The response of turkeys to dietary balanced protein during two periods of growth.

1. Two experiments were conducted to measure the response of growing turkeys to dietary protein content. In the first, 960 sexed British United Turkey (BUT 6) poults were used to measure the response to balanced protein from 3 to 6 weeks of age. In the second, 1440 sexed BUT and Hybrid Converter poults were raised from 14 to 17 weeks.2. In both experiments, six levels of dietary protein were fed, with feed intake, body and feather weight gain and changes in body composition measured. The levels of protein chosen ranged from 0.53 to 1.2 of the Aviagen requirements for growing turkeys.3. In the first experiment, six poults were sampled from each sex at the start of the experiment for carcass analysis, and four were sampled from each strain and sex in the second. At the end of each experiment, eight poults from each treatment were sampled. Body composition analyses were made on individual defeathered birds.4. Weight gain increased linearly with protein intake in the early period and exponentially in the later period. In both periods, feed intake decreased as protein content reduced.5. In the early period, body lipid content increased from 20.2 to 41.5 g/kg body weight, as dietary protein content decreased, but there was no change in the later period. Efficiency of utilisation of dietary protein declined linearly with an increase in dietary protein content, from 0.87 to 0.46 g/g in the first, and from 0.43 to 0.27 g/g in the later period.6. The inability of the growing turkey to increase feed intake on marginally limiting feeds may have been due to a genetic constraints to store excess energy consumed as body lipid, resulting in the observed decrease in feed intake as dietary protein content is reduced.

Dietary energy:protein ratio influences the efficiency of utilisation of dietary protein by growing turkeys.

1. The following experiment was designed to confirm that the efficiency of dietary protein utilisation (ep) can be reduced when the AMEn to digestible crude protein (DCP) ratio of the feed falls below a critical level. In addition, whether the efficiency would be improved at high DCP contents through the addition of oil or starch was determined.2. A 14d trial (starting at 21 d of age), using BUT 6 turkeys, was designed to measure the effects on ep of four feeds (12.1 MJ AMEn/kg) with AMEn:DCP ratios ranging from 45 to 72 MJ AMEn/kg, and two additional feeds with the same DCP as the highest protein feed, one with an AMEn:DCP ratio of 59, through the addition of canola oil, and the other with a ratio of 51 MJ/kg supplemented with both starch and oil. Twenty birds constituted each experimental unit, with two replications of each sex being used per dietary treatment.3. Ten birds per sex were sampled at the start of the trial and a further five per pen at the end for carcass analysis. Each carcass including feathers was ground and subsampled for water, protein and lipid determination.4. A split-line regression described ep on the four feeds unsupplemented with additional energy (R2 = 0.81) with breakpoint at 60.6 MJ AME/kg DCP, maximum ep at 0.736 g/g, and a slope of 0.017. No improvement in ep resulted from supplementing the high protein feed with oil or a mixture of oil and starch, but feed intake and protein and lipid retention increased significantly (P < 0.05).5. The argument that insufficient energy is available to enable high protein feeds to be utilised efficiently was not corroborated by the evidence from this trial.

The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.

BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.

Pre-treatment expectations of patients with spinal metastases: what do we know and what can we learn from other disciplines? A systematic review of qualitative studies.

BACKGROUND: Little is known about treatment expectations of patients with spinal metastases undergoing radiotherapy and/or surgery. Assuming that patients with spinal metastases share characteristics with patients who had spinal surgery for non-cancer related conditions and with advanced cancer patients, we performed a systematic review to summarize the literature on patient expectations regarding treatment outcomes of spinal surgery and advanced cancer care. METHODS: A comprehensive search was performed in MEDLINE, EMBASE and PsycINFO for studies between 2000 and sep-2019. Studies including adult patients (> 18 years), undergoing spinal surgery or receiving advanced cancer care, investigating patients' pre-treatment expectations regarding treatment outcomes were included. Two independent reviewers screened titles, abstracts and full-texts, extracted data and assessed methodological quality. RESULTS: The search identified 7343 articles, of which 92 were selected for full-text review. For this review, 31 articles were included. Patients undergoing spinal surgery had overly optimistic expectations regarding pain and symptom relief, they underestimated the probability of functional disability, and overestimated the probability of (complete) recovery and return to work. Studies highlighted that patients feel not adequately prepared for surgery in terms of post-treatment expectations. Similarly, advanced cancer patients receiving palliative treatment often had overly optimistic expectations regarding their survival probability and cure rates. CONCLUSIONS: Patients tend to have overly optimistic expectations regarding pain and symptom relief, recovery and prognosis following spinal surgery or advanced cancer care. Pretreatment consultation about the expected pain and symptom relief, recovery and prognosis may improve understanding of prognosis, and promote and manage expectations, which, in turn, may lead to better perceived outcomes. TRIAL REGISTRATION: PROSPERO registration number: CRD42020145151 .

