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BACKGROUND B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. OBJECTIVE To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. DESIGN Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003). SETTING England. PARTICIPANTS Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. INTERVENTION Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. MEASUREMENTS The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. RESULTS At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. LIMITATIONS Small sample size; biomarker primary end point. CONCLUSION Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. PRIMARY FUNDING SOURCE Versus Arthritis.

Socioeconomic deprivation and minority ethnic background are risk factors for adverse pregnancy outcomes. We aimed to quantify the magnitude of these socioeconomic and ethnic inequalities at the population level in England.In this cohort study, we used data compiled by the National Maternity and Perinatal Audit, based on birth records from maternity information systems used by 132 National Health Service hospitals in England, linked to administrative hospital data. We included women who gave birth to a singleton baby with a recorded gestation between 24 and 42 completed weeks. Terminations of pregnancy were excluded. We analysed data on stillbirth, preterm birth (37 weeks of gestation), and fetal growth restriction (FGR; liveborn with birthweight3rd centile by the UK definition) in England, and compared these outcomes by socioeconomic deprivation quintile and ethnic group. We calculated attributable fractions for the entire population and specific groups compared with least deprived groups or White women, both unadjusted and with adjustment for smoking, body-mass index (BMI), and other maternal risk factors.We identified 1 233 184 women with a singleton birth between April 1, 2015, and March 31, 2017, of whom 1 155 981 women were eligible and included in the analysis. 4505 (0·4%) of 1 155 981 births were stillbirths. Of 1 151 476 livebirths, 69 175 (6·0%) were preterm births and 22 679 (2·0%) were births with FGR. Risk of stillbirth was 0·3% in the least socioeconomically deprived group and 0·5% in the most deprived group (p0·0001), risk of a preterm birth was 4·9% in the least deprived group and 7·2% in the most deprived group (p0·0001), and risk of FGR was 1·2% in the least deprived group and 2·2% in the most deprived group (p0·0001). Population attributable fractions indicated that 23·6% (95% CI 16·7-29·8) of stillbirths, 18·5% (16·9-20·2) of preterm births, and 31·1% (28·3-33·8) of births with FGR could be attributed to socioeconomic inequality, and these fractions were substantially reduced when adjusted for ethnic group, smoking, and BMI (11·6% for stillbirths, 11·9% for preterm births, and 16·4% for births with FGR). Risk of stillbirth ranged from 0·3% in White women to 0·7% in Black women (p0·0001); risk of preterm birth was 6·0% in White women, 6·5% in South Asian women, and 6·6% in Black women (p0·0001); and risk of FGR ranged from 1·4% in White women to 3·5% in South Asian women (p0·0001). 11·7% of stillbirths (95% CI 9·8-13·5), 1·2% of preterm births (0·8-1·6), and 16·9% of FGR (16·1-17·8) could be attributed to ethnic inequality. Adjustment for socioeconomic deprivation, smoking, and BMI only had a small effect on these ethnic group attributable fractions (13·0% for stillbirths, 2·6% for preterm births, and 19·2% for births with FGR). Group-specific attributable fractions were especially high in the most socioeconomically deprived South Asian women and Black women for stillbirth (53·5% in South Asian women and 63·7% in Black women) and FGR (71·7% in South Asian women and 55·0% in Black women).Our results indicate that socioeconomic and ethnic inequalities were responsible for a substantial proportion of stillbirths, preterm births, and births with FGR in England. The largest inequalities were seen in Black and South Asian women in the most socioeconomically deprived quintile. Prevention should target the entire population as well as specific minority ethnic groups at high risk of adverse pregnancy outcomes, to address risk factors and wider determinants of health.Healthcare Quality Improvement Partnership.

