tbuckley/cabot-search huggingface dataset:
Exome Sequencing of Familial Bipolar Disorder
Authors: Fernando S. Goes, Mehdi Pirooznia, Jennifer S. Parla, Melissa Kramer, Elena Ghiban, Senem Mavruk, Yun-Ching Chen, Eric T. Monson, Virginia L. Willour, Rachel Karchin, Matthew Flickinger, Adam E. Locke, Shawn E. Levy, Laura J. Scott, Michael Boehnke, Eli Stahl, Jennifer L. Moran, Christina M. Hultman, Mikael Landén, Shaun M. Purcell, Pamela Sklar, Peter P. Zandi, W. Richard McCombie, James B. Potash
Journal: JAMA Psychiatry (2016)

<h3>Importance</h3> Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing. <h3>Objective</h3> To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis. <h3>Design, Setting, and Participants</h3> We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls. <h3>Main Outcomes and Measures</h3> We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets. <h3>Results</h3> We found 84 rare (frequency &lt;1%), segregating variants that were bioinformatically predicted to be damaging. These variants were found in 82 genes that were enriched for gene sets previously identified in de novo studies of autism (19 observed vs. 10.9 expected,<i>P</i> = .0066) and schizophrenia (11 observed vs. 5.1 expected,<i>P</i> = .0062) and for targets of the fragile X mental retardation protein (FMRP) pathway (10 observed vs. 4.4 expected,<i>P</i> = .0076). The case-control meta-analyses yielded 19 genes that were nominally associated with BD based either on individual variants or a gene-burden approach. Although no gene was individually significant after correction for multiple testing, this group of genes continued to show evidence for significant enrichment of de novo autism genes (6 observed vs 2.6 expected,<i>P</i> = .028). <h3>Conclusions and Relevance</h3> Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD.
Central pulmonary arteries in idiopathic pulmonary fibrosis: size really matters
Authors: Laura C. Price, Anand Devaraj, S. John Wort
Journal: European Respiratory Journal (2016)

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias and is often associated with pulmonary hypertension (PH). The presence of PH has major implications for a patient with IPF in terms of exercise capacity and mortality [1, 2]. Early and accurate detection of PH is therefore important for prognostication, timing of referral for transplantation and possible entry into clinical trials. The gold standard investigation for confirming PH in this population, as in any patient, remains right heart catheterisation (RHC). However, performing RHC in patients with IPF is not without risk in what is an older population, often with serious comorbidities. Informed referral for RHC, based on clinical signs and noninvasive tests suggestive of PH, is therefore desirable. Unfortunately, clinical signs of PH are often unreliable in patients with any chronic respiratory disease, let alone IPF, and standard tests such as echocardiography can be surprisingly inaccurate [3, 4]. There remains the need, therefore, to further interrogate noninvasive methods of detection of PH in patients with chronic respiratory disease, including IPF. The concept that the size of the pulmonary artery (PA) derived from a computed tomography (CT) scan might predict the presence of PH and even determine outcome in patients with IPF, as suggested by Shin et al. [5] in this issue of the European Respiratory Journal , is therefore very appealing and potentially widely applicable. Despite the uncertainties of why, when it comes to PH risk in IPF, pulmonary artery size clearly matters <http://ow.ly/YlKVy>
Phase II trial of nilotinib as third-line therapy for gastrointestinal stromal tumor (GIST) patients in Japan.
Authors: T. Nishida, A. Sawaki, T. Doi, Y. Yamada, Y. Komatsu, T. Kanda, Y. Kakeji, Y. Onozawa, M. Yamasaki, A. Ohtsu
Journal: Journal of Clinical Oncology (2010)