A description of the potential growth and body composition of two commercial broiler strains.

1. The potential growth of feathers and feather-free body and their chemical components was measured in two commercial broiler strains. 2. A total of 200 chicks of each sex x strain were fed adequate amounts of dietary protein using a four-phase feeding programme. Ten birds per genotype were sampled at 14, 28, 42, 56, 70, 84, 98 and 112 d of age. They were weighed before and after being dry-plucked to determine the weight of feathers, and the feather-free body was then minced and analysed for water, protein and lipid. 3. Body weights and chemical composition of males of the two strains were similar throughout the trial. Females of the two strains differed only in their body lipid contents, with mature Cobb females being higher than Ross (1371 vs. 1210 g). 4. Mature body weights of males and females from both strains averaged 8420 g and 6650 g; mature body protein weights averaged 1555 g and 1030 g; and mature body lipid contents averaged 908 and 1290 g, respectively. 5. Rates of maturing per day of body weights of males and females of both strains averaged 0.0385 and 0.0368; feather-free body protein was 0.0316 and 0.0348 and body lipid was 0.0503 and 0.0375, respectively. The rates for body lipid differed between Cobb and Ross females (0.0352 vs. 0.0397/d). Separate equations were required for males and females to describe the allometric relationship between lipid and protein in the feather-free body. 6. The rate of maturing of feathers in females was higher than in males (0.0526 vs. 0398/d) and the mature weight was lower (205 vs. 266 g), respectively. Mature body weights of broilers in this trial were considerably higher than those measured using the same protocol 24 years ago, whereas rates of maturing remained the same.

A description of the growth and moulting of feathers in commercial broilers.

1. Changes in feather length and weight and daily losses of down, contour feathers, remiges and retrices were studied in two commercial broiler strains to determine feather growth and moult in broilers up to 112 d of age. 2. Ten pens of 20 chicks for each sex x strain were fed adequate amounts of dietary protein in a four-phase feeding programme. Ten birds were sampled per genotype at 14, 28, 42, 56, 70, 84, 98 and 112 d. Feather loss was determined for individual birds caged within a nylon net. 3. All feathers were dry-plucked from each of seven tracts, with representative feathers from the capital-cervical, dorsopelvic and interscapular, pectoral and femoral tracts being randomly selected. Three rectrices of the dorsocaudal tract and three primaries and secondaries of the humeral-alar tract of the right wing were evaluated. 4. The length of the selected feathers was measured, and the feathers from each tract and from the whole bird were weighed. 5. A wide range of rates of maturing (0.0250-0.0907/d) and mature weights (9.62-52.9 g) were evident between sampled tracts. 6. Feather weight failed to predict some moults which were detected by the measurement of feather losses. From the weight data, moulting was evident only in the humeral-alar and dorsocaudal tracts, whereas, when daily losses were measured, contour feathers accounted for over 0.7 proportion of feather losses. Logistic equations adequately described the cumulative losses of down, contour feathers and remiges. 7. Feather loss needs to be considered when feather growth is determined from feather weight at different ages. 8. The rate of maturing (B) of feathers was numerically higher in Ross males and females than in the Cobb strain. In females, B was higher than in males (0.0483 vs. 0335/d) but the mature weight was lower (162 vs. 230 g).

Human Intestinal Enteroids as a Model System of Shigella Pathogenesis.

