tbuckley/cabot-search huggingface dataset:
Comparing bivalent and quadrivalent human papillomavirus vaccines: economic evaluation based on transmission model
Authors: M. Jit, R. Chapman, O. Hughes, Y. H. Choi
Journal: BMJ (2011)

<b>Objectives</b> To compare the effect and cost effectiveness of bivalent and quadrivalent human papillomavirus (HPV) vaccination, taking into account differences in licensure indications, protection against non-vaccine type disease, protection against disease related to HPV types 6 and 11, and reported long term immunogenicity. <b>Design</b> A model of HPV transmission and disease previously used to inform UK vaccination policy, updated with recent evidence and expanded to include scenarios where the two vaccines differ in duration of protection, cross protection, and end points prevented. <b>Setting</b> United Kingdom. <b>Population</b> Males and females aged 12–75 years. <b>Main outcome measure</b> Incremental cost effectiveness ratios for both vaccines and additional cost per dose for the quadrivalent vaccine to be equally cost effective as the bivalent vaccine. <b>Results</b> The bivalent vaccine needs to be cheaper than the quadrivalent vaccine to be equally cost effective, mainly because of its lack of protection against anogenital warts. The price difference per dose ranges from a median of £19 (interquartile range £12–£27) to £35 (£27–£44) across scenarios about vaccine duration, cross protection, and end points prevented (assuming one quality adjusted life year (QALY) is valued at £30 000 and both vaccines can prevent all types of HPV related cancers). <b>Conclusions</b> The quadrivalent vaccine may have an advantage over the bivalent vaccine in reducing healthcare costs and QALYs lost. The bivalent vaccine may have an advantage in preventing death due to cancer. However, considerable uncertainty remains about the differential benefit of the two vaccines.
Dopamine: Go/No-Go motivation versus switching
Authors: Robert D. Oades
Journal: Behavioral and Brain Sciences (1999)

Sensitivity to incentive motivation has a formative influence on extraversion. Mesoamygdaloid dopamine (DA) activity may, at one level, act as a micro-gate permitting an incentive to influence behavioral organization – “Go/No-Go” in this scheme. Data on function elsewhere in the mesocorticolimbic DA system are taken to support this particular function. At another level of analysis, the data in Depue &amp; Collins's review, along with those on the rest of the ventral tegmental area (VTA) system, may fit better with a “switching” function in information processing. This link is supported by correlations between measures of extraversion, learned inattention, and overall DA activity. The point is extended to the novelty-seeking feature of the extraverted personality.
Treatment of Brain Metastases
Authors: Xuling Lin, Lisa M. DeAngelis
Journal: Journal of Clinical Oncology (2015)

Brain metastases (BMs) occur in 10% to 20% of adult patients with cancer, and with increased surveillance and improved systemic control, the incidence is likely to grow. Despite multimodal treatment, prognosis remains poor. Current evidence supports use of whole-brain radiation therapy when patients present with multiple BMs. However, its associated cognitive impairment is a major deterrent in patients likely to live longer than 6 months. In patients with oligometastases (one to three metastases) and even some with multiple lesions less than 3 to 4 cm, especially if the primary tumor is considered radiotherapy resistant, stereotactic radiosurgery is recommended; if the BMs are greater than 4 cm, surgical resection with or without postoperative whole-brain radiation therapy should be considered. There is increasing evidence that systemic therapy, including targeted therapy and immunotherapy, is effective against BM and may be an early choice, especially in patients with sensitive primary tumors. In patients with progressive systemic disease, limited treatment options, and poor performance status, best supportive care may be appropriate. Regardless of treatment goals, use of corticosteroids or antiepileptic medications is helpful in symptomatic patients. In this review, we provide a summary of current therapy, as well as developments in the treatment of BM from solid tumors.
Haplotype-Sharing Analysis Showing Uyghurs Are Unlikely Genetic Donors
Authors: S. Xu, W. Jin, L. Jin
Journal: Molecular Biology and Evolution (2009)

The Uyghur (UIG) are a group of people primarily residing in Xinjiang of China, which is geographically located in Central Asia, from where modern humans were presumably spread in all directions reaching Europe, east, and northeast Asia about 40 kya. A recent study suggested that the UIG are ancestry donors of the East Asian (EAS) gene pool. However, an alternative hypothesis, that is, the UIG is an admixture population with both EAS and EUR ancestries is also supported by our previous studies. To test the two competing hypotheses, here we conducted a haplotype-sharing analysis (HSA) based on empirical and simulated data of high-density single nucleotide polymorphisms. Our results showed that more than 95% of UIG haplotypes could be found in either EAS or EUR populations, which contradicts the expectation of the null models assuming that UIG are donors. Simulation studies further indicated that the proportion of UIG private haplotypes observed in empirical data is only expected in alternative models assuming that UIG is an admixture population. Interestingly, the estimated ancestry contribution of 44%:56% (EAS:EUR) based on HSA is consistent with our previous estimation with STRUCTURE analysis. Although the history of UIGs could be complex, our method is explicit and conservative in rejecting the null hypothesis. We concluded that the gene pool of modern UIGs is more likely a sole recipient with contribution from both EAS and EUR.
Trends in treatment and outcomes of pediatric craniopharyngioma, 1975-2011
Authors: M. Cohen, U. Bartels, H. Branson, A. V. Kulkarni, J. Hamilton
Journal: Neuro-Oncology (2013)

