tbuckley/cabot-search huggingface dataset:
D-Index–Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial
Authors: Yoshinobu Kanda, Shun-ichi Kimura, Masaki Iino, Takahiro Fukuda, Emiko Sakaida, Tatsuo Oyake, Hiroki Yamaguchi, Shin-ichiro Fujiwara, Yumi Jo, Akinao Okamoto, Hiroyuki Fujita, Yasushi Takamatsu, Yoshio Saburi, Itaru Matsumura, Jun Yamanouchi, Souichi Shiratori, Moritaka Gotoh, Shingen Nakamura, Kazuo Tamura
Journal: Journal of Clinical Oncology (2020)

PURPOSE Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index–guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (−2.0%; 90% CI, −4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P &lt; .001). CONCLUSION A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.
Blinding may be unnecessary, but please divest
Authors: Fiona Godlee
Journal: BMJ (2020)

In the hierarchy of evidence, randomised trials are near the top, trumped only by meta-analysis of such trials, with blinding of patients and clinicians firmly established as being key to their validity. But new research published in The BMJ this week casts doubt on the benefits of blinding. Helene Moustgaard and colleagues have meta-analysed 142 Cochrane meta-analyses, incorporating 1153 randomised trials. They conclude that there’s no evidence that a lack of blinding leads to exaggerated estimates of treatment effects (doi:10.1136/bmj.l6802).

This apparent lack of benefit should be seen in the …
Rapid response teams must not divert resources away from other services, say clinicians
Authors: Abi Rimmer
Journal: BMJ (2020)

NHS England has announced plans to create multidisciplinary rapid response teams that will provide support for older people and adults with complex health needs who have very urgent care needs. However, clinicians have warned that the plans must not divert staff and funding away from existing services or place additional pressure on them.

The rapid response teams, which will be piloted at seven sites in England, will comprise a mix of NHS staff including GPs, specialty and associate specialist doctors, nurses, physiotherapists and occupational therapists, and social care staff.

Backed by £14m of investment, the teams will launch in April, aiming to get at least three areas fully up and running by next winter. NHS England said that the teams would …
CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy
Authors: Peter F. Zipfel, Thorsten Wiech, Emma D. Stea, Christine Skerka
Journal: Journal of the American Society of Nephrology (2020)

Sequence and copy number variations in the human CFHR-Factor H gene cluster comprising the complement genes CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR-Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1, CFHR3, and Factor H gene alterations combined with intact CFHR2, CFHR4, and CFHR5 genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five CFHR genes in the context of an intact Factor H gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.
Biodegradable stent placement for recurrent or refractory benign esophageal stricture: a perspective from the East
Authors: Tao Dong, Lili Zhao, Li Liu, Zhining Fan
Journal: Endoscopy (2019)

See also: Dilation or biodegradable stent placement for recurrent benign esophageal strictures: a randomized controlled trialEndoscopy 2018; 50(12): 1146-1155DOI: 10.1055/a-0602-4169 See also: Reply to Dong et al.Endoscopy 2019; 51(07): 700-700DOI: 10.1055/a-0919-4867
Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent
Authors: George G. Zhanel, Jenine Esquivel, Sheryl Zelenitsky, Courtney K. Lawrence, Heather J. Adam, Alyssa Golden, Rachel Hink, Liam Berry, Frank Schweizer, Michael A. Zhanel, Denice Bay, Philippe R. S. Lagacé-Wiens, Andrew J. Walkty, Joseph P. Lynch, James A. Karlowsky
Journal: Drugs (2020)
Brassinin compounds exhibit anti-cancer activity mediated through inhibition of the immunotolerogenic enzyme Indoleamine 2,3-dioxygenase (IDO)
Authors: Alexander Muller, James DuHadaway, Tinku Banerjee, David Munn, Andrew Mellor, Paul Gaspari, William Malachowski, George Prendergast
Journal: Cancer Research (2007)

