II, P = 0.7, and IIIa, P = 0.1. Sub-analysis by histological type demonstrated that females had superior survival with adenocarcinoma compared with males, P < 0.001, but no sex difference existed with squamous carcinomas, P = 0.2. Cox analyses demonstrated that female sex was an advantageous prognostic factor for the entire study group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.69-0.96] and Stage I only (HR 0.70, 95% CI 0.57-0.63). Sex was of no significance in Stage II and IIIa disease with regard to survival. Sub-analysis demonstrated that female sex was not a significant factor determining survival in patients with squamous carcinoma; however, it was significantly associated with increased survival in patients with adenocarcinoma (HR 0.63, 95% CI 0.51-0.78). A 1:1 propensity analysis confirmed the above findings., Conclusion: Propensity matching and Cox multivariate regression analysis confirmed the univariate finding that female sex is only associated with improved survival in patients with Stage I adenocarcinoma. Patient sex does not affect survival of patients with squamous carcinoma.

Objectives: Using a large, prospectively collected and independently validated thoracic database, we created a risk-prediction tool for in-hospital mortality with the aim of improving on the accuracy of Thoracoscore., Methods: A prospectively collected and independently validated database containing lung resections was utilized, N = 2574. Logistic regression analysis with bootstrapping, and by the use of a random training and test set was utilized. Comparisons against the Thoracoscore, ESOS.01 and the Society of Thoracic Surgeons (STS) models were performed., Results: A logistic model identified age [odds ratio (OR) 1.1, 95% confidence interval (CI) 1.0-1.2, P = 0.0002], sex (OR 0.34, 95% CI 0.14-0.83, P = 0.02), predicted postoperative FEV1 (OR 0.96, 95% CI 0.94-0.99, P = 0.002), emphysema (OR 3.2, 95% CI 1.0-9.9, P = 0.04), excess alcohol consumption (OR 1.0, 95% CI 1.0-1.0, P = 0.04), pre-existing renal disease (OR 4.3, 95% CI 1.1-17.1, P = 0.04), predicted in-hospital mortality with an receiver operating curve (ROC) of 0.81 and a Hosmer-Lemeshow test of 0.9. Bootstrap analysis confirmed the above risk factors (ROC 0.82 and Hosmer-Lemeshow 0.2). Comparisons between Thoracoscore, ESOS.01 and the STS risk models demonstrated that none was very accurate, as all had low ROC values of 0.69, 0.70 and 0.61, respectively. The STS risk model does not apply to our population (ROC 0.61, Hosmer-Lemeshow, P = 0.004), and the ESOS.01 has poor predictive power (Hosmer-Lemeshow, P < 0.0001)., Conclusions: Logistic regression based on age, sex, predicted postoperative FEV1, alcohol consumption and pre-existing renal disease predicts in-hospital mortality with improved accuracy compared with the use of Thoracoscore, ESOS.01 and the STS risk model.

Objectives: The study aimed to determine the importance of smoking status at operation and histology type with regard to long-term survival after potential curative surgery for lung cancer., Methods: We analysed a prospectively validated thoracic surgery database (n = 2485). We benchmarked our 5-year survival against the International Association for the Study of Lung Cancer (IALSC) results. Univariate and Cox multivariate analyses were performed for the study group and for isolated adenocarcinoma and squamous carcinoma histological subtypes., Results: Benchmarking failed to reveal any differences in survival of our study cohort compared with the IALSC results, P = 0.16. Univariate analysis revealed that non-smokers have a statistically better long-term outcome, P < 0.0001, than ever smokers. Patients with adenocarcinoma, n = 1216, had a worse outcome in ever smokers, P = 0.006. In patients with squamous carcinoma, n = 1065, smoking status made no difference, P = 0.4. Long-term survival was not significantly different for adenocarcinoma or squamous carcinoma, P = 0.87. Cox multivariate analysis revealed that patients with adenocarcinoma who were current smokers had a significantly worse long-term survival compared with ex-smokers and non-smokers (hazard ratio: 1.26, 95 confidence interval: 1.01-1.56), P = 0.04. Age, body mass index, sex, T stage, N stage, predicted postoperative forced expiratory volume in one second (FEV1), residual disease, alcohol consumption and oral diabetes were additional significant factors affecting long-term survival. Pneumonectomy, pack years, bronchial resection margin, New York Heart Association class, hypertension, previous cerebrovascular event, diet or insulin-controlled diabetes and previous myocardial infarction were excluded by the analysis as significant risk factors. Smoking status did not affect long-term survival in patients with squamous cell carcinoma., Conclusions: Smoking status at time of surgery does not effect long-term survival in patients with squamous cell carcinoma. Smoking status makes a significant difference to the long-term outcomes of patients with adenocarcinoma even after adjustment for their risk factors. This implies that a histological classification of adenocarcinoma may incorporate genetically diverse adenocarcinomas with regard to prognosis.