Craniopharyngioma tumors and their treatment can lead to significant long-term morbidity due to their proximity to vital structures. The optimal treatment has been debated for many years. We aimed to review the long-term outcomes of children treated for craniopharyngioma in our institution over the past decade and describe trends in treatment and outcomes over the past 3 decades.Charts of children with craniopharyngioma treated and followed at The Hospital for Sick Children between 2001 and 2011 were reviewed. Data regarding findings at diagnosis, treatment, and long-term outcomes were analyzed. Comparison was made with previously published data from our institution.Data from 33 patients are included; mean age at treatment, 10.7 ± 4.8 years. In 18 children (55%), the initial surgical approach was tumor cyst decompression with or without adjuvant therapy, compared with only 0-2% in the preceding decades (P < .01). Diabetes insipidus occurred in 55% of children and panhypopituitarism in 58% compared with 88% (P < .01) and 86% (P < .01), respectively, in the previous 10 years. Overall, there was a 36% reduction in the number of children who developed severe obesity compared with the preceding decade. Body mass index at follow-up was associated with body mass index at diagnosis (P = .004) and tumor resection as an initial treatment approach (P = .028).A shift in surgical treatment approach away from gross total resection has led to improved endocrine outcomes. This may have beneficial implications for quality of life in survivors.
Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab
Authors: Jeonghee Cho, Adam J Bass, Michael S Lawrence, Kristian Cibulskis, Ahye Cho, Shi-Nai Lee, Mai Yamauchi, Nikhil Wagle, Panisa Pochanard, Nayoung Kim, Angela KJ Park, Jonghwa Won, Hyung-Suk Hur, Heidi Greulich, Shuji Ogino, Carrie Sougnez, Douglas Voet, Josep Tabernero, Jose Jimenez, Jose Baselga, Stacey B Gabriel, Eric S Lander, Gad Getz, Michael J Eck, Woong-Yang Park, Matthew Meyerson
Journal: Molecular Cancer (2014)

Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear.We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors.The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.
The urgent need for clinical, diagnostic, and operational research for management of Buruli ulcer in Africa
Authors: Daniel P O'Brien, Eric Comte, Micaela Serafini, Geneviève Ehounou, Annick Antierens, Hubert Vuagnat, Vanessa Christinet, Mitima D Hamani, Philipp du Cros
Journal: The Lancet Infectious Diseases (2013)
Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis
Authors: Volkhard A.J. Kempf, Maria Lebiedziejewski, Kari Alitalo, Joo-Hee Wälzlein, Urs Ehehalt, Jeannette Fiebig, Stephan Huber, Burkhardt Schütt, Christian A. Sander, Steffen Müller, Guntram Grassl, Amir S. Yazdi, Bernhard Brehm, Ingo B. Autenrieth
Journal: Circulation (2005)