OBJECTIVE: To compare the incidence of systemic conditions between women who had surgical treatment for stress incontinence with mesh and without mesh. DESIGN: National cohort study. SETTING: English National Health Service. POPULATION: Women with no previous record of systemic disease who had first-time urinary incontinence surgery between 1 January 2006 and 31 December 2013, followed up to the earliest of 10 years or 31 March 2019. METHODS: Competing-risks regression was used to estimate hazard ratios (HR), adjusted for patient characteristics, with HR > 1 indicating increased incidence following mesh surgery. MAIN OUTCOME MEASURES: First post-operative admission with a record of autoimmune disease, fibromyalgia or myalgic encephalomyelitis up to 10 years following the first incontinence procedure. Competing-risks regression was used to estimate hazard ratios (HR) of admission, adjusted for patient characteristics, with HR > 1 indicating increased incidence following mesh surgery. RESULTS: The cohort included 88 947 women who had mesh surgery and 3 389 women who had non-mesh surgery. Both treatment groups were similar with respect to age, socio-economic deprivation, comorbidity, and ethnicity. The 10-year cumulative incidence of autoimmune disease, fibromyalgia or myalgic encephalomyelitis was 8.1% (95% confidence interval 7.9% to 8.3%) in the mesh group and 9.0% (8.0% to 10.1%) in the non-mesh group (adjusted HR 0.89 [0.79 to 1.01]; p = 0.07). A sensitivity analysis including only autoimmune diseases as an outcome returned a similar result. CONCLUSIONS: These findings do not support claims that synthetic mesh slings cause systemic disease.

Monitoring early diagnosis is a priority of cancer policy in England. Information on stage has not always been available for a large proportion of patients, however, which may bias temporal comparisons. We previously estimated that early-stage diagnosis of colorectal cancer rose from 32% to 44% during 2008-2013, using multiple imputation. Here we examine the underlying assumptions of multiple imputation for missing stage using the same dataset.Individually-linked cancer registration, Hospital Episode Statistics (HES), and audit data were examined. Six imputation models including different interaction terms, post-diagnosis treatment, and survival information were assessed, and comparisons drawn with the a priori optimal model. Models were further tested by setting stage values to missing for some patients under one plausible mechanism, then comparing actual and imputed stage distributions for these patients. Finally, a pattern-mixture sensitivity analysis was conducted.Data from 196,511 colorectal patients were analysed, with 39.2% missing stage. Inclusion of survival time increased the accuracy of imputation: the odds ratio for change in early-stage diagnosis during 2008-2013 was 1.7 (95% CI: 1.6, 1.7) with survival to 1 year included, compared to 1.9 (95% CI 1.9-2.0) with no survival information. Imputation estimates of stage were accurate in one plausible simulation. Pattern-mixture analyses indicated our previous analysis conclusions would only change materially if stage were misclassified for 20% of the patients who had it categorised as late.Multiple imputation models can substantially reduce bias from missing stage, but data on patient's one-year survival should be included for highest accuracy.

BACKGROUND: Some studies have suggested that women with SARS-CoV-2 infection during pregnancy are at increased risk of adverse pregnancy and neonatal outcomes, but these associations are still not clear. OBJECTIVE: This study aimed to determine the association between SARS-CoV-2 infection at the time of birth and maternal and perinatal outcomes. STUDY DESIGN: This is a population-based cohort study in England. The inclusion criteria were women with a recorded singleton birth between May 29, 2020, and January 31, 2021, in a national database of hospital admissions. Maternal and perinatal outcomes were compared between pregnant women with a laboratory-confirmed SARS-CoV-2 infection recorded in the birth episode and those without. Study outcomes were fetal death at or beyond 24 weeks' gestation (stillbirth), preterm birth (.05) in the rate of other maternal outcomes. The risk of neonatal adverse outcome (adjusted odds ratio, 1.45; 95% confidence interval, 1.27-1.66; P

OBJECTIVES The increasing complexity of surgical patients and working time constraints represent challenges for training. In this study, the European Association for Cardio-Thoracic Surgery Residents’ Committee aimed to evaluate satisfaction with current training programmes across Europe. METHODS We conducted an online survey between October 2018 and April 2019, completed by a total of 219 participants from 24 countries. RESULTS The average respondent was in the fourth or fifth year of training, mostly on a cardiac surgery pathway. Most trainees follow a 5–6-year programme, with a compulsory final certification exam, but no regular skills evaluation. Only a minority are expected to take the examination by the European Board of Cardiothoracic Surgery. Participants work on average 61.0 ± 13.1 h per week, including 27.1 ± 20.2 on-call. In total, only 19.7% confirmed the implementation of the European Working Time Directive, with 42.0% being unaware that European regulations existed. Having designated time for research was reported by 13.0%, despite 47.0% having a postgraduate degree. On average, respondents rated their satisfaction 7.9 out of 10, although 56.2% of participants were not satisfied with their training opportunities. We found an association between trainee satisfaction and regular skills evaluation, first operator experience and protected research time. CONCLUSIONS On average, residents are satisfied with their training, despite significant disparities in the quality and structure of cardiothoracic surgery training across Europe. Areas for potential improvement include increasing structured feedback, research time integration and better working hours compliance. The development of European guidelines on training standards may support this.