10015 Background: Patients with GIST resistant to both imatinib (IM) and sunitinib (SU) have a poor prognosis and few therapeutic options. The objective of this study is to investigate efficacy and safety of nilotinib as a third line therapy for Japanese GIST pts who have shown resistance and/or intolerance to imatinib and sunitinib. Methods: A single arm, open-label trial was conducted in 8 hospitals in Japan. The key eligibility criteria included histologically confirmed KIT-positive GIST and progression on or intolerance to both imatinib and sunitinib treatment. Pts were treated with nilotinib 400 mg b.i.d. The primary endpoint was disease control rate defined as rates of CR + PR + SD (lasting at least 24 weeks) assessed by central reviewers based on RECIST criteria. Registered with Clinical Trials.gov, number NCT00718562 and sponsored by Novartis Pharmaceuticals. Results: Among the 35 pts enrolled between Sep 2008 and Apr 2009, 26 (74.3%) were resistant to both IM and SU, 6 (17.1%) IM-resistant and SU-intolerant, 2 (5.7%) IM- intolerant and SU-resistant, and the remaining 1 (2.9%) intolerant to both. The median prior maximum doses were 400 mg (≥600 mg for 16/35 pts) for IM and 50 mg (50 mg for 34/35 pts) for SU. The median age was 57 years (range 26 - 76) and 22 (62.9%) pts were male. The most common primary sites of GIST were the small intestine (21 [60.0%] pts) and stomach (11 [31.4%] pts). The median exposure to nilotinib was 120 days (range 5-316) at the time of data cut-off (02Oct2009). Disease control rate at 24 weeks was 28.6% (90% CI ; [16.4%, 43.6%]). The median PFS was 113 days. The median OS was 310 days. The objective response rate was obtained for 2.9% with 1 PR pt who carried GIST with KIT mutations in exon 11 (dup 567 - 576) and exon 17 (D820G) after resistance to both imatinib and sunitinib, and 23 pts (65.7%) had SD as the best response. Nilotinib was well tolerated; the most common treatment-related AEs of any grade were nausea, vomiting, hyperbilirubinemia and appetite loss (28.6% each). No patients developed grade 3-4 hematological toxicities except for anemia (5.7%). Conclusions: These results suggest that nilotinib is effective in Japanese GIST pts who failed both imatinib and sunitinib and well tolerated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharmaceutical, Novartis, Pfizer, sanofi-aventis Tsumura Co. Daiichi Sankyo, Kyowa Hakko Kirin, Novartis, Taiho Pharmaceutical, Wyeth, Yakult Honsha
Authors’ reply to Ninan and Millar and Abou-saleh
Authors: Kevin M O’Shaughnessy, Lucinda Kennard
Journal: BMJ (2016)

Ninan highlights the importance of frailty in the context of treatment for hypertension.1 2 We did not intend to give the impression that “one size fits all.” We agree that an individualised approach is needed in all cases, with a balance being struck between the need to reduce cardiovascular risk versus the risk, for example, of falls from postural hypotension. With respect to evidence for treatment of hypertension in the frail elderly, we highlight the following:
Cell-Mediated Immune Responses of Breast Cancer Patients to Autologous Tumor-Associated Antigens2
Authors: J. H. Dean, J. L. McCoy, G. B. Cannon, C. M. Leonard, E. Perlin, A. Kreutner, R. K. Oldham, R. B. Herberman
Journal: JNCI Journal of the National Cancer Institute (1977)

Lymphocyte proliferation assays with autologous tumor material in mixed leukocyte-tumor interactions (MLTI) were employed to monitor tumor-associated cell-mediated immune responses of peripheral blood lymphocytes from patients with carcinoma of the breast. In addition, leukocyte migration inhibition (LMI) assays were employed to compare reactivity to autologous breast-tumor extracts versus allogeneic breast-tumor extracts. Positive lymphoproliferative responses to tumor-associated antigens (TAA) were observed in the MLTI assay with the use of either intact autologous tumor cells or crude extracts (in mug and ng quantities) in 12 of 34 (35%) breast cancer patients studied. Positive reactivity to tumor, but not to normal tissue of reactive patients, was observed in repeated assays. Finally, patients demonstrating positive MLTI responses to autologous tumor extracts likewise responded in LMI assays to these same autologus extracts as well as to allogeneic breast-tumor extracts, but not to non-breast-tumor extracts. Thus breast tumors appeared to possess common TAA among both male and female patients.
A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy
Authors: Courtney DiNardo, Daniel Pollyea, Keith Pratz, Michael J. Thirman, Anthony Letai, Mark Frattini, Brian Jonas, Joel Leverson, Ming Zhu, Martin Dunbar, Nancy Falotico, Rachel Kirby, Suresh Agarwal, Mack Mabry, Jalaja Potluri, Rod A. Humerickhouse, Hagop M. Kantarjian, Marina Konopleva
Journal: Blood (2015)
Concordance between central and local lab IHC and FISH HER2 testing in a community-based trial of first-line trastuzumab plus a taxane in HER2+ metastatic breast cancer (MBC)
Authors: S. Anderson, J. C. Reddy, S. Rai, G. Lieberman, P. Klein
Journal: Journal of Clinical Oncology (2004)