MarR family proteins constitute a group of >12 000 transcriptional regulators encoded in bacterial and archaeal genomes that control gene expression in metabolism, stress responses, virulence and multi-drug resistance. There is much interest in defining the molecular mechanism by which ligand binding attenuates the DNA-binding activities of these proteins. Here, we describe how PcaV, a MarR family regulator in Streptomyces coelicolor, controls transcription of genes encoding β-ketoadipate pathway enzymes through its interaction with the pathway substrate, protocatechuate. This transcriptional repressor is the only MarR protein known to regulate this essential pathway for aromatic catabolism. In in vitro assays, protocatechuate and other phenolic compounds disrupt the PcaV-DNA complex. We show that PcaV binds protocatechuate in a 1:1 stoichiometry with the highest affinity of any MarR family member. Moreover, we report structures of PcaV in its apo form and in complex with protocatechuate. We identify an arginine residue that is critical for ligand coordination and demonstrate that it is also required for binding DNA. We propose that interaction of ligand with this arginine residue dictates conformational changes that modulate DNA binding. Our results provide new insights into the molecular mechanism by which ligands attenuate DNA binding in this large family of transcription factors.

The histone methyltransferase EZH2 regulates cell proliferation and differentiation by silencing Polycomb group target genes. NIPP1, a nuclear regulator of serine/threonine protein phosphatase 1 (PP1), has been implicated in the regulation of EZH2 occupancy at target loci, but the underlying mechanism is not understood. Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1. Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1. Accordingly, a NIPP1-binding mutant of EZH2 is hypophosphorylated, and the knockdown of NIPP1 results in a reduced phosphorylation of endogenous EZH2. Conversely, the loss of PP1 is associated with a hyperphosphorylation of EZH2. A genome-wide promoter-binding profiling in HeLa cells revealed that the NIPP1-binding mutant shows a deficient association with about a third of the Polycomb target genes, and these are enriched for functions in proliferation. Our data identify PP1 as an EZH2 phosphatase and demonstrate that the phosphorylation-regulated association of EZH2 with proliferation-related targets depends on associated NIPP1.

The tumour-node metastasis (TNM) classification system is anatomically based. We investigated whether the addition of simple physiological variables, age and body mass index (BMI), would affect survival curves, i.e. a composite anatomical and physiological staging system. We retrospectively analysed a prospectively validated thoracic surgery database (n = 1981). Cox multivariate analysis was performed to determine possible significant factors. Kaplan-Meier survival curves were constructed with combined anatomical and physiological factors. Cox multivariate analysis revealed age (P < 0.001) and BMI (P = 0.01) as significant factors affecting survival. Receiver operating curve analysis determined cut-off levels for age of 67 and BMI of 27.6. A composite anatomical and physiological survival curve based on TNM for BMI > 27.6 and age < 67 was produced. Age and BMI criteria resulted in significantly different survival curves, for stage I (P < 0.0001) and stage II (P = 0.0032), but not for stage III (P = 0.06). Neural network analysis confirmed the importance of BMI and age above cancer stage with regard to long-term survival. Combining age < 67, BMI > 27.6 and TNM anatomical classification results in very different estimated survival curves from the usual TNM system. Patients from stages I, II and III may have survival equivalent to a stage higher or lower depending on their age and BMI.