Objectives Compare the functional outcomes of comparative studies of ankle arthrodesis (AA) and total ankle replacements (TAR). Design Systematic review using PRISMA guidelines. Data Sources Medline, Cochrane and EMBASE databases in July 2020. Eligibility Criteria Studies that directly compared TAR and AA which reported patient reported outcomes measures (PROMs) of pain, function and quality of life. Data Extraction and Synthesis Two authors independently reviewed all papers. PROMs were allocated into pain, function or quality of life domains. Two summary statistics were created to allow for analysis of the PROMs. These statistics were the mean difference in post-operative score and the mean difference in the change of score. Results 1323 papers were assessed of which 20 papers were included. 898 ankle arthrodesis and 1638 ankle replacements were evaluated. The mean follow up was 3.3 years (range 0.5-13.0 years). AA patients had a mean age of 55.7 (range 20-82) and TAR 62.5 (range 21-89). There was major heterogeneity in outcomes used. We were unable to find a significant difference between the reported change in PROMs following TAR and AA. 29.3% of PROMs and their subscores showed TAR had better outcomes, 68.7% showed no significant difference and only 2.0% showed AA to have better outcomes. Conclusions The majority of published studies found equality in patient reported outcomes following TAR and AA although the quality of the studies was of low-level evidence. There is an urgent need for randomised controlled studies to definitively answer this important clinical question.

Background Increasing diagnosis of cancer when the disease is still at early stages is a priority of cancer policy internationally. In England, reducing geographical inequalities in early diagnosis is also a key objective. Stage at diagnosis is not recorded for many patients, which may bias assessments of progress. We evaluate temporal and geographical changes in stage at diagnosis during 2008-2013 for colorectal, non-small cell lung, and ovarian cancers, using multiple imputation to minimise bias from missing data. Methods Population-based data from cancer registrations, routes to diagnosis, secondary care, and clinical audits were individually linked. Patient characteristics and recorded stage were summarised. Stage was imputed where missing using auxiliary information (including patient's survival time). Logistic regression was used to estimate temporal and geographical changes in early diagnosis adjusted for case mix using a multilevel model. Results We analysed 196,511 colorectal, 180,048 non-small cell lung, and 29,076 ovarian cancer patients. We estimate that there were very large increases in the percentage of patients diagnosed at stages I or II between 2008-09 and 2012-13: from 32% to 44% for colorectal cancer, 19% to 25% for non-small cell lung cancer, and 28% to 31% for ovarian cancer. Geographical inequalities reduced for colorectal and ovarian cancer. Interpretation Multiple imputation is an optimal approach to reduce bias from missing data, but residual bias may be present in these estimates. Increases in early-stage diagnosis coincided with increased diagnosis through the "two week wait" pathway and colorectal screening. Epidemiological analyses from 2013 are needed to evaluate continued progress.

Highlights • Each difference in tumour stage (I–IV) predicts lower five-year survival, so prognostic information is lost in binary indicators. • Emergency presentation is associated with lower survival, independently of stage. • A high proportion of patients whose stage is not recorded die immediately after diagnosis. • Interval from first symptoms to diagnosis is not consistently associated with survival., Background A key component of recent English cancer policy is the monitoring of trends in early diagnosis of cancer. Early diagnosis can be defined by the disease stage at diagnosis or by other indicators derived from electronic health records. We evaluate the association between different early diagnosis indicators and survival, and discuss the implementation of the indicators in surveillance of early diagnosis. Methods We searched the PubMed database and grey literature to identify early diagnosis indicators and evaluate their association with survival. We analysed cancer registrations for 355,502 cancer patients diagnosed in England during the period 2009–2013, and quantified the association between each early diagnosis indicator and 30-day mortality and five-year net survival. Results Each incremental difference in stage (I–IV) predicts lower 5-year survival, so prognostic information is lost in comparisons which use binary stage indicators. Patients without a recorded stage have high risk of death shortly following diagnosis and lower 5-year survival. Emergency presentation is independently associated with lower five-year survival. Shorter intervals between first symptoms and diagnosis are not consistently associated with improved survival, potentially due to confounding from tumour characteristics. Interpretation Contrary to current practice, we recommend that all the stage information should be used in surveillance. Patients missing stage should also be included to minimise bias. Combined data on stage and emergency presentation could be used to create summary prognostic measures. More work is needed to create statistics based on the diagnostic interval that will be useful for surveillance.