9580 Background: Trastuzumab (Herceptin®, H) is a humanized monoclonal antibody which showed a significant survival benefit in a randomized trial comparing chemotherapy plus H vs. chemotherapy alone in patients (pts) with MBC whose HER2 status was determined by immunohistochemistry (IHC). Retrospective analysis of this trial showed that the survival benefit was limited to pts who tested HER2+ by fluorescence in situ hybridization (FISH). We report concordance results between local lab (LL) and central lab (CL) HER2 testing from this phase IV study of H plus a taxane in MBC. Methods: 1269 pts were screened and 401 pts were enrolled. Pts with LL FISH+ or IHC 3+ scores were enrolled immediately and confirmatory tests were done at the CL. Pts with LL IHC 0–2+ or FISH- scores had samples tested at the CL and were enrolled on the basis of CL FISH+ or IHC 3+ status. All enrolled pts received H weekly combined with either paclitaxel or docetaxel. Results: Concordance between LL IHC scores and CL IHC and FISH scores is shown below. Concordance was low for LL IHC2+ samples; these also had a substantial rate of FISH+ results at the CL. The overall response rate (ORR=CR+PR) for the 352 evaluable pts was 49% (95% CI, 44–55%). For CL FISH+ pts (n=241) the ORR was 51% (95% CI, 45–58%) and for CL FISH- pts (n=67) it was 42% (95% CI, 30–54%). Conclusions: LL IHC testing had variable reproducibility. LL IHC 2+ specimens were the least concordant with CL results (26%); in addition 32% of LL IHC 2+ specimens tested CL FISH+. This is in agreement with the NCCN recommendation that IHC 2+ specimens be retested by FISH to determine HER2 status. This data shows that patients selected by FISH respond to treatment with taxane/H, and since taxane/H has been shown to confer a survival benefit, it is critical that we identify patients for treatment with H using appropriate testing methods. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc.; Laboratory Corp. of America Genentech, Inc.; Laboratory Corp. of America Genentech, Inc.; Laboratory Corp. of America
The cytotoxicity of select neutrophils in breast cancer patients and the role of chemokines in neutrophil cytotoxicity.
Authors: Elizabeth Anne Comen, Zvika Granot, Brian Blum, Courtney Coker, Riddhi Shah, Eileen Koh, Larry Norton, Robert Benezra
Journal: Journal of Clinical Oncology (2013)