Objective: To determine if positron emission tomography (PET) scanning has resulted in an improvement in the short- and long-term survival of patients undergoing potentially curative resections for non-small-cell lung cancer. No publications exist to demonstrate an increased survival of patients with lung cancer due to the use of PET scanning. If PET scanning reduces unnecessary resections, the results from surgery should be improved with its introduction., Methods: A prospective thoracic surgery database was retrospectively analysed. Patients (N=1999), who had undergone potentially curative resections for non-small-cell lung cancer, and those who had a PET scan pre operatively (N=934), were compared with patients who had not undergone PET scanning (N=1065), prior to surgical resection. PET scanning became routine for all patients 4 years ago in our unit. Staging was defined as pathological staging to eliminate bias by 'better' preoperative staging due multislice computed tomography (CT) and PET scanning. Propensity matching based on Cox regression analysis was performed for survival analysis at each stage., Results: Propensity matching revealed that the introduction of routine PET scanning did not result in improved survival in the short or long term, for patients undergoing resections for stage Ia (N=271 in each matched group), p=0.74, stage Ib (N=321 in each matched group), p=0.43 and stage II (N=164 in each matched group), p=0.06. PET has however resulted in a significant increased survival for patients undergoing resections for stage III primary lung cancer (N=68 in each matched group), p=0.03., Conclusion: We concur with current guidelines for the use of PET scanning for stage III non-small-cell lung cancer. Our results need to be corroborated with other groups as potentially stage-Ia-, Ib-, and stage-II patients may not benefit from PET scanning., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Traditionally non-small cell lung cancer (NSCLC) stage N2 is considered as a contraindication for curative resection. We investigated the outcome of patients with microscopic N2 disease, who underwent potentially curative resections. The independent effects of lobectomy vs. pneumonectomy, histology subtype, body mass index (BMI), sex, and PET-scanning were investigated. An N2 survival risk score was calculated and correlated with survival. Benchmarking revealed no discrepancies in our stage-specific survival data against the seventh edition of the International Association for the Study of Lung Cancer (IASLC) results. Of 1999 lung resections for primary lung cancer, 146 were pathologically staged as N2. Patients with resected microscopic N2 disease had a five-year survival equivalent to stage T3N1, P=0.39. Univariate analysis suggested pneumonectomy and T stage 3 as significant predictors of poor survival. Cox multivariate regression analysis revealed that age, BMI>30 kg/m(2), pneumonectomy, squamous type and positron emission tomography (PET)-scan all had a significant effect on survival, P<0.05. A low N2 survival risk score was associated with increased survival, P=0.001. Resecting microscopic N2 disease in NSCLC may be appropriate in some patients. An N2 survival scoring system may help select patients for surgery, and help evaluate adjuvant and neoadjuvant publications with regard to microscopic N2 disease.

The American College of Chest Physicians (ACCP) in 2001 and British Thoracic Society (BTS) in 1993 and 2003 published guidelines for the treatment of pneumothorax. Here, we review our experience of managing pneumothorax patients, comparing standards of management before and after the publication of the guidelines in 2003. One hundred and twenty patients were transferred to our care for management of pneumothorax between October 2001 and September 2006. One hundred and one patients underwent pleurectomy [28 by video-assisted thoracic surgery (VATS)]. There were 69 males and 32 females with a median age of 47 years (range 15-86 years). 24% (n=24) of patients had evidence of intrapleural infection at time of operation. This was more likely if the time to pleurectomy was >14 days (P=0.03). The median time of referral for patients in the pre-guideline group was 12 days [interquartile range (IQR) 9-12] while post guidelines it was 10 days (IQR 6-13). There was no statistical significance (P=0.09) between these groups in terms of time taken to refer patients. The ACCP and BTS guidelines are not being followed. Pneumothoraces should be managed by chest physicians who are aware of the current guidelines. Impact of delayed referral in the form of increased incidence of morbidity and financial burdens on hospitals needs to be recognized.

Oesophageal injury is an extremely rare complication of intra-operative transoesophageal echocardiography (TOE) associated with cardiac surgery. We report a case of delayed presentation (19 days after surgery) of oesophageal injury that was likely due to TOE following an aortic valve replacement. Lack of suspicion led to a delay in diagnosis but the patient fortunately survived. We advocate that in the event of postoperative hydropneumothorax, the differential diagnosis must include iatrogenic oesophageal injury from transoesophageal echo.