The enteric bacterium and intracellular human pathogen Shigella causes hundreds of millions of cases of the diarrheal disease shigellosis per year worldwide. Shigella is acquired by ingestion of contaminated food or water; upon reaching the colon, the bacteria invade colonic epithelial cells, replicate intracellularly, spread to adjacent cells, and provoke an intense inflammatory response. There is no animal model that faithfully recapitulates human disease; thus, cultured cells have been used to model Shigella pathogenesis. However, the use of transformed cells in culture does not provide the same environment to the bacteria as the normal human intestinal epithelium. Recent advances in tissue culture now enable the cultivation of human intestinal enteroids (HIEs), which are derived from human intestinal stem cells, grown ex vivo, and then differentiated into "mini-intestines." Here, we demonstrate that HIEs can be used to model Shigella pathogenesis. We show that Shigella flexneri invades polarized HIE monolayers preferentially via the basolateral surface. After S. flexneri invades HIE monolayers, S. flexneri replicates within HIE cells and forms actin tails. S. flexneri also increases the expression of HIE proinflammatory signals and the amino acid transporter SLC7A5. Finally, we demonstrate that disruption of HIE tight junctions enables S. flexneri invasion via the apical surface.

Saving the Male Breast: A Systematic Literature Review of Breast-Conservation Surgery for Male Breast Cancer.

BACKGROUND: Male breast cancer (MBC) management is extrapolated from female BC. Mastectomy remains the most frequently used surgical procedure for male breast cancer (MBC). We performed a literature review to assess the use of breast-conservation (BCS) in MBC as well as outcomes following BCS. METHODS: A systematic literature was performed, and articles screened to identify studies that measured overall survival (OS), disease-free survival (DFS), or local recurrence (LR) in patients undergoing BCS. Weighted averages based on study size were performed for LR, DFS, and 5-year OS. RESULTS: Eight studies met the inclusion criteria with male breast surgery cases, and 859 (14.7%) underwent BCS. The mean follow-up time was 53 months, and mean age was 62.6 years, with stage II as the most common presentation. Two studies reported that 50-71.4% of patients underwent sentinel lymph node biopsy, and four studies reported axillary lymph node dissection in 14.3-100%. Five studies reported on adjuvant radiation therapy in 12.0-100% of total patients undergoing BCS. Four studies reported use of hormonal therapy in 73.8-100% of patients. Four studies reported use of chemotherapy in 25-66.7% of patients. Seven studies reported LR among 116 patients, with a weighted average of 9.9%. Three studies reported on DFS in 14 patients, with a weighted average 85.6%. Two studies report OS in 143 patients with a weighted average of 84.4%. CONCLUSIONS: Breast conservation may be considered a safe alternative in the surgical treatment of MBC. Future research should focus on better standardization of local therapy for MBC and improved reporting of outcomes.

Bee community preference for an invasive thistle associated with higher pollen protein content.

Non-native plant species reliant on insect pollination must attract novel pollinators in their introduced habitat to reproduce. Indeed, pollination services provided by resident floral visitors may contribute to the spread of non-native species, which may then affect the pollination services received by native plants. To determine the mechanisms by which an invasive thistle attracts pollinators in its introduced range, and whether its presence changes the pollinator visitation to native plant species, we compared bee visitation to native plants in the presence or absence of the invader. We experimentally tested the effect of a thistle invasion into a native plant community. We found that the non-native thistle was the most attractive of the plant species to visiting bee species. However, there was no effect of experimental treatment (presence of thistle) on bee abundance or visitation rate (bees per unit floral area per sample) to native plant species. Across 68 bee and 6 plant species, we found a significant correlation between pollen protein content and bee abundance and visitation rate. Thistle pollen also had a similar protein:lipid ratio to legumes, which correlated with bumble bee visitation. The high protein content of the thistle pollen, as compared to four native asters, may allow it to attract pollinators in novel ecosystems, and potentially contribute to its success as an invader. At the same time, this high protein pollen may act as a novel resource to pollinators in the thistle's invaded range.

The use of laser-based diagnostics for the rapid identification of infectious agents in human blood.