Background There is a debate about the safety and effectiveness of surgical treatments for stress urinary incontinence. Controversy about the use of synthetic mesh sling insertion has led to an increased uptake of retropubic colposuspension and autologous sling procedures. Comparative evidence on the long-term outcomes from these procedures is needed. Objective To compare the risk of reoperation at 10 years after operation between women treated for stress urinary incontinence with retropubic colposuspension, mesh sling insertion, and autologous sling procedures. Study Design The records of admissions to National Health Service hosptials were used to identify women who had first-time stress incontinence surgery between 2006 and 2013 in England. The first incidence of the following outcomes was assessed: further stress incontinence surgery, surgery for a complication (either mesh removal, prolapse repair, or incisional hernia repair), and any reoperation (either further stress incontinence surgery, mesh removal, prolapse repair, or incisional hernia repair). The cumulative incidence of each of these outcomes up to 10 years after surgery was calculated, considering death as a competing event. Multivariable modeling was then used to estimate the reoperation hazard ratios for the different initial surgery types with adjustments for patient characteristics and concurrent prolapse surgery or hysterectomy. Results The analysis included 2262 women treated with retropubic colposuspension, 92,524 treated with mesh sling insertion, and 1234 treated with autologous sling. The cumulative incidence of any first reoperation at 10 years was 21.3% (95% confidence interval, 19.5–23.0) after retropubic colposuspension, 10.9% (10.7–11.1) after mesh sling insertion, and 12.0% (10.2–13.9) after autologous sling procedures. The women who had a retropubic colposuspension were significantly more likely to have a reoperation than women who had an autologous sling (adjusted hazard ratio for any reoperation: 1.79 [1.47–2.17]; for further stress incontinence surgery: 1.64 [1.19–2.26]; for surgery for complications: 1.89 [1.49–2.40]), whereas the women who had mesh slings had a similar hazard (for any reoperation: 0.90 [0.76–1.07]; for further stress incontinence surgery: 0.75 [0.57–0.99]; for surgery for complications: 1.11 [0.89–1.36]). A sensitivity analysis excluding the women who had concurrent prolapse surgery or hysterectomy produced similar results. Conclusion Retropubic colposuspension is associated with higher risk of reoperation at 10 years after surgery than mesh sling insertion or autologous sling procedures, with 1 in 5 women requiring reoperation.

IntroductionFew treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE.Methods and analysisBEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo.Ethics and disseminationThe protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available athttps://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences.Trial registration numberISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.

Background Approximately 70% of breast cancer patients have residual disease after neoadjuvant chemotherapy. This study was designed to determine whether breast cancer cells with stemlike properties are present in residual disease after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The presence of breast cancer cells with stemlike properties with specific mutations may help explain the poor prognosis associated with residual disease. Methods A total of 68 breast cancer specimens were collected at the time of mastectomy or lumpectomy. A total of 44 were chemotherapy naive and 24 were collected as residual disease after neoadjuvant chemotherapy. Tumor cells were collected by fluorescence-activated cell sorting, with breast cancer cells with stemlike properties specifically identified using breast stem cell associated antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast cancer cells with stemlike properties were analyzed for genetic mutations, including PIK3CA. Results Breast cancer cells with stemlike properties, demonstrating EpCAM-positive, CD44-positive, CD49f ± , CD24 ± expression were present in chemotherapy-naive tumors and residual disease. In both chemotherapy-naive and residual disease specimens the highest frequency of PIK3CA mutations were detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were detected in all stages of breast cancer (35%), in both chemotherapy naive (39%) and residual disease (29%) and in both estrogen receptor positive (41%) and negative tumors (14%) ( P = ns). Various PIK3CA mutations were identified in chemotherapy-naive specimens versus residual disease specimens in both patient-paired and unpaired breast cancers. Conclusion Breast cancer cells with stemlike properties with mutations in PIK3CA were present in chemotherapy-naive breast cancers and residual disease after neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy does not completely eradicate PIK3CA-defective breast cancer cells with stemlike properties. Although these findings may help explain the poor clinical outcomes in patients with residual disease, they also identify breast cancer cells with stemlike-property targets for therapies.