Objective: Survival after resections for non-small cell lung cancer remains poor. Recurrent lung cancer remains common. Due to the common risk factor of smoking, cardiovascular deaths occur in the absence of recurrent lung cancer in up to 15% of patients. Aspirin has been proven to reduce cardiovascular mortality as a secondary prophylactic agent, but not as a primary agent. Aspirin being a COX-2 inhibitor has been shown to reduce the chance of metastasis in adenocarcinoma but not squamous carcinoma. We sought to investigate the effect of long-term aspirin therapy on survival post potentially curative surgery., Methods: We analysed a prospective thoracic surgical database, from time period 2003 to date. Patients who were on aspirin pre-operatively, N=412 were compared to non users, N=1353. Patient long-term outcome was assessed utilising the national strategic tracking service that operates in the United Kingdom. Cox proportional hazards analysis was used to determine significant factors affecting survival., Results: 100% survival follow up was achieved. Regular users of aspirin had >5% increased survival, which was significant, p=0.05, despite having a higher cardiovascular risk profile. Mode of death data was not available., Conclusions: Adjuvant aspirin post resection for potentially curative non-small cell lung cancer significantly increases survival. The mechanism of increased survival needs further investigation and is the basis for the trial: Adjuvant Aspirin for Non-Small cell Lung Cancer--The Big A Trial. www.TheBigATrial.co.uk., (Copyright 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the effects of advanced age on the outcome and survival of patients undergoing oesophagectomy for oesophageal cancer at a single high-volume centre. We retrospectively reviewed the hospital survival of 326 patients in oesophagogastrectomies (OGs) in a period from May 2001 to April 2008. We divided the patients into two groups. Group A (n=218) consisted of patients younger than 70 years of age, while Group B (n=108) consisted of patients 70 years of age or older. The two groups were comparable. In-hospital mortality for Group A was 11 out of 218 (5%), while in-hospital mortality for Group B was 13 out of 108 (12%). This difference was statistically significant (P=0.024). Multivariate analysis showed that risk factors for in-hospital mortality after OG included age over 70 years [odds ratio (OR)=2.79], reduced % of predicted FEV(1) (OR=0.13) and cardiac co-morbidity (OR=2.53). Despite age over 70 years proving not to be predictive of survival (P=0.21), significant independent predictors were advancing age [hazard ratio (HR)=1.03] and stage of disease (HR=1.84). P-values were 0.0278 and 0.018, respectively. Increasing age is a significant risk factor for mortality and survival after oesophageal resection operations. This mortality is particularly high if associated with a preoperative cardiac or respiratory morbidity.

Objective: Tumour length is an adverse prognostic factor in oesophageal cancer. However, the prognostic role of the degree of oesophageal circumference (DOC) involved by tumour with or without resection margin invasion is not clear. This work assessed the relationship between DOC involved by tumour, clinico-pathological variables and prognosis., Methods: The clinico-pathological details of 320 patients who underwent potentially curative oesophagogastrectomy for cancer between 1994 and 2007 were analysed. The DOC involved with tumour measured macroscopically on the resected specimen was classified as small (<2.5 cm, n = 115), large (> or = 2.5 cm, n = 144) or circumferential (i.e. involving the whole circumference, n = 61). Univariate and multivariate survival analyses were carried out., Results: The DOC with tumour was higher in ulcerating tumours than stenosing or polypoidal types (p = 0.017). Tumour length, T-stage, neoadjuvant chemotherapy and vascular invasion were independently associated with DOC with tumour on multivariate analysis (p < 0.05 for all). DOC > or = 2.5 cm was an adverse prognostic factor in univariate analysis (p = 0.002) with a hazard ratio of 1.52 [95% CI 1.13-2.04] compared with those <2.5 cm. Circumferential tumours had a similar prognosis to tumours > or = 2.5 cm (p = 0.60). The prognostic significance of DOC with tumour was lost in multivariate analysis where the factors retaining independence were patient age, T-stage, lymph node metastasis, vascular invasion and positive resection margins. However, when patients were stratified by use of neoadjuvant chemotherapy (n = 121), the DOC with tumour retained prognostic significance on multivariate analysis in the 199 patients who did not undergo neoadjuvant chemotherapy (p = 0.04)., Conclusion: The DOC with tumour appears to provide prognostic information in oesophageal cancer surgery, especially in patients who do not undergo preoperative chemotherapy.

