tbuckley/cabot-search huggingface dataset:
Balanced Crystalloids or 0.9% Saline in Sepsis. Beyond Reasonable Doubt?
Authors: Paul J. Young
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

challenge.A phase 3 randomized controlled trial to assess efficacy of TLD would require selecting the appropriate patient population (either frequent exacerbators and/or potentially those with severe respiratory symptoms), as well as the appropriate primary outcome (perhaps frequency of exacerbations).We recommend that the Global Initiative for Chronic Obstructive Ling Disease 2019 treatment strategy be followed before classifying an individual patient as having an increased risk for exacerbations despite optimal therapy (6).This includes long-acting b agonist/long-acting muscarinic antagonist or long-acting b agonist/long-acting muscarinic antagonist/inhaled corticosteroids pharmacotherapy plus consideration of roflumilast and azithromycin based on established criteria.Acquired immunoglobulin deficiency should also be excluded as a cause for repeated chest infections before trial enrolment ( 7).What's the bottom line?New effective treatments for COPD are desperately needed.Patients with moderate and severe COPD continue to suffer from unresolved symptoms of breathlessness, activity limitation, and risk for exacerbation.Pharmacologic treatments for symptomatic COPD have not significantly evolved since the introduction of long-acting anticholinergic bronchodilators in 2003.A treatment with a novel therapeutic device, such as TLD, would be most welcome if treatment could be shown to improve patient-reported outcomes such as symptoms, quality of life, and activity limitation in patients with advanced COPD.A therapeutic breakthrough for treatment of COPD would be enthusiastically welcomed by patients and healthcare professionals.
The IARC Monographs: Updated Procedures for Modern and Transparent Evidence Synthesis in Cancer Hazard Identification
Authors: Jonathan M Samet, Weihsueh A Chiu, Vincent Cogliano, Jennifer Jinot, David Kriebel, Ruth M Lunn, Frederick A Beland, Lisa Bero, Patience Browne, Lin Fritschi, Jun Kanno, Dirk W Lachenmeier, Qing Lan, Gérard Lasfargues, Frank Le Curieux, Susan Peters, Pamela Shubat, Hideko Sone, Mary C White, Jon Williamson, Marianna Yakubovskaya, Jack Siemiatycki, Paul A White, Kathryn Z Guyton, Mary K Schubauer-Berigan, Amy L Hall, Yann Grosse, Véronique Bouvard, Lamia Benbrahim-Tallaa, Fatiha El Ghissassi, Béatrice Lauby-Secretan, Bruce Armstrong, Rodolfo Saracci, Jiri Zavadil, Kurt Straif, Christopher P Wild
Journal: JNCI Journal of the National Cancer Institute (2019)

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals, and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.
The impact of short-term incentives on physical activity in a UK behavioural incentives programme
Authors: Cother Hajat, Ali Hasan, Shaun Subel, Adam Noach
Journal: npj Digital Medicine (2019)

This observational study investigates whether the provision of ongoing short-term-incentives for verified physical activity increases and sustains levels of physical activity. We compared UK members at baseline (years 1 and 2) prior to Vitality's Active Rewards (VAR) intervention commencing (year 3) and follow-up (year 4) for verified, self-reported (encompassing additional physical activities), mortality relative risk and satisfaction with physical activity. Members were categorised into low-active, medium-active and high-active by tertiles of baseline physical activity. Of 11,881 participants, 6477(54.5%) were male, with mean age 39.7(SD 9.8) years. At follow-up, annual active days had increased by 56% overall [60.8(59.7-61.9)-94.8(93.0-96.5)]; 554% in low-active [8.5(8.3-8.7)-47.1(44.7-49.5)]; 205% in medium-active [39.8(39.4-40.2)-81.4(78.7-84.1)] and 17% in high-active members [131.7(129.9-133.5)-153.7(150.7-156.7)] (all p < 0.001). Annual weeks of attaining international physical activity recommendations increased by 19% overall [22.2(42.8%)-26.4(50.8%)] and by 316% for low-active members [4.9(9.5%)-15.5(29.8%)]. Self-reported active minutes/week increased by 45% overall [1423(139.4-145.2)-207.0(201.8-212.3)] and 712% in low-active members [20.1(19.3-21.0)-143.2(134.6-151.9)]. Happiness with exercise levels also increased from 1985(49.4%) to 3414(84.9%) members (all p < 0.001). The relative risk of mortality from a lack of physical activity reduced by 7% for low-active members [from 0.99 to 0.92], 5% for medium-active [0.94-0.89] and 3% for high-active [0.89-0.86](p < 0.001) and by 0.02% for each additional year of age (p = 0.02). This large-scale, real-world, short-term-incentives intervention led to a dramatic increase in physical activity which was sustained for, and still increasing after, two years. If applied at broader level, this approach could considerably aid progress towards WHO targets in its Global Action Plan for Physical Activity.
<b>Association of Food Insecurity and Acute Health Care Utilization in Children With End-stage Kidney Disease</b>
Authors: Michelle C. Starr, Aaron Wightman, Raj Munshi, Ang Li, Sangeeta Hingorani
Journal: JAMA Pediatrics (2019)