e22148 Background: Recent research in murine breast cancer models demonstrates that primary breast tumors can mobilize select neutrophils, which have the unique capacity to inhibit metastatic seeding in the lung through cell-kill mechanisms. (Granot Z et al. Cancer Cell. 2010). In both breast cancer patients and healthy women, we investigated whether neutrophils were cytotoxic to breast cancer cell lines. We also assessed whether serum chemokines were associated with neutrophil cytotoxicity. Methods: Neutrophils were purified from the blood of 59 randomly selected newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 50 metastatic breast cancer patients, 15 DCIS patients, and 45 healthy female volunteers with no history of cancer. Cytotoxicity was evaluated by incubating neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity was measured as a reflection of % cytotoxicity. Serum was also isolated from breast cancer patients and healthy volunteers. Millipore Milliplex Human Cytokine Plex Kit was used to assess the concentration of 42 different chemokines in each of the serum samples. Results: In comparison to healthy volunteers whose mean neutrophil cytotoxicity to MDA-MB-231 cells was 6.5%, pre-operative breast cancer patients demonstrated a mean neutrophil cytotoxicity of 13.4%, p&lt;0.0001, metastatic patients mean neutrophil cytotoxicity was 19.4%, p &lt;0.003 and DCIS patients had a mean neutrophil cytotoxicity of 11.7%. p &lt;0.01. By Kruskal-Wallist test, the relative concentrations of three chemokines, Il.1a, MCP.1 and TNF-a, were found to have a statistically significant association with neutrophil cytotoxicity (p-value: 0.005, 0.002, 0.0005 respectively). Conclusions: Our work demonstrates the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with neutrophils from healthy women. We further demonstrate that select chemokines appear to be correlated with neutrophil cytotoxicity, in varying concentrations. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils as well as the role of chemokines in neutrophil cytotoxicity.
Mast Cell-Derived PAI-1 Promotes Airway Inflammation and Remodeling in a Murine Model of Asthma*****
Authors: Ara Jo, Sun Hye Lee, Dong-Young Kim, Hyun Young Koo, Dae Woo Kim, Mesut Eren, Douglas E. Vaughan, Seong Ho Cho
Journal: Journal of Allergy and Clinical Immunology (2016)
Laser Speckle Imaging to Monitor Microvascular Blood Flow: A Review
Authors: Pedro G. Vaz, Anne Humeau-Heurtier, Edite Figueiras, Carlos Correia, Joao Cardoso
Journal: IEEE Reviews in Biomedical Engineering (2016)

Laser speckle is a complex interference phenomenon that can easily be understood, in concept, but is difficult to predict mathematically, because it is a stochastic process. The use of laser speckle to produce images, which can carry many types of information, is called laser speckle imaging (LSI). The biomedical applications of LSI started in 1981 and, since then, many scientists have improved the laser speckle theory and developed different imaging techniques. During this process, some inconsistencies have been propagated up to now. These inconsistencies should be clarified in order to avoid errors in future works. This review presents a review of the laser speckle theory used in biomedical applications. Moreover, we also make a review of the practical concepts that are useful in the construction of laser speckle imagers. This study is not only an exposition of the concepts that can be found in the literature but also a critical analysis of the investigations presented so far. Concepts like scatterers velocity distribution, effect of static scatterers, optimal speckle size, light penetration angle, and contrast computation algorithms are discussed in detail.
Abstract 113: The Benign Nature of Therapeutic Hypothermia--Induced Long QTc
Authors: Daniel Weitz, Brian Greet, Robert Roswell, Scott A Bernstein, Jeffrey S Berger, Douglas S Holmes, Neil Bernstein, Anthony Aizer, Larry Chinitz, Norma M Keller
Journal: Circulation (2011)

Introduction: Therapeutic hypothermia (TH) can prolong the QT interval, however, this is generally not associated with Torsade de pointes (TdP). We hypothesize that the danger of the lengthened QTc...
GP inspections are damaging patient care, shows practice survey
Authors: Jacqui Wise
Journal: BMJ (2016)

England’s inspection programme for GP surgeries is having a damaging effect on patient care, with NHS resources wasted on employing extra locums and staff, a survey by the BMA has found.

Over 1900 general practices in England responded to the survey, which asked a range of questions covering practices’ experience of Care Quality Commission (CQC) inspections. Some 62% of the practices had undergone an inspection under the Ofsted-style rating system, which was launched in October 2014.1

In the survey 80% of practices reported that preparing for a CQC inspection had resulted in less time available …
Do invitations for cervical screening provide sufficient information to enable informed choice? A cross-sectional study of invitations for publicly funded cervical screening
Authors: Sie Karen Kolthoff, Mie Sara Hestbech, Karsten Juhl Jørgensen, John Brodersen
Journal: Journal of the Royal Society of Medicine (2016)