Background— Bartonella species are the only known bacterial pathogens causing vasculoproliferative disorders in humans (bacillary angiomatosis [BA]). Cellular and bacterial pathogenetic mechanisms underlying the induction of BA are largely unknown. Methods and Results— Activation of hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in angiogenesis, was detected in Bartonella henselae –infected host cells in vitro by immunofluorescence, Western blotting, electrophoretic mobility shift, and reporter gene assays and by immunohistochemistry in BA tissue lesions in vivo. Gene microarray analysis revealed that a B henselae infection resulted in the activation of genes typical for the cellular response to hypoxia. HIF-1 was essential for B henselae –induced expression of vascular endothelial growth factor as shown by inhibition with the use of HIF-1–specific short-interfering RNA. Moreover, infection with B henselae resulted in increased oxygen consumption, cellular hypoxia, and decreased ATP levels in host cells. Infection with a pilus-negative variant of B henselae did not lead to cellular hypoxia or activation of HIF-1 or vascular endothelial growth factor secretion, suggesting a crucial role of this bacterial surface protein in the angiogenic reprogramming of the host cells. Conclusions— B henselae induces a proangiogenic host cell response via HIF-1. Our data provide for the first time evidence that HIF-1 may play a role in bacterial infections.
Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti–IL-6) in multiple myeloma
Authors: Jesús San-Miguel, Joan Bladé, Ofer Shpilberg, Sebastian Grosicki, Frédéric Maloisel, Chang-Ki Min, Marta Polo Zarzuela, Tadeusz Robak, Sripada V. S. S. Prasad, Yeow Tee Goh, Jacob Laubach, Andrew Spencer, María-Victoria Mateos, Antonio Palumbo, Tom Puchalski, Manjula Reddy, Clarissa Uhlar, Xiang Qin, Helgi van de Velde, Hong Xie, Robert Z. Orlowski
Journal: Blood (2014)
Costs and effectiveness of community postnatal support workers: randomised controlled trial
Authors: C J. Morrell
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objectives:</b> To establish the relative cost effectiveness of postnatal support in the community in addition to the usual care provided by community midwives. <b>Design:</b> Randomised controlled trial with six month follow up. <b>Setting:</b> Recruitment in a university teaching hospital and care provided in women9s homes. <b>Participants:</b> 623 postnatal women allocated at random to intervention (311) or control (312) group. <b>Intervention:</b> Up to 10 home visits in the first postnatal month of up to three hours duration by a community postnatal support worker. <b>Main outcome measure:</b> General health status as measured by the SF-36 and risk of postnatal depression. Breast feeding rates, satisfaction with care, use of services, and personal costs. <b>Results:</b> At six weeks there was no significant improvement in health status among the women in the intervention group. At six weeks the mean total NHS costs were £635 for the intervention group and £456 for the control group (P=0.001). At six months figures were £815 and £639 (P=0.001). There were no differences between the groups in use of social services or personal costs. The women in the intervention group were very satisfied with the support worker visits. <b>Conclusions:</b> There was no health benefit of additional home visits by community postnatal support workers compared with traditional community midwifery visiting as measured by the SF-36. There were no savings to the NHS over six months after the introduction of the community postnatal support worker service.
Renal Function and Risk Stratification of Diabetic and Nondiabetic Patients Undergoing Evaluation for Coronary Artery Disease
Authors: Abdul Hakeem, Sabha Bhatti, Kunal N. Karmali, Kathryn S. Dillie, Jeffrey R. Cook, Jiaqiong Xu, Zainab Samad, Su Min Chang
Journal: JACC. Cardiovascular imaging (2010)
Observations on the Hyponatremia following Mitral Valvulotomy
Authors: ALLAN V. N. GOODYER, WILLIAM W. L. GLENN
Journal: Circulation (1955)

Thirty-seven patients subjected to mitral valvulotomy were studied before and after operation with regard to the incidence, extent, and mechanism of postoperative hyponatremia. Balances of water, sodium, and chloride were carried out on 27 patients. The serum sodium fell below 131 mEq. per liter in 16 cases in the immediate postoperative period, the serum chloride fell below 99 mEq. per liter in all cases but one and below 90 mEq. per liter in 11 cases. The small negative balances of sodium and chloride were inadequate, by themselves, to account for the observed hyponatremia in any case. Appreciable (over 100 mEq.) intracellular shifts of sodium (using the chloride space as a reference) were associated with hyponatremia in only three cases. The retention of water during the immediate postoperative period (allowing for insensible losses) was enough to explain the observed hyponatremia in all but three cases, although the level of fluid intake was not well correlated with the occurrence of hyponatremia. These results indicate the presence of an unusually prolonged antidiuretic stimulus in these patients, the etiology of which remains uncertain. Except in a few cases it is unnecessary to correct the hyponatremia with hypertonic salt, since it is usually a transient, limited, and essentially asymptomatic phenomenon.
How Segmental Duplications Shape Our Genome: Recent Evolution of ABCC6 and PKD1 Mendelian Disease Genes
Authors: O. Symmons, A. Varadi, T. Aranyi
Journal: Molecular Biology and Evolution (2008)

The completion of the Human Genome Project has brought the understanding that our genome contains an unexpectedly large proportion of segmental duplications. This poses the challenge of elucidating the consequences of recent duplications on physiology. We have conducted an in-depth study of a subset of segmental duplications on chromosome 16. We focused on PKD1 and ABCC6 duplications because mutations affecting these genes are responsible for the Mendelian disorders autosomal dominant polycystic kidney disease and pseudoxanthoma elasticum, respectively. We establish that duplications of PKD1 and ABCC6 are associated to low-copy repeat 16a and show that such duplications have occurred several times independently in different primate species. We demonstrate that partial duplication of PKD1 and ABCC6 has numerous consequences: the pseudogenes give rise to new transcripts and mediate gene conversion, which not only results in disease-causing mutations but also serves as a reservoir for sequence variation. The duplicated segments are also involved in submicroscopic and microscopic genomic rearrangements, contributing to structural variation in human and chromosomal break points in the gibbon. In conclusion, our data shed light on the recent and ongoing evolution of chromosome 16 mediated by segmental duplication and deepen our understanding of the history of two Mendelian disorder genes.
Gas exchange during simulated airway secretion in the anaesthetized rabbit
Authors: L Lagerstrand, M Dahlback, G Hedenstierna
Journal: European Respiratory Journal (1992)