224  Tumors benefit greatly from a local inflammatory environment but must escape immune-mediated rejection. Indoleamine 2.3-dioxygenase (IDO) suppresses T cell activation by catalyzing the breakdown of the essential amino acid tryptophan. Increased IDO activity has been associated with a broad spectrum of cancers and is implicated in the pathophysiological process of tumoral immune escape. Using the small molecule IDO inhibitory compound 1-methyl-tryptophan (1MT) in transgenic MMTV-Neu mice, we have previously shown that inhibiting the IDO enzyme can leverage the efficacy of cytotoxic chemotherapy in this autochthonous breast cancer model. Further preclinical evaluation of 1MT has indicated that the D and L stereoisomers show marked cell type variation in their ability to inhibit IDO activity with clear biological consequences. Here we report on a novel structural class IDO inhibitory compounds based on the core lead structure brassinin. Brassinin is a naturally occurring, indole-containing phytoalexin with chemopreventative activity in preclinical models. Identification of brassinin as a competitive IDO inhibitor led us to develop a pharmacologic formulation of brassinin, along with the more potent derivative 5-Br-brassinin, that achieves sufficient systemic exposure to evaluate these compounds for therapeutic efficacy in mice. We will present data in both autochthonous and isograft tumor models demonstrating the anti-tumor properties of these compounds. Follow-up studies in nude mice and IDO knockout mice directly support inhibition of both T cell function and IDO activity as necessary to the mechanism of action. We will also present data in a mouse carcinogenesis model evaluating the relevance of IDO inhibition to the ability of brassinin to act as a chemopreventative agent. Derivatization around the brassinin core structure has led to the identification of more potent compounds, providing the basis for structure activity relationship analysis that will inform future IDO inhibitor development.
Use of e-cigarettes and smoked tobacco in youth aged 14–15 years in New Zealand: findings from repeated cross-sectional studies (2014–19)
Authors: Natalie Walker, Varsha Parag, Sally F Wong, Ben Youdan, Boyd Broughton, Christopher Bullen, Robert Beaglehole
Journal: The Lancet Public Health (2020)

Media reports of a vaping epidemic among youth have raised concerns about the creation of a new generation of nicotine-dependent individuals who could graduate to cigarette smoking. We investigated the use of e-cigarettes and cigarettes in the youth of New Zealand from 2014 to 2019, with focus on daily use of these products as an indicator of potential dependence.We analysed data from the Action for Smokefree 2025 Year-10 survey, an annual cross-sectional survey of tobacco use undertaken by almost half of all school students aged 14-15 years (21 504-31 021 students). The survey includes questions on whether students had ever smoked (even just a few puffs) and their current smoking behaviour (at least once a day, week, or month, or less often than once a month). In 2014, a question was added asking if students had ever tried an e-cigarette. Subsequent surveys asked about e-cigarette use at least once a day, week, or month, or less often than once a month. We compared the frequency of e-cigarette use with cigarette smoking by survey year, age, gender, ethnicity, and school decile (a proxy for socioeconomic status). We did χ2 analyses to compare categorical variables and Cochran-Armitage trend tests to assess changes over time. Multiple logistic regression was used to determine predictors of e-cigarette and cigarette use in 2019.All measures of e-cigarette use increased and all measures of cigarette use decreased or remained static over time. Although the proportion of students who had ever tried e-cigarettes in 2019 (37·3%, 10 093 of 27 083), exceeded the proportion who had ever smoked (19·6%, 5375 of 27 354), daily use of products was low: e-cigarettes (3·1%, 832 of 26 532), cigarettes (2·1%, 575 of 27 212), both (0·6%, 159 of 27 633). In 2019, daily use of e-cigarettes was very low in never-smokers (0·8%, 175 of 21 385). Students who were Māori, Pacific, gender diverse, or from low-decile and mid-decile schools were more likely to be daily users of e-cigarettes or cigarettes, and males were more likely to be daily e-cigarette users, but less likely to smoke daily than females.The overall decline in smoking over the past 6 years in New Zealand youth suggests that e-cigarettes might be displacing smoking. Ongoing monitoring will be important to determine whether the liberalisation of e-cigarette availability and marketing in New Zealand has any effect on long-term patterns of daily e-cigarette and cigarette use.New Zealand Ministry of Health.
Human Herpesvirus 6 Detection in Alzheimer’s Disease Cases and Controls across Multiple Cohorts
Authors: Mary Alice Allnutt, Kory Johnson, David A. Bennett, Sarah M. Connor, Juan C. Troncoso, Olga Pletnikova, Marilyn S. Albert, Susan M. Resnick, Sonja W. Scholz, Philip L. De Jager, Steven Jacobson
Journal: Neuron (2020)
<i>BRAF</i> and <i>DIS3</i> Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma
Authors: Eileen M. Boyle, Cody Ashby, Ruslana G. Tytarenko, Shayu Deshpande, Hongwei Wang, Yan Wang, Adam Rosenthal, Jeffrey Sawyer, Erming Tian, Erin Flynt, Antje Hoering, Sarah K. Johnson, Michael W. Rutherford, Christopher P. Wardell, Michael A. Bauer, Charles Dumontet, Thierry Facon, Sharmilan Thanendrarajan, Carolina D. Schinke, Maurizio Zangari, Frits van Rhee, Bart Barlogie, David Cairns, Graham Jackson, Anjan Thakurta, Faith E. Davies, Gareth J. Morgan, Brian A. Walker
Journal: Clinical Cancer Research (2020)

Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets.We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials.As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance.Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.
Poverty status is linked to worse quality of care
Authors: Adrian O'Dowd
Journal: BMJ (2020)

People living in England’s most deprived areas of England seem to receive the worst quality of healthcare across various types of service, concludes new research from health experts.1

Examples of inequality included spending longer in hospital accident and emergency departments and having worse experiences when making GP appointments.

The research from QualityWatch, a joint programme of the health think tanks the Nuffield Trust and the Health Foundation, involved looking at 23 measures of healthcare quality to see how these were affected by deprivation. The measures included avoidable mortality rate, smoking prevalence, emergency admissions for various types of care, obesity prevalence in children, infant mortality rate, experience of making a GP appointment and …
Superantigen-related TH2 CD4+ T cells in nonasthmatic chronic rhinosinusitis with nasal polyps
Authors: Min-Seok Rha, Sang-Wook Kim, Dong-Yeop Chang, Jin-Ku Lee, Jihye Kim, Su-Hyung Park, Roza Khalmuratova, Hee-Suk Lim, Kyoung Mi Eun, Seung-No Hong, Dae Woo Kim, Eui-Cheol Shin
Journal: Journal of Allergy and Clinical Immunology (2020)
Meningitis vaccine: cases fall in UK, but herd immunity remains elusive in Australia
Authors: Jacqui Wise
Journal: BMJ (2020)

The UK’s infant vaccination programme against group B meningococcal disease has resulted in a significant reduction in cases of the disease in young children, according to research from Public Health England published in the New England Journal of Medicine .1

However, an Australian study published in the same journal found that while the meningitis B vaccine also works in teenagers it does not provide herd protection against the meningococcal bacteria so will only protect those who are adequately immunised.2

In September 2015 the UK became the first country to offer the 4CMenB vaccine (Bexsero) to babies at 8 and 16 weeks of age, followed by a booster at 12 months.

The results show that from September 2015 through to August 2018 there …
Physical activity and mortality: what is the dose response and how big is the effect?
Authors: Ulf Ekelund, Knut Eirik Dalene, Jakob Tarp, I-Min Lee
Journal: British Journal of Sports Medicine (2020)