AIMS: To investigate the use of a laser-based method of detection as a potential diagnostic test for the rapid identification of infectious agents in human blood. METHODS AND RESULTS: In this study, the successful differentiation of blood spiked with viruses, bacteria or protozoan parasites to clinically relevant levels is demonstrated using six blood types (O+, O-, AB+, A+, A-, B+) using blood from different individuals with blood samples prepared in two different laboratories. Experiments were performed using various compositions of filters, experimental set-ups and experimental parameters for spectral capture. CONCLUSIONS: The potential for developing a laser-based diagnostic instrument to detect the presence of parasites, bacteria and viruses in human blood capable of providing analysis results within minutes was demonstrated. SIGNIFICANCE AND IMPACT OF THE STUDY: There is an ongoing need for clinical diagnostics to adapt to newly emerging agents and to screen simultaneously for multiple infectious agents. A laser-based approach can achieve sensitive, multiplex detection with minimal sample preparation and provide rapid results (within minutes). These properties along with the flexibility to add new agent detection by simply adjusting the detection programming make it a promising tool for clinical diagnosis.

The growth of turkeys 2. Body components and allometric relationships.

1. The relationships between the main components of the body and body protein among males and females of BUT 6 (BUT) and Hybrid Converter (HYB) turkey strains were examined. 2. The weights of breast meat, breast skin, drumstick meat, drumstick skin, thigh meat, thigh skin and wing-plus-skin as well as the head, neck, feet, blood, heart, liver and gizzard were measured at different stages of growth after which all components of each bird were minced together in order to determine the feather-free body protein weight of each bird sampled. Using the weights of the components and the protein content of each bird the allometric relationships between the components and body protein were determined and then compared for each strain x sex combination. 3. By excluding the breast weights at day-old and at 7 d, the remaining points produced an acceptable allometric relationship (R2 = 0.992). Thigh weight could be predicted for all strain x sex combinations using one allometric equation, as could drumstick skin weight. Breast and thigh skin weights differed between males and females. Females of the HYB strain exhibited heavier drumstick and wing-plus-skin weights at a given body protein weight than the other three strain x sex combinations. These differences in both the constant term and regression coefficient in the allometric equations between genotypes are probably due to differences in the amount of lipid that is deposited in these tissues. 4. Sexes differed in the allometric relationships for head, feet, heart and liver, while breeds differed in gizzard weight. A common relationship between the four genotypes could be used to predict the weight of blood in the carcass. 5. The allometric equations fitted to the data in this trial enable the accurate prediction of the weights of the different physical components given the weight of body protein.

The growth of turkeys 1. Growth of the body and feathers and the chemical composition of growth.

1. The potential growth of modern turkey genotypes was measured using male and female BUT 6 (BUT) and Hybrid Converter (HYB) strains. At one-day-old, 720 male and 960 female poults were randomly allocated to 48 littered pens in two houses with 30 males or 40 females of each strain per pen. Five feeds of decreasing protein content were fed to both sexes during the growing period. 2. Birds were weighed at 1, 7, 14, 21, 35, 56, 77, 119 d (males only), 126 d (females only) and 140 d (males only) and, on each occasion, six birds were selected and removed for carcass analysis. 3. Growth was similar in both strains, but the growth rate of females appeared to decline relative to the earlier trajectory after 70 d, and this tendency being greater in HYB females. 4. HYB birds of both sexes had more feathers than BUT to 77 d, but thereafter these differences were non-significant. A single allometry between feather and body protein weight was observed over all genotypes with no differences apparent between sexes within strains. The Gompertz curve adequately described the growth of body protein, water and ash. 5. Body lipid (g/100g bodyweight) declined in the early stages of growth. This might reflect an energy deficiency in the diet or might indicate that the present description of lipid growth does not apply in turkeys as it does in other species. 6. Whereas the description of body growth, feather growth and the chemical components of growth given in this paper may not fully reflect the true potential of the genotypes used, nevertheless they provide useful information regarding the latest genotypes available in the turkey industry. Some of the observations suggested that current performance might be improved if further research is conducted regarding dietary energy transactions.

New developments in rabies vaccination.