Animals produced from assisted reproductive technologies suffer from developmental abnormalities and early fetal death at a higher frequency than that observed in those produced by natural breeding. These symptoms are reminiscent of imprinting disruptions in the human and mouse, suggesting the possibility of perturbations in the expression of imprinted genes such as biallelic expression or silencing. H19 is one of the imprinted genes first identified in mice and humans, but its sequence and imprinting status have not been determined in cattle. In the present study, we obtained the majority of the bovine H19 gene sequence (approximately 2311 base pairs), identified a single nucleotide polymorphism (SNP) in exon 5 and determined the frequencies of different alleles containing the SNP. Our analysis demonstrated that, in cattle produced by natural breeding, H19 was indeed imprinted as shown by either predominant or exclusive expression of the maternal allele. We also analyzed the imprinting pattern of H19 in organs of four animals produced by somatic cell nuclear transfer that died shortly after birth or had developed abnormalities that necessitated immediate killing at birth. Three out of four cloned animals showed biallelic expression of H19, supporting our hypothesis that imprinting disruption is present in cloned animals that suffered from developmental abnormalities at birth. Examination of the expression of H19 in the offspring of a cloned animal produced by artificial insemination showed that the imprinting pattern in this animal was indistinguishable from those of control animals, suggesting that either imprinting disruptions in cloned animals are corrected through natural reproduction or that they are not present in healthy cloned animals capable of undergoing natural reproduction.

Gemifloxacin (SB-265805) is a potent, novel fluoroquinolone with broad-spectrum antimicrobial activity. In this study, the efficacy of gemifloxacin was studied in experimental models of Gram-negative pyelonephritis (caused by Escherichia coli or Proteus mirabilis) and Gram-positive wound infection resulting from Streptococcus pyogenes, Staphylococcus epidermidis or Staphylococcus aureus. Gemifloxacin activity against these pathogens was compared with those of amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin, levofloxacin and tosufloxacin. Oral treatment was initiated 1 h after infection and continued once or twice daily for 3 days. Around 17 h after the end of treatment, animals were killed and the infected kidneys or the skin around the wound site were excised for the enumeration of viable bacteria. In the pyelonephritis model (either microorganism), gemifloxacin reduced bacterial numbers significantly (P < 0.01) compared with no treatment. No comparator agent had a greater effect than gemifloxacin. Notably, grepafloxacin and azithromycin were significantly less effective (P < 0.01) than gemifloxacin against E. coli pyelonephritis, and amoxycillin-clavulanate, azithromycin and trovafloxacin were inferior (P < 0.01) against P. mirabilis infection. In the S. pyogenes wound infection model, gemifloxacin, amoxycillin-clavulanate, cefuroxime and azithromycin reduced bacterial numbers significantly compared with controls (P < 0.01). Results for the comparator quinolones were not significantly different from untreated controls (P > 0.05). Gemifloxacin was also effective against staphylococcal infection, as were grepafloxacin and levofloxacin, while ciprofloxacin, trovafloxacin and tosufloxacin were significantly less effective against these pathogens than gemifloxacin (P < 0.01). No comparator agent had greater activity than gemifloxacin against S. pyogenes or S. aureus infections. These data demonstrate the potential benefit of gemifloxacin in the treatment of Gram-negative urinary tract infection and Gram-positive skin and soft tissue infection.

The in vivo efficacy of the novel quinolone gemifloxacin (SB-265805) was examined in a rat respiratory tract infection (RTI) model against four strains of Streptococcus pneumoniae and two strains of Haemophilus influenzae with varying susceptibilities to standard antimicrobial agents. Animals were infected intrabronchially to produce pneumonia and therapy with oral gemifloxacin, amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin or levofloxacin was started 24 h after infection. The doses administered were chosen to approximate in the rat the serum or tissue concentrations measured in humans following therapeutic dosing. Therapy continued once- or twice-daily for 3 days, and approximately 17 h after the end of therapy the lungs were excised for bacterial enumeration. Following infection with strains of S. pneumoniae, gemifloxacin produced a 3-5 log reduction in bacterial numbers compared with untreated animals. Gemifloxacin was as effective as amoxycillin- clavulanate, and was as potent or more potent than all other comparators. Notably, the quinolone agents trovafloxacin, ciprofloxacin, grepafloxacin and levofloxacin were significantly less effective (P < 0.01) than gemifloxacin: these agents reduced bacterial numbers by < or =3 log compared with untreated animals. Gemifloxacin produced a marked response against H. influenzae infection, reducing bacterial numbers significantly (P < 0.01) compared with untreated controls. Gemifloxacin was significantly more potent than cefuroxime and azithromycin. None of the other comparator agents was more potent than gemifloxacin. The excellent efficacy seen in these experimental models of RTI with S. pneumoniae and H. influenzae confirms the in vitro activity of gemifloxacin against these organisms. This indicates that gemifloxacin may be of significant benefit in the treatment of RTI.