This study assesses food insecurity and acute health care utilization among pediatric patients with end-stage kidney disease undergoing peritoneal dialysis or hemodialysis.
No deal Brexit: Yellowhammer document shows scale of risk to drug supplies
Authors: Adrian O’Dowd
Journal: BMJ (2019)

The government has acknowledged the scale of the potential impact of a no deal Brexit, including disruption to drug supplies, price rises on certain foods and fuel, lorries waiting more than two days to cross the English Channel, and public protests.

The Operation Yellowhammer document1—the government’s planning for a reasonable worst case scenario in the event of a no deal Brexit—was published on 11 September after MPs passed a motion on 9 September that forced such a move. This version was last updated in August.

The document says there may be “significant disruption” to the flow of trade lasting up to six months. “Unmitigated, this will have an impact on the supply …
Stretchable, Patch‐Type Calorie‐Expenditure Measurement Device Based on Pop‐Up Shaped Nanoscale Crack‐Based Sensor
Authors: Ki Yoon Kwon, Yiel Jae Shin, Joo Hwan Shin, Chanho Jeong, Yei Hwan Jung, Byeonghak Park, Tae‐il Kim
Journal: Advanced Healthcare Materials (2019)

Abstract Demands for precise health information tracking techniques are increasing, especially for daily dietry requirements to prevent obesity, diabetes, etc. Many commercially available sensors that detect dynamic motions of the body lack accuracy, while novel strain sensors at the research level mostly lack the capability to analyze measurements in real life conditions. Here, a stretchable, patch‐type calorie expenditure measurement system is demonstrated that integrates an ultrasensitive crack‐based strain sensor and Bluetooth‐enabled wireless communication circuit to offer both accurate measurements and practical diagnosis of motion. The crack‐based strain gauge transformed into a pop‐up‐shaped structure provides reliable measurements and broad range of strain (≈100%). Combined with the stretchable analysis circuit, the skin attachable tool translates variation of the knee flexion angle into calorie expenditure amount, using relative resistance change ( R / R 0 ) data from the flexible sensor. As signals from the knee joint angular movement translates velocity and walking/running behavior, the total amount of calorie expenditure is accurately analyzed. Finally, theoretical, experimental, and simulation analysis of signal stability, dynamic noises, and calorie expenditure calculation obtained from the device during exercise are demonstrated. For further applications, the devices are expected to be used in broader range of dynamic motion of the body for diagnosis of abnormalities and for rehabilitation.
Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma
Authors: Ian Bayles, Malgorzata Krajewska, W. Dean Pontius, Alina Saiakhova, James J. Morrow, Cynthia Bartels, Jim Lu, Zachary J. Faber, Yuriy Fedorov, Ellen S. Hong, Jaret M. Karnuta, Brian Rubin, Drew J. Adams, Rani E. George, Peter C. Scacheri
Journal: Journal of Clinical Investigation (2019)

Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enabled preclinical screening of compounds against metastatic OS cells in the context of the native lung microenvironment. Using this strategy to screen a library of epigenetically targeted compounds, we identified inhibitors of CDK12 to be most effective, reducing OS cell outgrowth in the lung by more than 90% at submicromolar doses. We found that knockout of CDK12 in an in vivo model of lung metastasis significantly decreased the ability of OS to colonize the lung. CDK12 inhibition led to defects in transcription elongation in a gene length– and expression-dependent manner. These effects were accompanied by defects in RNA processing and altered the expression of genes involved in transcription regulation and the DNA damage response. We further identified OS models that differ in their sensitivity to CDK12 inhibition in the lung and provided evidence that upregulated MYC levels may mediate these differences. Our studies provided a framework for rapid preclinical testing of compounds with antimetastatic activity and highlighted CDK12 as a potential therapeutic target in OS.
Targeted Delivery of Cisplatin-Derived Nanoprecursors via a Biomimetic Yeast Microcapsule for Tumor Therapy by the Oral Route
Authors: Xing Zhou, Kaijian Ling, Mengyu Liu, Xiangjun Zhang, Jun Ding, Yan Dong, Zhiqing Liang, Jianjun Li, Jianxiang Zhang
Journal: Theranostics (2019)