Hemorrhage and coagulopathy are major contributors to death after trauma. The contribution of red blood cells (RBCs) in correcting coagulopathy is poorly understood. Current methods of measuring coagulopathy may fail to accurately characterize in vivo clotting. We aimed to determine the effect of RBCs on clotting parameters by comparing resuscitation regimens containing RBCs and plasma with those containing plasma alone.Thirty-two Yorkshire swine were anesthetized, subjected to a complex model of polytrauma and hemorrhagic shock, and resuscitated with either fresh frozen plasma, lyophilized plasma (LP), or 1:1 ratios of fresh frozen plasma:packed RBC (PRBC) or LP:PRBC. Activated clotting time, prothrombin time, partial thromboplastin time, and thrombelastography (TEG) were performed at 1 hour, 2 hours, 3 hours, and 4 hours after resuscitation.Animals treated with 1:1 LP:PRBC had less blood loss than the other groups (p0.05). The activated clotting time was shorter in the 1:1 groups when compared with the pure plasma groups at all time points (p0.05). The 1:1 groups had shorter TEG R times (time to onset of clotting) at 1 hour, 3 hours, and 4 hours compared with pure plasma groups (p0.05). Other TEG parameters did not differ between groups. Partial thromboplastin time was shorter in the pure plasma groups than the 1:1 groups at all time points (p0.05).Whole blood assays reveal that RBCs accelerate the onset of clot formation. Coagulation assays using spun plasma underestimate the effect of RBCs on clotting and do not completely characterize clot formation.

The contribution of the cracked stretched concrete is taken into account in the calculations of structures to estimate accurately the deformations and also to limit, for the sake of security, the opening of cracks. The aim of this study is to lay down the expressions which are necessary to perform these calculations, the basic element of which is the tie-beam. Some methods of calculation resting on the relation between the adherence-stress and the steel-concrete sliding are produced according to the specifications of the materials in use, and especially the rate of steel.

Treatment resistance, long latency, and high recurrence rates suggest that breast cancers arise from defective breast stem cells.Within cancers, subpopulations of cells will demonstrate differences in stem/progenitor potential, HER2/neu amplification, and gene expression. Related cells will be found in normal breast tissue.ER-/PR-/HER2/neu + breast cancer cells were flow-sorted into subpopulations: (A) CD49f(+) CD24(-), (B) CD49f(+)CD24(+), (C) CD49f CD24(-), and (D) CD49f(-)CD24(+). Gel matrix cell invasion, fluorescence in situ hybridization (FISH) HER2/neu amplification, and qRT-PCR gene expression were measured in all groups. Cells from sorted groups were implanted into rat brains. Resultant tumors were analyzed by immunohistochemistry (IHC) and FISH. Normal breast tissue was examined by IHC.Tumor development varied among sorted groups (25-75%), but was highest in group A. Tumor cells were mostly CD49f(-)CD24(-), with variable fractions of other stem/progenitor cells. Tumors showed HER2/neu amplification, but fewer chromosome 17 per cell than inoculates. Group A tumors exhibited cells with normal chromosome 17 copy number and near normal HER2/neu amplification. Cell invasion was 61% higher in unsorted cells and 34-42% in sorted groups compared with controls. Sorted groups showed significantly different expression of development, proliferation, and invasion associated genes. In normal breast tissue, CD49f(+) cells were identified in CD14(+) CK19(-) basal epithelial layers of mammary glands; these were 95% CD24(+) and 60% CD44(+).Breast cancer stem/progenitor cell populations differ in tumor-initiating potential but are not solely responsible for metastasis. Cancer stem/progenitor cells are less polyploid than cancer cells in general and may not be HER2/neu amplified. In normal breast tissue, breast stem/progenitor cell-like populations are present.