Recent MRI studies in multiple sclerosis have highlighted the potential importance of spinal cord atrophy (implicating axonal loss) in the development of disability. However, the techniques applied in these initial studies have poor reproducibility which limits their application in the serial monitoring of patients. The aim of this study was to develop a highly reproducible and accurate method for the quantification of atrophy. The technique we describe demonstrates an intra-observer coefficient of variation (scan-rescan) of only 0.8%. When applied to 60 patients with clinically definite multiple sclerosis there was a strong correlation between spinal cord area and disability measured by Kurtzke's Expanded Disability Status Scale (EDSS) (r = -0.7, P < 0.001). The correlation was graded providing evidence for a causal connection. At levels 3 and 8 of the EDSS we observed a reduction in average cord area of 12 and 35%, respectively. Given its reproducibility, the magnitude of the change detected and the strong correlation with disability, this new technique should prove to be a sensitive measure of progressive neurological deterioration and could be readily incorporated into imaging protocols aimed at monitoring therapy.

Actinobacillus actinomycetemcomitans is frequently associated with severe periodontitis. Many periodontitis patients have elevated levels of serum IgG antibodies to A. actinomycetemcomitans, but the role of these antibodies is unknown. This study evaluated the functional capacity of anti-A. actinomycetemcomitans IgG antibody to enhance phagocytosis of A. actinomycetemcomitans by polymorphonuclear leukocytes. Chemoluminescence assays were done using sera from 64 subjects, 61 of whom had severe periodontitis; results were compared with the subject's anti-A. actinomycetemcomitans IgG titer and avidity. There was a strong correlation between chemoluminescence and antibody log titer (P < .00001) and a weak correlation between chemoluminescence and antibody avidity (P < .05). The results support the hypothesis that anti-A. actinomycetemcomitans IgG antibodies are important in promoting phagocytosis and killing of A. actinomycetemcomitans. Subjects who develop high levels of highly avid antibodies against A. actinomycetemcomitans may have greater resistance to continued or repeated infection by this pathogen.

Ventilatory support for 24 h after surgery is standard practice in many units after oesophagectomy, especially for patients in whom respiratory problems are anticipated. Weaning difficulties may occur, however, and there is increasing evidence that mechanical ventilation is associated with alveolar trauma. A deliberate change in policy was instituted in the authors' unit in January 1990 to make early extubation mandatory in all patients undergoing elective oesophagectomy, apart from those in whom serious perioperative problems were encountered. The present study compared two sets of patients: group 1 (n = 36) underwent oesophagectomy in the year before the policy change and group 2 (n = 45) oesophagectomy in the year after. The two groups were similar in age, sex and respiratory risk factors. Early extubation was carried out in 38 patients in group 2 compared with eight in group 1 (P < 0.001). Only two patients in group 2 required prolonged ventilation compared with ten in group 1 (P < 0.005). No patient in group 2 required reventilation compared with seven in group 1 (P < 0.005), and no patient in group 2 who had undergone early extubation required delayed ventilation. The mean ventilation time and length of stay in the intensive care unit were significantly reduced following the policy change. Early extubation after elective oesophagectomy is an attainable goal and results in a significant reduction in both the morbidity rate and cost of surgery.

Clinical, radiological, histological, and anatomical features in 2 patients with necrotizing infundibulo-hypophysitis are reported. The patients presented with a combination of diabetes insipidus and hypopituitarism. Each was found to have a sellar mass lesion with an abnormally thickened enlarged pituitary stalk that intensively enhanced on contrast magnetic resonance imaging. They were suspected to have pituitary tumors with suprasellar extension. However, tissue obtained at transphenoidal surgery revealed necrosis, fibrosis, and chronic inflammation; there was no evidence of infiltrative, infective, or neoplastic disease processes. Postoperatively, they continued to have diabetes insipidus and hypopituitarism despite radiological improvement and steroid therapy. Several clinical and anatomical features distinguish these 2 cases from classical lymphocytic hypophysitis, the most common entity in the differential diagnosis. Specifically, diabetes insipidus has not been observed preoperatively in 30 cases of lymphocytic hypophysitis, but was present in the 2 cases reported. Histological evidence of tissue necrosis present in these 2 cases is not a feature of lymphocytic hypophysitis. Pituitary stalk involvement on magnetic resonance imaging or computed tomographic scan present in these 2 cases is highly unusual in lymphocytic hypophysitis. Finally, 29 of 30 cases of lymphocytic hypophysitis were females, whereas the 2 cases reported are men. On the basis of these disparate findings, we suggest that these 2 cases represent a unique syndrome, which may be recognized clinically and radiologically.

