Developing User Personas to Aid in the Design of a User-Centered Natural Product-Drug Interaction Information Resource for Researchers

Pharmacokinetic interactions between natural products and conventional drugs can adversely impact patient outcomes. These complex interactions present unique challenges that require clear communication to researchers. We are creating a public information portal to facilitate researchers’ access to credible evidence about these interactions. As part of a user-centered design process, three types of intended researchers were surveyed: drug-drug interaction scientists, clinical pharmacists, and drug compendium editors. Of the 23 invited researchers, 17 completed the survey. The researchers suggested a number of specific requirements for a natural product-drug interaction information resource, including specific information about a given interaction, the potential to cause adverse effects, and the clinical importance. Results were used to develop user personas that provided the development team with a concise and memorable way to represent information needs of the three main researcher types and a common basis for communicating the design’s rationale

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Fonterra: The economic effects of the dairy industry merger

In 2001, the New Zealand government passed the Dairy industry Restructuring (DIR) Act, exempting the dairy industry from certain sections of the Commerce Act and paving the way for the industry wide merger that was to create Fonterra. In a purported market economy such as New Zealand's, the passing of legislation to encourage the creation of a monopoly is a significant event. The decision to override the Commerce Commission and the existing anti-trust legislation should not be taken lightly. The consequences of this merger are all the more important as the dairy industry generates approximately seven percent of GDP and consequently has a significant influence on the national economy. This study will use the draft determination of the Commerce Commission to analyse the effects of the merger on the New Zealand economy.UnpublishedArmentano, Dominic. Antitrust and monopoly: anatomy of a policy failure. Wiley, [1982]. Baldwin, Tony. Fonterra Must Hasten its Capital Overhaul, New Zealand Herald [2004]. http://www.nzherald.co.nz/index.cfm?ObjectID=3601383 Baldwin, Tony. Hopes over birth of Synlait premature [2005]. http://www.stuff.co.nz/stuff/0,2106,3266603a1865,00.html Bates, Winton. The Dairy Board's export monopoly. New Zealand Business Roundtable, [1997]. Commerce Commission. Open Country Cheese Company Ltd – Draft Determination [2005]. http://www.comcom.govt.nz/PublicRegisters/dairy.aspx Commerce Commission. Independent Dairy Producers Ltd – Final Determination [2003] http://www.comcom.govt.nz/PublicRegisters/dairy.aspx Commerce Commission. 'NewCo' – Draft Determination [1999] http://www.comcom.govt.nz/PublicRegisters/mergersacquisitions-authorisations.aspx Cox, Andrea. Bitter-sweet opener for farmers, The New Zealand Herald [2005]. http://www.nzherald.co.nz/index.cfm?ObjectID=10127929 Dairy Section of Federated Farmers. Structure of the NZ dairy industry: discussion paper. [1994]. Evans, Lewis. Watershed for New Zealand dairy industry. New Zealand Institute for the Study of Competition and Regulation, [2001] Fonterra Financial Accounts [2004]. http://www.fonterra.com/content/shareholderfinancial/resultsreports/default.j sp Kissun, Sidesh. Dairy Industry Meets its Brief Rural News [2004] http://www.ruralnews.co.nz/article.asp?channelid=141&articleid=8589 Ministry of Agriculture and Fisheries. The NZ Dairy Industry Merger [2002] http ://www.maf.govt.nz/mafnet/rural-nz/statistics-and- forecasts/sonzaf/2001/2001- 01.htm Ministry of Foreign Affairs and Trade. Trade Statistics [2004]. http://www.mfat.govt.nz/foreign/eco/tradestatsindex.html Statistics New Zealand. Food Price Index [2004]. http://www.stats.govt.nz/datasets/economic-indicators/food-price-index.htm Townsend, Harry. Scale, innovation, merger, and monopoly; an introduction to industrial economics. Pergamon Press, [1968]. Van der Heyden, Henry. Long View Needed of Dairy Co-op Debate, New Zealand Herald [2004]. http://www.nzherald.co.nz/index.cfin?ObjectID=359707

CAN A PASSIVE DYNAMIC WALKING ROBOT EXHIBIT A DETERMINISTIC NONLINEAR GAIT?

There is a growing body of evidence that nonlinear step-to-step variations are related to how the nervous system controls stable locomotion. However, we still have

Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333.

PurposeAtypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT.Patients and methodsPatients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored.ResultsOf 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients.ConclusionThe ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents

Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas

High-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier-penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors.1