tbuckley/cabot-search huggingface dataset:
A poisoned bouquet from Peru
Authors: A. Vermorel, N. Issa, F. Gabriel, I. Accoceberry, G. Valenzuela, A.-S. Darrigade, F. Camou
Journal: Clinical Microbiology and Infection (2019)

A 59-year-old woman without any significant medical history (no diabetes, no chronic alcoholism) was admitted to an intensive care unit during a trek in Peru, for acute renal failure and septic shock. Cutaneous necrotic lesions were noted in the arch of her right foot and attributed to a spider bite. Broad-spectrum antibiotics, anidulafungin, inotropic support, mechanical ventilation and renal replacement therapy were started. All microbiological, immunological and radiological tests remained negative. Despite several lines of antibiotics, new necrotic skin lesions were appearing. A skin biopsy revealed vasculitis only, its culture was negative. Four successive surgical debridements failed to control the process and, after 1 month, she was repatriated to France. A new computed tomography scan found a micro-aneurysm on a renal artery, and multiple renal infarcts. Hepatitis B virus serology showed highly positive anti-HBc and anti-HBs. In the event of a periarteritis nodosa, methylprednisolone pulse therapy was initiated with liposomal amphotericin B (started 1 month after first symptoms) and continuation of antibiotics. Twenty-four hours later, she developed a disseminated intravascular coagulation and a fulminant progression of necrotic skin lesions. Despite supportive care, she died of multi-organ failure on the 4th day after admission. Autopsy revealed ischaemic renal, pulmonary and splenic lesions due to multivascular thrombi. Mycological culture yielded an unusual mucorale (see Fig. 1) identified as Apophysomyces ossiformis by sequencing of the complete internal transcribed spacer regions and the D1/D2 region of the large subunit of the ribosomal DNA. Disseminated infections with the Apophysomyces elegans species complex are almost always reported in immunocompetent hosts, after a quickly necrotizing cutaneous infection following traumatic inoculation [[1]Gomes M.Z. Lewis R.E. Kontoyiannis D.P. Mucormycosis caused by unusual Mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species.Clin Microbiol Rev. 2011; 24: 411-445Crossref PubMed Scopus (261) Google Scholar]. The overall mortality exceeds 60%, and steroids can contribute to the dissemination of these infections. Identification on standard culture is difficult (sporulation is rarely observed). Mucorales are intrinsically resistant to echinocandins and amphotericin B must be the first-line treatment [[2]Skiada A. Lass-Floerl C. Klimko N. Ibrahim A. Roilides E. Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis.Med Mycol. 2018; 56: 93-101Crossref PubMed Scopus (211) Google Scholar]. The authors declare that they have no conflict of interest. No external funding was received for this observation.
<i>FADS1</i> and <i>FADS2</i> Polymorphisms Modulate Fatty Acid Metabolism and Dietary Impact on Health
Authors: Berthold Koletzko, Eva Reischl, Conny Tanjung, Ines Gonzalez-Casanova, Usha Ramakrishnan, Suzanne Meldrum, Karen Simmer, Joachim Heinrich, Hans Demmelmair
Journal: Annual Review of Nutrition (2019)

Variants in the FADS gene cluster modify the activity of polyunsaturated fatty acid (PUFA) desaturation and the lipid composition in human blood and tissue. FADS variants have been associated with plasma lipid concentrations, risk of cardiovascular diseases, overweight, eczema, pregnancy outcomes, and cognitive function. Studies on variations in the FADS genecluster provided some of the first examples for marked gene–diet interactions in modulating complex phenotypes, such as eczema, asthma, and cognition. Genotype distribution differs markedly among ethnicities, apparently reflecting an evolutionary advantage of genotypes enabling active long-chain PUFA synthesis when the introduction of agriculture provided diets rich in linoleic acid but with little arachidonic and eicosapentaenoic acids. Discovering differential effects of PUFA supply that depend on variation of FADS genotypes could open new opportunities for developing precision nutrition strategies based either on an individual's genotype or on genotype distributions in specific populations.
Efficacy and Safety of Endoscopic Sleeve Gastroplasty: A Systematic Review and Meta-Analysis
Authors: Abdellah Hedjoudje, Barham K. Abu Dayyeh, Lawrence J. Cheskin, Atif Adam, Manoel Galvão Neto, Dilhana Badurdeen, Javier Graus Morales, Adrian Sartoretto, Gontrand Lopez Nava, Eric Vargas, Zhixian Sui, Lea Fayad, Jad Farha, Mouen A. Khashab, Anthony N. Kalloo, Aayed R. Alqahtani, Christopher C. Thompson, Vivek Kumbhari
Journal: Clinical Gastroenterology and Hepatology (2019)
Phase 1 combination therapy with pexidartinib (PEX) and sirolimus (S) to target tumor-associated macrophages in pigmented villonodular synovitis, malignant peripheral nerve sheath tumors, and other soft tissue sarcomas.
Authors: Gulam Abbas Manji, Brian Andrew Van Tine, Shing Mirn Lee, Alexander Raufi, Parag Patwardhan, Lauren Esther Blumberg, Naomi Sender, Jennifer Wang, Daniel Otap, Shahnaz V. Singh-Kandah, Khanh Tu Do, Angela C. Hirbe, Gideon Bollag, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2019)