Current rabies vaccines are safe and, when administered properly, they are highly effective. In addition, they elicit long-lasting immunity, with virus-neutralising antibody titres persisting for years after vaccination. However, current regimens require multiple doses to achieve high neutralising titres and they are costly, which means that it is difficult for developing countries, where rabies deaths are highest, to implement widespread vaccination. New innovations are the only way to reduce rabies disease to acceptable rates. Numerous preclinical and clinical studies are under way, testing novel vaccines, adjuvants and injection methods. Research into the use of live vaccines and alternative vaccine vectors is ongoing, while attempts to develop DNA vaccines have so far failed to match the immunogenicity and neutralising capability of traditional vaccines. The development of molecular adjuvants that induce faster, stronger immune responses with less antigen has yielded exciting preclinical results and appears to edge us closer to a better rabies vaccine. However, steep challenges remain: molecular adjuvants require administration with live vaccines, and differences in species specificity of immune molecules complicate development. Over all, the array of research undertaken over the past decade is impressive and encouraging, but most new vaccines have yet to be tested in clinical trials, and the viability of such experimental vaccines in the global market remains to be seen. Only a vaccine that outperforms currently available vaccines in every area will have a chance at widespread adoption. Nevertheless, the authors are confident that some vaccine candidates will meet these criteria.

Les vaccins actuels contre la rage sont sûrs et très efficaces lorsqu'ils sont administrés correctement. En outre, ils confèrent une immunité durable, avec le maintien de titres neutralisants d'anticorps plusieurs années après la vaccination. Néanmoins, les régimes actuels nécessitent l'administration de plusieurs doses pour obtenir des titres élevés d'anticorps neutralisants et ils sont onéreux, de sorte que la vaccination à grande échelle est difficile à mettre en oeuvre dans les pays en développement, pourtant les plus touchés par la mortalité par rage. Seule l'adoption de solutions innovantes permettra de ramener l'incidence de la rage à un niveau acceptable. De nombreuses études précliniques et cliniques sont en cours, visant à tester les innovations en matière de vaccins, de modes d'injection et d'adjuvants. La recherche sur l'utilisation de vaccins à virus vivant et sur de nouveaux vecteurs vaccinaux se poursuit, alors que les tentatives de développement de vaccins à ADN n'ont pas réussi jusqu'à présent à obtenir un effet immunogène ou des capacités de neutralisation virale équivalents à ceux des vaccins traditionnels. Les résultats d'essais précliniques sur de nouveaux adjuvants moléculaires induisant une réponse immune plus rapide et plus puissante avec moins d'antigène sont extrêmement prometteurs et semblent annoncer l'imminence de meilleurs vaccins contre la rage. Il subsiste toutefois d'importantes difficultés : les adjuvants moléculaires ne peuvent être administrés qu'avec des vaccins vivants et les différences de spécificité d'espèce des molécules immunes rendent le développement plus complexe. Globalement, les efforts déployés depuis une décennie par la recherche sont impressionnants et encourageants mais la plupart des nouveaux vaccins doivent encore être soumis à des essais cliniques ; d'autre part la viabilité de ces vaccins expérimentaux dans le marché mondial reste à démontrer. Seul un vaccin capable de surpasser les performances des vaccins actuels dans chaque domaine aura une chance d'être largement adopté. Les auteurs estiment cependant que certains vaccins candidats pourront satisfaire à ces exigences.

Las actuales vacunas antirrábicas son seguras y, si se administran debidamente, muy eficaces. Además, inducen inmunidad duradera, con títulos de anticuerpos neutralizantes que subsisten años después de la vacunación. Sin embargo, los regímenes actuales resultan costosos y exigen dosis múltiples para lograr títulos de neutralización elevados, lo que dificulta a los países en desarrollo, que son los más golpeados por la rabia, la implantación generalizada de la vacunación. El único camino para reducir la rabia a niveles aceptables pasa por la innovación. Están en marcha numerosos estudios preclínicos y clínicos en los que se ensayan vacunas, adyuvantes y métodos de inyección novedosos. También sigue adelante la investigación sobre el uso de vacunas vivas y vectores vacunales alternativos, mientras que ninguna de las tentativas realizadas hasta la fecha con vacunas de ADN ha deparado niveles de inmunogenicidad y capacidad de neutralización equiparables a los de las vacunas tradicionales. La obtención de adyuvantes moleculares que inducen una respuesta inmunitaria más rápida y vigorosa en presencia de menos cantidad de antígeno ha dado resultados preclínicos muy interesantes y poco a poco parece acercarnos al logro de una mejor vacuna antirrábica. Subsisten, empero, arduas dificultades: los adyuvantes moleculares solo funcionan si se administran con vacunas vivas, y las diferencias existentes entre las especies en cuanto a la especificidad de las moléculas inmunitarias complican las labores de desarrollo. Globalmente, el conjunto de investigaciones emprendidas en el último decenio es impresionante y alentador, pero la mayoría de las nuevas vacunas aún deben pasar por la fase de ensayo clínico, y está por ver qué viabilidad tienen estas vacunas experimentales en el mercado mundial. Solo una vacuna que supere a las actuales en todos los aspectos tiene posibilidades de ser adoptada a gran escala. Pese a todo, los autores expresan su confianza en que algunas de las vacunas candidatas cumplan estos criterios.