We developed a complex combat-relevant model of abdominal and extremity trauma, hemorrhagic shock, hypothermia, and acidosis. We then simulated injury, preoperative, and operative phases. We hypothesized that this model is reproducible and useful for randomized multicenter preclinical trials. Yorkshire swine were anesthetized, intubated, and instrumented. They then underwent femur fracture, 60% total blood volume hemorrhage, a 30-min shock period, induced hypothermia to 33 degrees C, and hemorrhage volume replacement with 3:1 isotonic sodium chloride solution (NS) at each of three centers. Hemodynamic parameters were measured continuously. Thromboelastography, arterial blood gas, and laboratory values were collected at baseline, after the shock period, and after NS replacement. Thirty-seven animals were used for model development. Eight (21%) died before completion of the study period. Twenty-nine survivors were included in the analysis. MAP (+/-SEM) after the shock period was 32 +/- 2 mmHg and was similar between centers (P = 0.4). Mean pH, base deficit, and lactate levels were 7.29 +/- 0.02, 8.20 +/- 0.65 mmol/L, and 5.29 +/- 0.44 mmol/L, respectively, after NS replacement. These were similar between centers (P0.05). Prothrombin time values increased significantly over time at all centers, reflecting a progressive coagulopathy (P0.02). Thromboelastography maximum amplitude values were similar among centers (P0.05) and demonstrated progressively weakened platelet interaction over time (P0.03). Hematocrit was similar after controlled hemorrhage (P = 0.15) and dilution (P = 0.9). The pH, lactate, base deficit, and coagulation tests reflect a severely injured state. A complex porcine model of polytrauma and shock can be used for multi-institutional study with excellent reproducibility. A consistent severe injury profile was achieved, after which experimental interventions can be applied. This is the first report of a reproducible multicenter trauma and resuscitation-related animal model.

Background We previously reported that breast cancer patients who used hormone replacement therapy (HRT) had significantly lower stage tumors and higher survival than never-users. We present an update with longer follow-up, HRT use data, and in vitro research. Methods Our database of 292 postmenopausal breast cancer patients was updated to include HRT type, duration, and disease status. In vitro effects of estrogen (E) and/or medroxyprogesterone (MPA) on breast cancer cell growth were measured. Results Tumor prognostic factors were better and survival rates higher for both E and combination HRT users of any duration. Use greater than 10 years correlated with node-negative disease, mammographically detected tumors, and 100% survival. E supported minimal proliferation; MPA induced cell death; E+MPA results were similar to E alone. Conclusions HRT users, regardless of type or duration of HRT use, continued to have higher survival rates. In vitro results supported the clinical finding that outcomes for users of E and E+MPA were similar.

Background: Inhalational anesthetics can cause profound hemodynamic effects including decreases in systemic vascular resistance and cardiac inotropy. Although widely used in uncontrolled hemorrhagic shock (UHS), their consequences compared with other anesthetic regimens are not well-studied. Ketamine-based total intravenous anesthesia (TIVA) may produce less profound cardiovascular depression, and has been used during elective surgery but rarely during traumatic shock. The purpose of this study was to compare the effects of isoflurane (ISO) and TIVA regimens in a swine grade V liver injury model. We hypothesized that TIVA would result in less hypotension and dysfunctional inflammation than ISO. Methods: Twenty swine were randomized blindly to receive either 1% to 3% ISO, or intravenous ketamine, midazolam, and buprenorphine for maintenance anesthesia. Six animals acted as controls. After sedation and intubation, randomized anesthesia was initiated and monitored by an independent animal technician. Invasive lines were placed followed by celiotomy and splenectomy. Baseline mean arterial pressure (MAP) was documented and a grade V liver injury created. After 30 minutes of UHS, animals were resuscitated with 8 mL of Ringer's lactate per milliliter blood loss at 165 mL/ min. MAP and tissue oxygen saturation (StO 2 ) were continuously recorded. The animals were sacrificed 120 minutes after injury and lung tissue was harvested. Serum cytokines (interleukin-6 [IL-6], IL-8, and tumor necrosis factor-a [TNF-a]) were quantified with enzyme-linked immunosorbent assay. Lung cytokine mRNA levels were quantified with real time reverse transcriptase polymerase chain reaction. Results: Animal weight, liver injury pattern, and blood loss were similar (p > 0.1). The ISO group had a lower MAP at baseline (p = 0.02), at injury (p = 0.004), and study completion (p = 0.001). After resuscitation, MAP decreased in the ISO group but remained stable in the TIVA group. StO 2 was significantly higher in the TIVA group immediately after injury (p = 0.004), but similar between groups throughout the remainder of the study. Animals who received TIVA trended toward higher levels of lactate and lower pH throughout the study, reaching significance at 30 minutes postinjury (p = 0.037 and 0.043). Inflammatory cytokine (IL-6, IL-8, and TNF-a) production did not differ between groups, however TNF-a mRNA production was significantly lower in the TIVA group (p = 0.04). Conclusion: Although a TIVA regimen produced less pronounced hypotension in a swine model of UHS than did ISO, end-organ perfusion with TIVA appeared to be equivalent or inferior to ISO. In circumstances of limited resources, such as those experienced by forward Army surgical teams, a ketamine-based TIVA regimen may be an option for use in UHS.