Targeted therapy via the patient-friendly oral route remains the holy grail of chemotherapy for cancer. Herein we report a yeast-derived platform for targeted oral delivery of cisplatin (CDDP) that is one of the most effective drugs for chemotherapy of various types of cancers. Methods: The optimal conditions were first established to fabricate yeast microcapsules (YCs) with desirable loading capability. Then, CDDP-derived precursor nanoparticles (PreCDDP) were prepared and packaged into YC to produce orally deliverable PreCDDP/YC. The physiochemical properties, in vitro drug release profiles, in vitro antitumor activity, oral targeting capability, in vivo pharmacokinetics, and in vivo efficacy of the YC-based biomimetic delivery system were examined. Results: YCs obtained under the optimized condition showed desirable loading efficiency for quantum dots that were used as a model nanocargo. In vitro experiments demonstrated rapid endocytosis and prolonged retention of YC in macrophages. By electrostatic force-mediated self-deposition, PreCDDP was efficiently loaded into YC. PreCDDP/YC showed potent cytotoxicity in different tumor cells, indicating that PreCDDP loaded in YC maintained its antitumor activity after intracellular release. As compared to CDDP and PreCDDP, orally administered PreCDDP/YC displayed significantly higher bioavailability. Post oral delivery, YC could accumulate in A549 human lung carcinoma xenografts in mice, achieving by monocyte/macrophage-mediated translocation via the lymphatic system. Through this targeting effect, orally administered PreCDDP/YC showed desirable efficacy in A549 xenograft-bearing mice, which was comparable to that of free CDDP administered by intravenous injection. Orally administered free CDDP, however, did not afford antitumor effects. Furthermore, oral treatment with PreCDDP/YC displayed better safety than free CDDP administered via the oral or intravenous route. Conclusions: This biomimetic approach can serve as an effective strategy to develop targeted oral chemotherapies based on CDDP or its derivatives.
Reply to Franco Gaboardi, Guglielmo Mantica, and Nazareno Suardi’s Letter to the Editor re: Giuseppe Simone, Umberto Anceschi, Gabriele Tuderti, et al. Robot-assisted Partial Adrenalectomy for the Treatment of Conn’s Syndrome: Surgical Technique, and Perioperative and Functional Outcomes. Eur Urol 2019;75:811–6
Authors: Umberto Anceschi, Giuseppe Simone
Journal: European Urology (2019)
Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis
Authors: Kjetil Bjornevik, Kassandra L. Munger, Marianna Cortese, Christian Barro, Brian C. Healy, David W. Niebuhr, Ann I. Scher, Jens Kuhle, Alberto Ascherio
Journal: JAMA Neurology (2019)

<h3>Importance</h3> Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease. <h3>Objective</h3> To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. <h3>Design, Setting, and Participants</h3> Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding. <h3>Exposures</h3> Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). <h3>Main Outcomes and Measurements</h3> Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models. <h3>Results</h3> Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL;<i>P</i> = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063;<i>P </i>= .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples;<i>P</i> = .009). <h3>Conclusions and Relevance</h3> The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
Discovery of 2 Distinctive Lineages of Lymphocytes, T Cells and B Cells, as the Basis of the Adaptive Immune System and Immunologic Function
Authors: Max Dale Cooper, Jacques F. A. P. Miller
Journal: JAMA (2019)

In this Viewpoint, 2019 Albert Lasker Basic Medical Research Award winners Max Dale Cooper and Jacques F. A. P. Miller discuss their discovery of B and T cells, which provided the organizing principle of the adaptive immune system and launched the course of modern immunology.
Identification of Acetylation, Immune Cell Alterations and Gene Signature As Dynamic Biomarkers of Response to Panobinostat Treatment in Multiple Myeloma Patients
Authors: Sridurga Mithraprabhu, Ioanna Savvidou, Malarmathy Ramachandran, Anna Kalff, Tiffany T. Khong, Kate Reed, John Reynolds, Andrew Spencer
Journal: Blood (2017)
Drug Therapies for Chronic Cholestatic Liver Diseases
Authors: Martin Wagner, Peter Fickert
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.
FRI-191-EDP-514, a novel HBV core inhibitor with potent antiviral activity both in vitro and in vivo
Authors: Michael Vaine, Victor Dellisola, Susan Clugston, Hui Cao, Xuri Gao, Jorden Kass, Wei Li, Xiaowen Peng, Yao-Ling Qiu, Lijuan Jiang, Kellye Daniels, Yat Sun Or, Bryan Goodwin, Kai Lin
Journal: Journal of Hepatology (2019)
Stimuli-responsive nanodrug self-assembled from amphiphilic drug-inhibitor conjugate for overcoming multidrug resistance in cancer treatment
Authors: Ping Huang, Guanchun Wang, Yue Su, Yongfeng Zhou, Wei Huang, Rong Zhang, Deyue Yan
Journal: Theranostics (2019)