Impact of the Spinal Instability Neoplastic Score on Surgical Referral Patterns and Outcomes.

BACKGROUND: The Spinal Instability Neoplastic Score (sins) was developed to identify patients with spinal metastases who may benefit from surgical consultation. We aimed to assess the distribution of sins in a population-based cohort of patients undergoing palliative spine radiotherapy (rt) and referral rates to spinal surgery pre-rt. Secondary outcomes included referral to a spine surgeon post-rt, overall survival, maintenance of ambulation, need for re-intervention, and presence of spinal adverse events. METHODS: We retrospectively reviewed ct simulation scans and charts of consecutive patients receiving palliative spine rt between 2012 and 2013. Data were analyzed using Student's t-test, Chi-squared, Fisher's exact, and Kaplan-Meier log-rank tests. Patients were stratified into low (<7) and high (≥7) sins groups. RESULTS: We included 195 patients with a follow-up of 6.1 months. The median sins was 7. The score was 0 to 6 (low, no referral recommended), 7 to 12 (intermediate, consider referral), and 13 to 18 (high, referral suggested) in 34%, 59%, and 7% of patients, respectively. Eleven patients had pre-rt referral to spine surgery, with a surgery performed in 0 of 1 patient with sins 0 to 6, 1 of 7 with sins 7 to 12, and 1 of 3 with sins 13 to 18. Seven patients were referred to a surgeon post-rt with salvage surgery performed in two of those patients. Primary and secondary outcomes did not differ between low and high sins groups. CONCLUSION: Higher sins was associated with pre-rt referral to a spine surgeon, but most patients with high sins were not referred. Higher sins was not associated with shorter survival or worse outcome following rt.

The differential effects of norepinephrine and dopamine on cerebrospinal fluid pressure and spinal cord perfusion pressure after acute human spinal cord injury.

STUDY DESIGN: Prospective vasopressor cross-over interventional studyObjectives:To examine how two vasopressors used in acute traumatic spinal cord injury (SCI) affect intrathecal cerebrospinal fluid pressure and the corresponding spinal cord perfusion pressure (SCPP). SETTING: Vancouver, British Columbia, Canada. METHODS: Acute SCI patients over the age of 17 with cervical or thoracic ASIA Impairment Scale (AIS). A, B or C injuries were enrolled in this study. Two vasopressors, norepinephrine and dopamine, were evaluated in a 'crossover procedure' to directly compare their effect on the intrathecal pressure (ITP). The vasopressor cross-over procedures were performed in the intensive care unit where ITP, mean arterial pressure (MAP) and heart rate were being continuously measured. The SCPP was calculated as the difference between MAP and ITP. RESULTS: A total of 11 patients were enrolled and included in our analysis. There were 6 patients with AIS A, 3 with AIS B and 2 with AIS C injuries at baseline. We performed 24 cross-over interventions in these 11 patients. There was no difference in MAP with the use of norepinephrine versus dopamine (84±1 mm Hg for both; P=0.33). Conversely, ITP was significantly lower with the use of norepinephrine than with dopamine (17±1 mm Hg vs 20±1 mm Hg, respectively, P<0.001). This decrease in ITP with norepinephrine resulted in an increased SCPP during the norepinephrine infusion when compared with dopamine (67±1 mm Hg vs 65±1 mm Hg respectively, P=0.0049). CONCLUSION: Norepinephrine was able to maintain MAP with a lower ITP and a correspondingly higher SCPP as compared with dopamine in this study. These results suggest that norepinephrine may be preferable to dopamine if vasopressor support is required post SCI to maintain elevated MAPs in accordance with published guidelines.