11055 Background: No effective therapy exists for unresectable malignant peripheral nerve sheath tumors (MPNSTs). We previously reported that the combination of PEX and the mTOR inhibitor S synergistically inhibited MPNST growth (CCR 20: 3146, 2014) by depleting M2 TAMs and by inhibiting receptor tyrosine kinases (RTKs), including c-KIT, PDGFR, CSF1R. We characterized the safety, tolerability, recommended phase 2 dose (RP2D) of PEX plus S in all sarcoma sub-types. Methods: Patients (pts) received PEX plus S orally in 28 days cycle as per Table. The RP2D was determined using the time-to-event continual reassessment method (TITE-CRM) in advanced sarcoma who have progressed on standard therapy. DLT was defined as any need for a dose reduction. Results: 24 pts were accrued (Acr) of which 18 were evaluable (MPNST – 6, pigmented villonodular synovitis (PVNS) – 3, leiomyosarcoma – 5, and other – 9). The mean age was 46y, 56% were male, and 67% had greater than 2 prior therapies. Most common ( &gt; 20%) grade 2 or higher TEAEs were anemia (33%), WBC count decrease (28%), fatigue, neutropenia, and lymphopenia (22% each). There were 5 dose limiting toxicities (DLT): 2 for elevated LFTs both of which resolved with dose reduction, 2 for supra-therapeutic S trough levels, and 1 for grade 5 dehydration at dose level (DL) 3. Four subjects experienced a partial response (PR; -44% to -77% by RECIST, 18 – 61 wks on therapy). Seven subjects experienced stable disease (SD; +19.7% to -20.7% by RECIST; 9.4 – 30 wks on therapy). Five subjects progressed on therapy and two subjects experienced early DLTs and did not undergo tumor assessment. The RP2D is DL 3 (S 2mg/PEX 1000mg) with an estimated probability of DLT of 26.7% as determined by TITE-CRM. This recommendation is based on a target DLT rate of 25%. TAMs and immune subtypes from available tissue specimens and historical controls will be presented. Conclusions: 1000mg of PEX in combination with 2mg of S daily has an acceptable safety profile. Objective responses and durable SD was observed in PNVS and MPNST patients justifying proceeding with a multi-center single arm phase 2 study in advanced MPNST. Clinical trial information: NCT02584647. [Table: see text]
Prognostic impact of allelic losses in 1p32–36 (HYTM1), 4p15.2 (D4S2397), 5q22.2 (D5S346), 8p22 (D8S254), 18q12.3 (D18S474), and microsatellite instability for colorectal cancer
Authors: R. Melcher, T. Kudlich, H. Luehrs, T. Katzenberger, B. Illert, O. Al-Taie, H. Einsele, W. Scheppach, M. Scheurlen
Journal: Journal of Clinical Oncology (2009)