To investigate whether invitations for publicly funded cervical screening provide sufficient information to enable an informed choice about participation.Cross-sectional study using a checklist of 23 information items on benefits and harms from cervical screening and the risks related to cervical cancer.Invitations to publicly funded cervical screening in 10 Scandinavian and English-speaking countries.Ten Scandinavian and English speaking countries.Sixteen screening units representing 10 Scandinavian and English speaking countries.Number of information items presented in invitations for cervical screening.We contacted 21 coordinating units from 11 countries and 20 (95%) responded. Of these, four units did not issue invitations, but the remaining 16 coordinating units in 10 different countries supplied a sample. The invitations for cervical screening were generally information poor and contained a median of only four out of 23 information items possible (17%), ranging from 0 to 12 (0-52%). The most important harms of cancer screening, overdiagnosis and overtreatment, were typically downplayed or unmentioned. The same applied to other important harms, such as false-positive results and the psychological consequences from an abnormal test result. The majority of invitations took a paternalistic approach. While only two invitations (17%) included a pre-assigned appointment date, eight (70%) of the invitations contained strong appeals for participation.Invitations to cervical cancer screening were information poor and biased in favour of participation. This means that informed choice is not possible, which is in conflict with modern requirements for personal involvement in medical decisions.
TCTAP C-183 Acute Stroke Endovascular Intervention with Emergent Carotid Artery Stenting 22.5 Hours After Symptom Onset - Emphasizing the Importance of Brain Perfusion CT for Case Selection
Authors: Mu-Yang Hsieh, Wei-Jen Wang, Boon Lead Tee
Journal: Journal of the American College of Cardiology (2016)
Abstract 2819: Cross-correlation Analysis of Myocardial Velocity is Superior to Conventional Time-to-Peak Parameters for Quantifying Left Ventricular Dyssynchrony
Authors: Brandon K Fornwalt, Takeshi Arita, Mohit Bhasin, George Voulgaris, John D Merlino, Angel R León, Derek A Fyfe, John N Oshinski
Journal: Circulation (2007)

Background- A recent study showed that the most commonly used Tissue Doppler imaging (TDI) parameters to diagnose left ventricular dyssynchrony agree only 50% of the time. Most of these parameters require calculation of the ``time-to-peak” myocardial velocity. This ``time-to-peak” based analysis utilizes only one of &gt;100 data points collected per heart cycle. Methods- We developed and tested a new dyssynchrony parameter, cross-correlation delay (XCD), that utilizes all velocity data points from 3 consecutive beats (~420 points). We hypothesized that XCD would be superior to existing methods at diagnosing dyssynchrony. We tested XCD on 11 members of a positive control group (echocardiographic responders to cardiac resynchronization therapy) and 12 members of a negative control group (normal echocardiogram and 12-lead ECG). We compared XCD to septal-to-lateral delay in time-to-peak (SLD), maximum difference in the basal 2- or 4-chamber times-to-peak (MaxDiff) and standard deviation of the 12 basal and mid-wall times-to-peak (Ts-SD). Results- An XCD threshold of 31ms discriminated between positive and negative controls with 100% sensitivity and specificity (Figure 1 ). SLD, MaxDiff and Ts-SD showed sensitivities of 36, 55 and 100% and specificities of 50, 42 and 50%, respectively. ROC analysis showed XCD and Ts-SD were superior to SLD and MaxDiff in discriminating between positive and negative controls (p&lt;0.01). XCD was the only parameter which decreased after resynchronization in the positive controls (from 160±88ms to 69±61ms, p=0.003). Conclusion- XCD is superior to existing parameters at discriminating patients with LV dyssynchrony from those with normal function. Figure 1. XCD shows the greatest discrimination between positive and negative controls. Dyssynchrony values for each positive control are shown as x’s and values for each negative control are shown as circels. Different dyssynchrony parameters are shown in each subplot (A-D). Threshold values to diagnose dyssynchrony are plotted as horizontal lines in each figure. Note that x’s above the threshold line represent false positives while circles below the threshold line represent false negatives.