The impact of postmastectomy and regional nodal radiation after neoadjuvant chemotherapy for clinically lymph node-positive breast cancer: a National Cancer Database (NCDB) analysis.

BACKGROUND: Following neoadjuvant chemotherapy (NAC), the optimal strategies for postmastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after breast-conserving surgery (BCS) are controversial. In this analysis, we evaluate the impact of these radiotherapy (RT) approaches for women with clinically node-positive breast cancer treated with NAC in the National Cancer Database (NCDB). PATIENTS AND METHODS: Women with cT1-3 cN1 M0 breast cancer treated with NAC were divided into four cohorts by surgery [Mastectomy (Mast) versus BCS] and post-chemotherapy pathologic nodal status (ypN0 versus ypN+). Overall survival (OS) was estimated using the Kaplan-Meier method and RT approaches were analyzed using the log-rank test, multivariate Cox models, and propensity score-matched analyses. RESULTS: From 2003 to 2011, 15 315 cases were identified including 3040 Mast-ypN0, 7243 Mast-ypN+, 2070 BCS-ypN0, and 2962 BCS-ypN+ patients. On univariate analysis, PMRT was associated with improved OS for both Mast-ypN0 (P = 0.019) and Mast-ypN+ (P < 0.001) patients. On multivariate analyses adjusted for factors including age, comorbidity score, cT stage, in-breast pathologic complete response, axillary surgery, ypN stage, estrogen receptor status and hormone therapy, PMRT remained independently associated with improved OS among Mast-ypN0 [hazard ratio (HR) = 0.729, 95% confidence interval (CI) 0.566-0.939, P = 0.015] and Mast-ypN+ patients (HR = 0.772, 95% CI 0.689-0.866, P < 0.001). No differences in OS were observed with the addition of RNI to breast RT for BCS-ypN0 or BCS-ypN+ patients. Propensity score-matched analyses demonstrated identical patterns of significance. On subset analysis, OS was improved with PMRT in each pathologic nodal subgroup (ypN0, ypN1, and ypN2-3) (all P < 0.05). CONCLUSIONS: In the largest reported analysis of RT for cN1 patients treated with NAC, PMRT was associated with improved OS for all pathologic nodal subgroups. No OS differences were observed with the addition of RNI to breast RT.

Sensitivity of blood and tissue diagnostics for gastrointestinal cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: Gastrointestinal (GI) cytomegalovirus (CMV) disease is the most common manifestation of tissue-invasive CMV infection in solid organ transplant (SOT) recipients, but the diagnostic yields of blood and tissue testing have not been systematically assessed in a large patient cohort. METHODS: We retrospectively identified consecutive SOT recipients with biopsy-confirmed GI CMV disease who had both tissue and blood (CMV polymerase chain reaction or antigenemia) diagnostic testing performed within 14 days of diagnosis. Descriptive statistics and logistic regression were used to assess the association between patient factors and viremia and the diagnostic yield of tests performed on biopsy specimens. RESULTS: A total of 101 patients (73% donor seropositive/recipient seronegative [D+/R-], 22% recipient seropositive [R+]) had GI CMV disease (58% upper, 22% lower, and 20% both) at a median of 185 days (range, 21-6345 days) post transplant. In multivariate analysis, R+ CMV serostatus (odds ratio [OR] 0.1 [0.0-0.4], P < 0.001) and diagnosis >6 months post transplant (OR 0.3 [0.1-0.9], P = 0.03) were each independently associated with absence of CMV viremia at time of diagnosis. In the subset of patients (n = 29) in whom both histopathology and viral culture were performed on biopsy specimens, 11 (39%) had CMV detected only by culture and had similar clinical characteristics and outcomes to those with positive histopathology (P > 0.05 for all comparisons). CONCLUSIONS: The sensitivity of viremia in SOT recipients with GI CMV disease is significantly lower in CMV-seropositive patients and in those >6 months post transplant. Addition of viral culture to endoscopic biopsy specimens significantly increases the diagnostic yield for GI CMV disease.

Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens.