BACKGROUND Normal saline (NS) and lactated Ringer's solution (LR) continue to be used interchangeably for the resuscitation of hemorrhagic shock in some institutions. We hypothesized that, aside from hyperchloremic acidosis, NS resuscitation would be similar to that of LR in a swine model of uncontrolled hemorrhage. METHODS Twenty swine weighing a mean of 37 kg underwent invasive line placement, midline celiotomy, and splenectomy. After a 15-minute stabilization period, we recorded a baseline mean arterial pressure (MAP) and created a grade V liver injury. The animals bled freely for 30 minutes after which we measured blood loss. We blindly randomized the swine to receive NS (10 animals) versus LR (10 animals) to achieve and maintain the baseline MAP for 90 minutes postinjury. Laboratory values were obtained at baseline and upon completion of the 2-hour study period. RESULTS Initial blood loss was 25 mL/kg in the NS group and 22 mL/kg in the LR group (p = 0.54). Animals required 256.3 +/- 145.4 mL/kg of fluid in the NS group as compared with 125.7 +/- 67.3 mL/kg in the LR group (p = 0.04). The urine output was higher in the NS group (46.6 +/- 39.5 mL/kg versus 18.9 +/- 12.9 mL/kg, p = 0.04). Upon study completion, the NS group had a significant hyperchloremia (119 +/- 1.9 mEq/L versus 105 +/- 2.9 mEq/L, p < 0.01) with acidosis (7.28 +/- 0.12 versus 7.45 +/- 0.06, p < 0.01) in comparison to the LR group. In addition, resuscitation with NS resulted in significantly lower fibrinogen levels (99 +/- 21 mg/dL versus 123 +/- 20 mg/dL, p = 0.02). The serum lactate was 4.7 +/- 2.2 in the LR group and 1.7 +/- 1.7 in the NS swine (p < 0.01) at the end of the study. CONCLUSIONS Resuscitation of uncontrolled hemorrhagic shock with NS requires significantly greater volume and is associated with greater urine output, hyperchloremic acidosis, and dilutional coagulopathy as compared with LR. Resuscitation with LR results in an elevation of the lactate level that is not associated with acidosis. Lactated Ringer's solution is superior to NS for the resuscitation of uncontrolled hemorrhagic shock in swine.

Introduction Cancers are believed to adapt to continual changes in glucose and oxygen availability by relying almost exclusively on glycolytic metabolism for energy (i.e. the Warburg effect). The process by which breast cancers sustain growth in avascular tissue is thought to be mediated via aberrant hypoxia response with ensuing shifts in glycolytic metabolism. Given their role in initiating and perpetuating tumors, we sought to determine whether breast cancer stem and progenitor cells play an instrumental role in this adaptive metabolic response. Methods Breast cancer stem/progenitor cells were isolated from invasive ductal carcinomas, and benign stem cells (SC) were isolated from reduction mammoplasty tissues. Relative expression of 33 genes involved in hypoxia and glucose metabolism was evaluated in flow cytometrically isolated stem and progenitor cell populations. Significance between cohorts and cell populations was determined using Student’s 2-tailed t test. Results While benign stem/progenitor cells exhibited few significant inter-group differences in expression of genes involved in hypoxia regulation or glucose metabolism, breast cancer stem/progenitor cells demonstrated significant inter-group variability. Breast cancer stem/progenitor cells adapted to microenvironments through changes in stem cell numbers and transcription of glycolytic genes. One of four breast cancer stem/progenitor cells subpopulations exhibited an aerobic glycolysis gene expression signature. This subpopulation comprises the majority of the tumor and therefore best reflects invasive ductal carcinoma tumor biology. Although PI3K/AKT mutations are associated with increased proliferation of breast cancer cells, mutations in breast cancer stem/progenitor cells subpopulations did not correlate with changes in metabolic gene expression. Conclusions The adaptive capacity of breast cancer stem/progenitor cells may enable tumors to survive variable conditions encountered during progressive stages of cancer growth.