Fifty-three patients, 17 with stage IIIB and 36 with stage IV non-small-cell lung cancer, were given CODE (cisplatin, vincristine, doxorubicin, and etoposide) plus antibiotic prophylaxis and an antiemetic regimen in an intensive chemotherapy program emphasizing weekly treatment and a planned brief duration (9-12 weeks); for 45 of these patients, the CODE program also included antifungal prophylaxis and supportive corticosteroids. Of the total study population, 33 patients (62%) responded to treatment, including five (9%) with complete response. The median survival for the entire group was 42 weeks (55 weeks for those with stage IIIB and 39 weeks for those with stage IV). More than 40% were alive at 1 year. Comparison of granulocyte counts of patients receiving prednisone with those of the subgroup to whom no corticosteroids were given showed less granulocytopenia for those receiving prednisone. Use of prednisone thus allowed improved delivery of myelosuppressive drugs. CODE was halted in nine patients because of disease progression. Although more constitutional side effects are associated with weekly chemotherapy than with standard chemotherapy, only 12 of the remaining 44 patients (27%) failed to receive at least 9 weeks of treatment. Serious toxicity was uncommon: There were no treatment-related deaths and only three episodes of neutropenia with fever. CODE is a novel treatment for non-small-cell lung cancer that this pilot study provided entirely in an outpatient setting over a 9-12 week period with an acceptable incidence of toxicity and a promising level of efficacy. Additional testing and comparison with other regimens or supportive care alone are warranted.

Immunotherapy, with interleukin-2 (IL-2) or IL-2 plus lymphokine-activated killer (LAK) cells, has been used to treat cancer and acquired immunodeficiency syndrome (AIDS) in man. Similarities between feline leukemia virus (FeLV) infection in the cat and human immunodeficiency virus (HIV) infection in man have prompted immunotherapeutic studies in the cat. To develop baseline data on hematological responses to infused IL-2, cats were given daily (1-14 days) i.v. injections of 5 x 10(4) U/kg of recombinant human IL-2 (rHulL-2). Complete blood cell (CBC) counts were done weekly. Red blood cell (RBC), neutrophil, and lymphocyte numbers did not change appreciably over the course of the study. In contrast, rHulL-2 caused an eosinophilia in all but the 1 day treatment group. Treatment for 3 days generated a transient eosinophilia on day 7 that returned to baseline by 3 weeks. Five day and 7 day treatments generated an eosinophilia by day 7 that peaked on day 14 and returned to normal values by day 28. Treatment of cats for 14 days did not increase the magnitude or duration of the eosinophilia beyond the 5 or 7 day treatments. Bone marrow (BM) biopsies from rHulL-2-treated cats revealed a marked selective hyperplasia of eosinophil precursors. In the 5 day treatment group, all maturation stages of eosinophils were elevated by week 1 of treatment. By week 2, the early stages had returned to normal, whereas the late stage cells remained elevated, suggesting an ordered maturation response. Numbers of all eosinophil precursors approximated pretreatment numbers by weeks 3-4. Thus the BM hyperplasia preceded the blood eosinophilia by 1 week, suggesting that an enhanced maturation response of BM eosinophil precursors is a major contributor to the rHulL-2-induced blood eosinophilia. In addition to a maturation signal, rHulL-2 induces a potent activation signal for eosinophils as measured by a decrease in density and an increase in longevity in culture. The significance of the activated eosinophil in the therapeutic or toxicologic response to rHulL-2 infusion is discussed.

At present it is not established whether lateralization of pituitary venous drainage occurs in humans. To explore this possibility, we performed bilateral simultaneous inferior petrosal sinus sampling for ACTH in three patients with surgically proven ACTH-secreting pituitary microadenomas laterally located in the pituitary gland. In each patient, a gradient for ACTH correctly identified the location of the tumor. This finding suggests that pituitary venous drainage in humans is lateralized. These data also demonstrate that inferior petrosal sinus sampling needs to be bilateral before the pituitary origin of ACTH hypersecretion can be safely excluded in patients with Cushing's syndrome. In at least one and possibly two patients, the pituitary origin of ACTH excess would have been missed had we only sampled one inferior petrosal sinus. Finally, the demonstration of a left to right central gradient for PRL in addition to ACTH in one patient suggests that this technique may be useful in lateralizing functioning pituitary tumors other than ACTH-secreting tumors.