4132 Background: The aim of this prospective study was to analyse the prognostic impact of allelic losses in the chromosomal regions 1p32–36 (HYTM1), 4p14–16 (D4S2397), 5q22 (D5S346), 8p21–22 (D8S254), 18q12.3 (D18S474) and microsatellite instability (MSI) in colorectal cancer (CRC). The microsatellite markers HYTM1, D4S2397, D8S254, and D18S474 were previously shown to have prognostic relevance in retrospective studies. The National Cancer Institute (NCI) microsatellite panel (BAT25, BAT26, D2S123, D5S346 and D17S250) was used for MSI-Analysis. Methods: Between July 1999 and February 2004, the data from a total of 165 patients, preoperatively diagnosed with colorectal cancer, and operated on in the Department of Surgery, University of Wuerzburg were collected. Inclusion criteria were: (a) electively operated primary adenocarcinomas; (b) obtainment of fresh paired normal mucosa-tumor samples; (c) no postoperative death (survival &lt; 1 month); and (d) availability of follow-up data. Allelic loss (LOH) was determined by comparing the PCR-patterns of tumor DNA with corresponding normal tissue (signal reduction of at least 50%). MSI-L (low microsatellite instability) was defined as one marker out of five NCI-markers, MSI-H (high microsatellite instability) as more than two markers to display microsatellite instability. MSI-H tumours were excluded for further LOH-analysis. The endpoint of the study was tumour specific death. Kaplan-Meier survival curves were compared using the log-rank test. Results: We found expected frequencies in age, gender, tumour stage, and tumour grading. Tumour stage, grading, and an allelic loss of D18S474 was confirmed to be of prognostic significance for UICC I-IV, I-III, and II cancer in univariate analysis. Tumour stage and LOH D18S474 were also independent prognostic variables in stage I-IV and I-III. There was no significant prognostic impact of a loss of the markers HYTM1, D4S2397, D5S346, D8S254, MSI-L and MSI-H in either UICC stage I-IV, I-III, and II colorectal cancer patients. Conclusions: A loss of D18S474 defines a high-risk subgroup of patients with stage I-IV, I-III and stage II colorectal cancers. No significant financial relationships to disclose.
Cost-effectiveness of Housing First Intervention With Intensive Case Management Compared With Treatment as Usual for Homeless Adults With Mental Illness
Authors: Eric A. Latimer, Daniel Rabouin, Zhirong Cao, Angela Ly, Guido Powell, Carol E. Adair, Jitender Sareen, Julian M. Somers, Vicky Stergiopoulos, Andrew D. Pinto, Erica E. M. Moodie, Scott R. Veldhuizen
Journal: JAMA Network Open (2019)

<h3>Importance</h3> In the At Home/Chez Soi trial for homeless individuals with mental illness, the scattered-site Housing First (HF) with Intensive Case Management (ICM) intervention proved more effective than treatment as usual (TAU). <h3>Objective</h3> To evaluate the cost-effectiveness of the HF plus ICM intervention compared with TAU. <h3>Design, Setting, and Participants</h3> This is an economic evaluation study of data from the At Home/Chez Soi randomized clinical trial. From October 2009 through July 2011, 1198 individuals were randomized to the intervention (n = 689) or TAU (n = 509) and followed up for as long as 24 months. Participants were recruited in the Canadian cities of Vancouver, Winnipeg, Toronto, and Montreal. Participants with a current mental disorder who were homeless and had a moderate level of need were included. Data were analyzed from 2013 through 2019, per protocol. <h3>Interventions</h3> Scattered-site HF (using rent supplements) with off-site ICM services was compared with usual housing and support services in each city. <h3>Main Outcomes and Measures</h3> The analysis was performed from the perspective of society, with days of stable housing as the outcome. Service use was ascertained using questionnaires. Unit costs were estimated in 2016 Canadian dollars. <h3>Results</h3> Of 1198 randomized individuals, 795 (66.4%) were men and 696 (58.1%) were aged 30 to 49 years. Almost all (1160 participants, including 677 in the HF group and 483 in the TAU group) contributed data to the economic analysis. Days of stable housing were higher by 140.34 days (95% CI, 128.14-153.31 days) in the HF group. The intervention cost $14 496 per person per year; reductions in costs of other services brought the net cost down by 46% to $7868 (95% CI, $4409-$11 405). The incremental cost-effectiveness ratio was $56.08 (95% CI, $29.55-$84.78) per additional day of stable housing. In sensitivity analyses, adjusting for baseline differences using a regression-based method, without altering the discount rate, caused the largest change in the incremental cost-effectiveness ratio with an increase to $60.18 (95% CI, $35.27-$86.95). At $67 per day of stable housing, there was an 80% chance that HF was cost-effective compared with TAU. The cost-effectiveness of HF appeared to be similar for all participants, although possibly less for those with a higher number of previous psychiatric hospitalizations. <h3>Conclusions and Relevance</h3> In this study, the cost per additional day of stable housing was similar to that of many interventions for homeless individuals. Based on these results, expanding access to HF with ICM appears to be warranted from an economic standpoint. <h3>Trial Registration</h3> isrctn.org Identifier:ISRCTN42520374
PTU-012 Learning curve for optical diagnosis of colorectal polyps using cumulative sum analysis
Authors: R Rameshshanker, A Wilson, N Kamperidis, N O’shea, S Thomas-Gibson, BP Saunders
Journal: Gut (2017)