An analytical model is presented for predicting complete shear load-deformation response of reinforced or prestressed concrete beams. Equilibrium, compatibility and stress-strain relationships are formulated in term of average stresses and average strains. according to the assumption of smeared cracks. This model is able to analyze sections having unusual forms or reinforcing details, loaded in combined bending, axial load and shear. Predictions of the model are compared with several tests on reinforced or prestressed beams and are shown to give a fair agreement with the experimental behaviour.

Background Estrogen-receptor (ER)–, progesterone-receptor (PR)–, and androgen-receptor (AR)–negative breast cancer cells are unaffected by treatment with dehydroepiandrosterone-sulfate (DHEAS) and an aromatase inhibitor (AI). We hypothesized that cell growth would be inhibited with DHEAS/AI treatment after successful transfection of an AR expression vector. Methods ER/PR/AR–negative breast cancer cells were transfected with an AR expression vector and treated with DHEAS/AI for 2 days. Growth inhibition of these cells was compared with that of transfected cells treated with only AI or with nontransfected cells treated with DHEAS/AI. Mann-Whitney U test was used to determine statistical significance. Results Cell death rates of 53.5% ( P = .001) and 40.1% ( P = .006) were seen in transfected cells treated with DHEAS/AI compared with controls for days 1 and 2, respectively. Nontransfected cells were unaffected by treatment. Comments ER/PR/AR–negative cells transfected with AR were killed by DHEAS/AI treatment, providing evidence that AR is responsible for this effect. This provides the first AR-targeted hormonal therapy for ER breast cancer.

In this note, one considers a 1 d.-o.-f. oscillator consisting of a mass and a viscoelastic spring, the rheology of which is represented by a so-called Zener 3-parameters model. Such a system has three eigenmotions: two of them are damped with or without oscillations (as in the case of viscous damping), the third is damped without oscillation. Introducing appropriate parameters, one has performed a detailed discussion of the nature of these eigenmotions.

Resume Dans cette Note, on considere les mouvements propres d'un oscillateur a un degre de liberte constitue d'une masse et d'un ressort viscoelastique correspondant a un modele rheologique de Biot a 2 n + 1 parametres. On montre qu'il y a n + 2 mouvements propres independants : aux deux mouvements propres amortis avec ou sans oscillations, bien connus dans le cas d'un amortissement visqueux classique, viennent s'ajouter n mouvements propres amortis sans oscillations induits par la rheologie viscoelastique. Pour citer cet article : P. Muller, C. R. Mecanique 333 (2005).

Detection of systemic breast cancer recurrence is limited by lack of universally expressed tumor cell markers. We hypothesized that a test that detects genetic alterations specific to breast cancer cells of an individual patient would provide a superior cancer marker. DNA was extracted from blood, primary tumor, and axillary lymph nodes of 33 breast cancer patients and normal breast tissue of 12 control patients. A patient’s genome was scanned by PCR amplification between Alu sequences. A DNA fingerprint of approximately 17–40 bands was produced for comparison between normal blood and sampled tissues. There were 7 stage I, 18 stage II, 7 stage III, and 1 stage IV breast cancer cases; 33 of 33 cancer cases showed DNA fingerprint differences between blood and primary tumor (P < .0001).This test predicted 100% of positive nodes. No false-negatives occurred, and in two cases malignancy was detected in histologically negative nodes. Three of the 12 controls showed a single similar band change. DNA fingerprinting is a method for detecting and characterizing genetic alterations specific to an individual patient’s primary tumor in 100% of cases tested. These specific changes were also identified in 100% of positive nodes, proving the capacity of the test to detect metastases.