Severe multidrug resistance (MDR) often develops in the process of chemotherapy for most small molecule anticancer drugs, which results in clinical chemotherapy failures.Methods: Here, a nanodrug is constructed through the self-assembly of amphiphilic drug-inhibitor conjugates (ADIC) containing a redox-responsive linkage for reversing the multidrug resistance (MDR) in cancer treatment.Specifically, hydrophilic anticancer irinotecan (Ir) and hydrophobic P-gp protein inhibitor quinine (Qu) are linked by a redox responsive bridge for overcoming MDR of tumors.Results: Ir-ss-Qu is able to self-assemble into nanoparticles (NPs) in water and shows the longer blood retention half-life compared with that of free Ir or Qu, which facilitates drug accumulation in tumor site.After endocytosis of Ir-ss-Qu NPs by drug-resistant tumor cells, the disulfide bond in the linkage between Ir and Qu is cleaved rapidly induced by glutathione (GSH) to release anticancer drug Ir and inhibitor Qu synchronously.The released Qu can markedly reduce the expression of P-gp in drug-resistant tumor cells and inhibits P-gp to pump Ir out of the cells.The increased concentration of intracellular Ir can effectively improve the therapeutic efficacy.Conclusions: Such redox-responsive Ir-ss-Qu NPs, as a drug delivery system, exhibit very high cytotoxicity and the most effective inhibitory to the growth of drug-resistant breast cancer compared with that of free therapeutic agents in vitro and in vivo.
Use of an Online Crowdfunding Platform for Unmet Financial Obligations in Cancer Care
Authors: Andrew J. Cohen, Hartley Brody, German Patino, Medina Ndoye, Aron Liaw, Christi Butler, Benjamin N. Breyer
Journal: JAMA Internal Medicine (2019)

cited a trial registration number (Table ).Moreover, only 283 abstracts (39.3%) specified a primary outcome, and 353 (49.0%) included the word randomized, randomised, or RCT in the title.A total of 442 abstracts (61.4%) specified the number of participants randomized, and 181 (25.1%) specified the number of participants analyzed in each group.In addition, only 101 (14.0%) included dates of recruitment and follow-up.Overall, only 249 abstracts (34.6%) included at least 3 of 6 key CONSORT reporting items.Although trial registration numbers were included in only 97 abstracts, they could be found for an additional 380 by searching registries and publications, thereby increasing the percentage of abstracts that reported registered trials to 66.2% (477 abstracts).Discussion | Our analysis, albeit limited to select major medical conferences, found that clinical trial registration numbers are rarely cited in conference abstracts and adherence to CONSORT guidelines for abstracts is minimal.These findings reflected the abstract submission guidelines for the 8 conferences that were reviewed, none of which mentioned the inclusion of clinical trial registration numbers or CONSORT reporting items.In contrast, almost all abstracts reporting RCT results at the annual meeting of the American Society of Clinical Oncology, held from May 29 to June 2, 2015, at Chicago, Illinois were found to cite trial registration numbers, 5 reflecting the society's abstract guidelines, which required registration numbers to be cited for registered trials. 6The priority given to trial registration and compliance with CONSORT guidelines by that organization arguably reflects their urgency to promote translation of clinical trial results into advances in cancer care.It is unrealistic for most, much less all, CONSORT reporting items to be included in conference abstracts given abstract word-count restrictions.However, such restrictions further emphasize the importance of including trial registration numbers because they may be used to access essentially all CONSORT reporting items in registry data sets. 4oreover, because many trials presented at conferences remain unpublished, detailed and timely information about them may be accessible only through a trial registry.Even when published, access to the publications may not be open, and registration numbers may provide the only means by which clinicians could readily acquire sufficient information about a trial to judge the value and relevance of its results to clinical practice.