Introduction  Optical diagnosis (OD) for diminutive and small colorectal polyps is an attractive option to reduce costs and streamline patient care. The American Society of Gastrointestinal Endoscopy Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) established a 90% diagnostic threshold for real time endoscopic assessment of diminutive colorectal polyps. The learning curve for trainees to achieve the competency has not been fully explored. Our aim is to evaluate the minimum number of polyps to achieve and maintain the OD thresholds per PIVI standards using an upward CUSUM plot.  Method  Four trainees without previous experience in OD at our institution participated in this prospective study. Four weeks before the commencement of the study they were given a training module on OD. OD was based on NICE and WASP classification. During the study period (January 2016-August 2016), each trainee documented the OD of polyps less than 10 mm in size. Patient demographics, polyp details and polyp histology were collected prospectively. OD of each polyp was compared against the polyp histology.  Results  A total of 708 polyp observations were performed by trainees during the study period. Total number of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps (SSA/P) were 3 64 214 and 52 respectively. All 4 trainees achieved sustained accuracy (90% threshold) in OD within 12–58 observations. Image 1 illustrates the upward CUSUM plot of 4 trainees. The number of polyps required to reach the plateau varied between 12 to 58. Every trainee’s confidence level improved over time (from 69% to 89%) and the effect was augmented by in-vivo feedback and revision of training module. Table 1 summarises the optical diagnostic performance of all 4 trainees. Negative predictive value for adenomas were above 90% for all trainees.  Conclusion  The CUSUM scores of all 4 trainees in the study reached the PIVI standards plateau by the 58th polyp observation. In-vivo feedback and continued training appears important to maintain the performance. Our preliminary findings could be used as a guide to plan the certification process for implementation of optical diagnosis.  Disclosure of Interest  None Declared
Predicting overweight and obesity in young adulthood from childhood body-mass index: comparison of cutoffs derived from longitudinal and cross-sectional data
Authors: Noora Kartiosuo, Rema Ramakrishnan, Stanley Lemeshow, Markus Juonala, Trudy L Burns, Jessica G Woo, David R Jacobs, Stephen R Daniels, Alison Venn, Julia Steinberger, Elaine M Urbina, Lydia Bazzano, Matthew A Sabin, Tian Hu, Ronald J Prineas, Alan R Sinaiko, Katja Pahkala, Olli Raitakari, Terence Dwyer
Journal: The Lancet Child & Adolescent Health (2019)
Association Between Immune-Related Adverse Events During Anti–PD-1 Therapy and Tumor Mutational Burden
Authors: David Bomze, Omar Hasan Ali, Andrew Bate, Lukas Flatz
Journal: JAMA Oncology (2019)

This database study compares surveillance data on immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors to determine whether irAEs experienced during anti–PD-1 therapy correlate with tumor mutational burden across 18 cancer types.
Abstract 10751: NADPH Oxidase - a Therapeutic Target to Restore Endothelial Function in Insulin Resistance
Authors: Piruthivi Sukumar, Hema Viswambharan, Helen Imrie, Matthew Gage, Nadira Yuldasheva, Stephen Wheatcroft, Mark Kearney
Journal: Circulation (2011)

Insulin resistance (IR) plays pivotal role in the development and progression of a number disorders of human health including type 2 diabetes. A hallmark of IR is reduced bioavailability of the ant...
Studies on the State of Insulin in Blood
Authors: Harry N. Antoniades, James A. Bougas, Hugh M. Pyle
Journal: New England Journal of Medicine (1962)

EXPERIMENTAL studies on the state of insulin in the blood of diabetic and nondiabetic human subjects led to the discovery that diabetes mellitus may result from extrapancreatic malfunction of the mechanism regulating insulin activity in blood, and not from a lack of endogenous insulin. This proposition is based on a series of investigations revealing that insulin circulates in the blood of diabetic subjects as a biologically inactive complex in amounts comparable or even higher to those found in nondiabetic subjects.1 , 2 It was also observed that the rate of dissociation of the insulin complexes in diabetic patients, after glucose administration, is . . .
MetaCarvel: linking assembly graph motifs to biological variants
Authors: Jay Ghurye, Todd Treangen, Marcus Fedarko, W. Judson Hervey, Mihai Pop
Journal: Genome biology (2019)