We wished to study the effect of airways secretion on gas exchange. Peripheral airway secretion was simulated in 9 rabbits by the continuous inhalation of nebulized isotonic saline, at a droplet size of about 3 microns. Intrapulmonary deposition of saline in the peripheral airways (83% in airways smaller than 0.5 mm) did not alter total inspiratory resistance (mean 5.4 kPa.l-1.s), but led to a decrease in compliance of the total respiratory system from 45.9 to 21.8 ml.kPa-1 after one hour of nebulization. Arterial oxygen tension decreased from 17.8 kPa to 12.1 and 6.9 kPa after 5 and 60 min of nebulization, respectively. PaCO2 was unaffected after 5 min (4.5 kPa) but increased to 7.0 kPa after 60 min of nebulization. Ventilation-perfusion relationships (VA/Q) showed a significant increase in perfusion of areas with low VA/Q ratios (from 0.7 to 6.3% of cardiac output) and in shunt (from 1.4 to 4.3%) after 5 min of nebulization. At the end of the experiment shunt was increased markedly to 29.7% of cardiac output whereas perfusion of low VA/Q regions remained at the same level (7.3%). The results from this animal model indicate that all gas exchange abnormalities known to occur in asthma can be reproduced without measurably increasing the resistance of the respiratory system.
Blood–brain-barriers in aging and in Alzheimer’s disease
Authors: Fernanda Marques, João Carlos Sousa, Nuno Sousa, Joana Almeida Palha
Journal: Molecular Neurodegeneration (2013)

Abstract The aging process correlates with a progressive failure in the normal cellular and organ functioning; these alterations are aggravated in Alzheimer’s disease (AD). In both aging and AD there is a general decrease in the capacity of the body to eliminate toxic compounds and, simultaneously, to supply the brain with relevant growth and nutritional factors. The barriers of the brain are targets of this age related dysfunction; both the endothelial cells of the blood–brain barrier and the choroid plexus epithelial cells of the blood-cerebrospinal fluid barrier decrease their secretory capacity towards the brain and their ability to remove toxic compounds from the brain. Additionally, during normal aging and in AD, the permeability of the brain barriers increase. As such, a greater contact of the brain parenchyma with the blood content alters the highly controlled neural environment, which impacts on neural function. Of interest, the brain barriers are more than mere obstacles to the passage of molecules and cells, and therefore active players in brain homeostasis, which is still to be further recognized and investigated in the context of health and disease. Herein, we provide a review on how the brain barriers change during aging and in AD and how these processes impact on brain function.
Do GLP-1–Based Therapies Increase Cancer Risk?
Authors: Michael A. Nauck, Nele Friedrich
Journal: Diabetes Care (2013)

Cases of pancreatitis have been described in connection with the use of exenatide (1), liraglutide (2) and other glucagon-like peptide (GLP)-1 receptor agonists. From these findings, the following hypothesis has been generated: stimulating the GLP-1 receptor with respective agonists has a potential to cause pancreatitis, perhaps chronic pancreatitis, and in the long term, potentially even pancreatic cancer (3–5). Furthermore, in rodents like mice and rats, stimulating the GLP-1 receptor raises cAMP in thyroid C cells, initiates the release of calcitonin, and upon longer-term exposure, is accompanied by C-cell proliferation and the formation of C-cell adenomas and (medullary thyroid) carcinomas (6). Based on these findings, it was hypothesized that GLP-1–derived medications have a potential to cause medullary thyroid carcinoma in humans as well (3,7). It is the purpose of the current review to discuss the evidence in favor and against the hypothesis that GLP-1–based therapies increase cancer risk, specifically the risk for pancreatic and thyroid carcinomas in patients with type 2 diabetes treated with exenatide and sitagliptin.

In principle, there could be weak or strong evidence, either in favor of or against, the hypothesis that incretin-based medications can increase the risk for pancreatic, (medullary) thyroid, or other carcinomas. For the purpose of this review, GLP-1–based therapies are GLP-1 receptor agonists such as exenatide, liraglutide, and others or dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin (8). However, almost all available data and quoted studies have specifically examined exenatide and sitagliptin, which have been available for the longest time.

The questions of whether certain drugs can cause pancreatitis and whether certain drugs can cause pancreatic carcinoma are interrelated, since chronic pancreatitis increases the risk for pancreatic carcinoma approximately 26-fold compared with subjects not suffering from chronic pancreatitis (9). There is an etiological sequence leading …