AIMS: To demonstrate standardized methods for spiking pathogens into human matrices for evaluation and comparison among diagnostic platforms. METHODS AND RESULTS: This study presents detailed methods for spiking bacteria or protozoan parasites into whole blood and virus into plasma. Proper methods must start with a documented, reproducible pathogen source followed by steps that include standardized culture, preparation of cryopreserved aliquots, quantification of the aliquots by molecular methods, production of sufficient numbers of individual specimens and testing of the platform with multiple mock specimens. Results are presented following the described procedures that showed acceptable reproducibility comparing in-house real-time PCR assays to a commercially available multiplex molecular assay. CONCLUSIONS: A step by step procedure has been described that can be followed by assay developers who are targeting low prevalence pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: The development of diagnostic platforms for detection of low prevalence pathogens such as biothreat or emerging agents is challenged by the lack of clinical specimens for performance evaluation. This deficit can be overcome using mock clinical specimens made by spiking cultured pathogens into human matrices. To facilitate evaluation and comparison among platforms, standardized methods must be followed in the preparation and application of spiked specimens.

Disparities in disease presentation in the four screenable cancers according to health insurance status.

OBJECTIVES: Current guidelines support the use of screening for early detection in breast, prostate, colorectal and cervical cancer. The purpose of this study was to evaluate whether insurance status predicts for more advanced disease in these four currently screened cancers. STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) database was queried for breast, prostate, colorectal and cervix in patients aged 18-64 years. The database was queried from 2007 to 2011, with 425,614 patients with known insurance status included. METHODS: Multinomial logistic regression was used to evaluate insurance status and cancer presentation. RESULTS: Under multivariate analysis for breast cancer, uninsured patients more often had invasive disease (odds ratio [OR]: 1.55), T- (OR: 2.00), N- (OR: 1.59) stage, and metastatic disease (OR: 3.48), and were more often high-grade (OR: 1.21). For prostate cancer, uninsured patients again presented more commonly with higher T-stage (OR: 1.45), nodal (OR: 2.90) and metastatic (OR: 4.98) disease, in addition to higher prostate-specific antigen (OR: 2.85) and Gleason score (OR: 1.65). Colorectal cancer had similar findings with uninsured individuals presenting with more invasive disease (OR: 1.78), higher T (OR: 1.86), N (OR: 1.22), and M (OR: 1.58) stage, in addition to higher carcinoembryonic antigen levels (OR: 1.66). Similar results were seen for cervical cancer with uninsured having higher T (OR: 2.03), N (OR: 1.21), and M (OR: 1.45) stage. CONCLUSION: In the four cancers detected by screening exams, those without health insurance present with more advanced disease, with higher stage and grade, and more elevated tumour markers.

Surgical treatment of gastrointestinal stromal tumour of the rectum in the era of imatinib.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) of the rectum often require radical surgery to achieve complete resection. This study investigated the management and outcome of surgery for rectal GISTs and the role of imatinib. METHODS: A cohort study was undertaken of patients identified from a database at one tertiary sarcoma referral centre over a continuous period, from January 2001 to January 2013. RESULTS: Over 12 years, 19 patients presented with a primary rectal GIST. Median age was 57 (range 30-77) years. Neoadjuvant imatinib was used in 15 patients, significantly reducing mean tumour size from 7·6 (95 per cent c.i. 6·1 to 9·0) to 4·1 (2·8 to 5·3) cm (P < 0·001). Nine of these patients underwent surgical resection. Imatinib therapy enabled sphincter-preserving surgery to be undertaken in seven patients who would otherwise have required abdominoperineal resection or pelvic exenteration for tumour clearance. Neoadjuvant imatinib treatment also led to a significant reduction in mean(s.d.) tumour mitotic count from 16(16) to 4(9) per 50 high-power fields (P = 0·015). Imatinib was used only as adjuvant treatment in two patients. There were three deaths, all from unrelated causes. Eleven of the 13 patients who underwent resection were alive without evidence of recurrence at latest follow-up, with a median disease-free survival of 38 (range 20-129) months and overall survival of 62 (39-162) months. CONCLUSION: The use of neoadjuvant imatinib for rectal GISTs significantly decreased both tumour size and mitotic activity, which permitted less radical sphincter-preserving surgery.