Reconstructing genomic segments from metagenomics data is a highly complex task. In addition to general challenges, such as repeats and sequencing errors, metagenomic assembly needs to tolerate the uneven depth of coverage among organisms in a community and differences between nearly identical strains. Previous methods have addressed these issues by smoothing genomic variants. We present a variant-aware metagenomic scaffolder called MetaCarvel, which combines new strategies for repeat detection with graph analytics for the discovery of variants. We show that MetaCarvel can accurately reconstruct genomic segments from complex microbial mixtures and correctly identify and characterize several classes of common genomic variants.
TERRAIN: A randomized, double-blind, phase II study comparing MDV3100 with bicalutamide (Bic) in men with metastatic castrate-resistant prostate cancer (CRPC).
Authors: Edwina S. Baskin-Bey, Neal D. Shore, Kenya Barber, Taoufik Ouatas, Axel Heidenreich
Journal: Journal of Clinical Oncology (2012)

TPS4698^ Background: MDV3100 is a novel androgen receptor (AR) signaling inhibitor (ARSI) in clinical development for treatment of prostate cancer (PCa). Compared with Bic in nonclinical CRPC models, MDV3100 showed higher affinity AR binding, inhibited nuclear translocation and AR-DNA binding, showed no evidence of AR agonism, and caused tumor regression in Bic-resistant xenografts. MDV3100 has shown antitumor activity in men with advanced PCa. We present the study design of a trial comparing MDV3100 and Bic in men with progressive metastatic PCa. Methods: Multinational study (Table) with planned enrollment of 370 patients (randomized 1:1 to MDV3100 160 mg/d or Bic 50 mg/d). Inclusion criteria include metastatic (≥2 bone lesions or soft tissue disease at screening) progressive CRPC (≥3 rising prostate-specific antigen [PSA] levels or new bone/soft tissue disease), ongoing stable gonadotropin-releasing hormone (GnRH) analog therapy or surgical castration (serum testosterone &lt;50 ng/dL), Eastern Cooperative Oncology Group performance status 0–1, and life expectancy ≥1 year. Exclusion criteria include previous chemotherapy, current/prior antiandrogens (except if administered for &lt;12 wk and discontinued no less than 6 mo before study). Patients will be stratified by time of bilateral orchiectomy or GnRH analog initiation (before/after diagnosis of metastases) and will receive treatment until occurrence of radiographic progression/skeletal-related event, start of new antineoplastic therapy, or development of an adverse event requiring discontinuation. Results: The primary endpoint is progression-free survival; secondary endpoints are safety, PSA response, and time to PSA progression. Exploratory endpoints include circulating tumor cell conversion rate and quality of life. Patients are currently enrolling. Conclusions: This ongoing, head-to-head, phase II trial is the first to prospectively assess whether MDV3100 can provide improved antitumor effects vs Bic in men with metastatic CRPC. [Table: see text]
Association of novel measures of sleep disturbances with blood pressure: the Multi-Ethnic Study of Atherosclerosis
Authors: John S. Kim, Ali Azarbarzin, Rui Wang, Ina E. Djonlagic, Naresh M. Punjabi, Phyllis C. Zee, Brian B. Koo, Elsayed Z. Soliman, Magdy Younes, Susan Redline
Journal: Thorax (2019)

Background Mechanisms underlying blood pressure (BP) changes in obstructive sleep apnoea (OSA) are incompletely understood. We assessed the associations between BP and selected polysomnography (PSG) traits: sleep depth, airflow limitation measurements and OSA-specific hypoxic burden. Methods This cross-sectional analysis included 2055 participants from the Multi-Ethnic Study of Atherosclerosis who underwent PSG and BP measurements in 2010–2013. Sleep depth was assessed using the ‘OR product’, a continuous measure of arousability. Airflow limitation was assessed by duty cycle (T i /T t ) and % of breaths with flow limitation, and hypoxia by ‘hypoxic burden’. Primary outcomes were medication-adjusted systolic BP (SBP) and diastolic BP (DBP). We used generalised linear models adjusted for age, sex, race/ethnicity, smoking, education, body mass index, alcohol use, periodic limb movements and alternative physiological disturbances. Results The sample had a mean age of 68.4 years and apnoea–hypopnoea index of 14.8 events/hour. Sleep depth was not significantly associated with BP. Every 1 SD increment in log-transformed non-rapid eye movement duty cycle was associated with 0.9% decrease in SBP (95% CI: 0.1% to 1.6%), even after adjusting for sleep depth and hypoxic burden. Every 1 SD increment in log-transformed hypoxic burden was associated with a 1.1% increase in SBP (95% CI: 0.1% to 2.1%) and 1.9% increase in DBP (95% CI: 1.0% to 2.8%) among those not using hypertension medications. Conclusions Higher duty cycle was associated with lower SBP overall and hypoxic burden with higher SBP and DBP among non-BP medication users. These findings suggest changes in both respiratory effort and oxygenation during sleep influence BP.