More than 60 years of research have consistently shown that physical activity beneficially affects several health outcomes and reduces the risk of premature mortality. The Harvard Alumni Study, one of the first studies to suggest a dose–response association between physical activity and health, examined the association between ‘total’ physical activity (defined as strenuous sports, walking and stair climbing) and participation in strenuous sports and the risk of heart attack in about 17 000 men.1 ‘Total’ physical activity was categorised into groups based on energy expenditure in physical activity per week. The following were the important observations: (1) there was a substantial risk reduction when comparing the ‘inactive’ reference group expending <500 kcal per week in ‘total’ physical activity with the second group expending 500–999 kcal per week; (2) there was graded dose–response association, with declining risk up to about 3000 kcal per week of ‘total’ physical activity, beyond which the benefits plateaued; and (3) energy expenditure from strenuous sports appeared to have greater protective effect than ‘total’ volume of activity. However, the latter observation may partly be explained by more accurate reporting of sporting activities compared with physical activities of daily living of lower intensity (eg, stair climbing and walking). The dose–response curve from the landmark paper by Paffenbarger et al 1 was subsequently confirmed after accounting for confounding,2 and it has been replicated in women and ethnically diverse populations from low-income and middle-income countries.3–5

These previous studies assessed physical activity using different self-report instruments, which may be prone to cognitive biases (eg, recall bias) and which may result in overestimation of physical activity and underestimation of sedentary time. Due to …
WHO’s rollout of malaria vaccine in Africa: can safety questions be answered after only 24 months?
Authors: Peter Aaby, Ane B Fisker, Anders Björkman, Christine Stabell Benn
Journal: BMJ (2020)

### Key messages

World malaria day on 23 April 2019 saw the start of the first routine malaria vaccine programme in Africa—a pilot study in Malawi. Ghana and Kenya have now followed. The RTS,S/AS01 malaria vaccine has been under development by GlaxoSmithKline for 30 years and is the first malaria vaccine to receive regulatory approval for human use. The pilot study aims to enrol 720 000 children in vaccination and control clusters over a two year period; it is planned to last about 50 months.

Media and leading medical journals have celebrated the news,1234 …
Re: Veeru Kasivisvanathan, Armando Stabile, Joana B. Neves, et al. Magnetic Resonance Imaging-targeted Biopsy Versus Systematic Biopsy in the Detection of Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2019;76:284–303
Authors: Jae Heon Kim, In Gab Jeong
Journal: European Urology (2020)
Dose-Dense Sequential Adjuvant Chemotherapy With Epirubicin, Paclitaxel and CMF Versus Epirubicin, Cmf and Weekly Docetaxel or Paclitaxel Followed by Trastuzumab for One Year in Patients With Early Breast Cancer
Authors: G. Fountzilas, H. Gogas, N. Pavlidis, A. Eleftheraki, D. Skarlos, A. Koutras, E. Timotheadou, C. Papandreou, D. Pectasides, M. Dimopoulos
Journal: Annals of Oncology (2012)
Inter-technique variability between antimicrobial susceptibility testing methods affects clinical classification of cefuroxime in strains close to breakpoint
Authors: M. Ballestero-Téllez, E. Jiménez-Morgades, P. Arjona-Camacho, A. Blanco-Suárez, E. Padilla-Esteba, J. Pérez-Jové
Journal: Clinical Microbiology and Infection (2020)
Response to Comment on Segar et al. Machine Learning to Predict the Risk of Incident Heart Failure Hospitalization Among Patients With Diabetes: The WATCH-DM Risk Score. Diabetes Care 2019;42:2298–2306
Authors: Matthew W. Segar, Muthiah Vaduganathan, Darren K. McGuire, Mujeeb Basit, Ambarish Pandey
Journal: Diabetes Care (2020)

Identifying patients with type 2 diabetes mellitus (T2DM) at high risk for future heart failure (HF) has been challenging given the multisystem inputs that contribute to HF risk, inaccuracies in administrative coded data, and complexities with risk prediction models. In the machine learning–derived WATCH-DM (Weight [BMI], Age, hyperTension, Creatinine, HDL-C, Diabetes control [fasting plasma glucose], QRS Duration, MI, and CABG) score, we considered 147 candidate variables to create a simple, user-friendly, integer-based risk score to predict adjudicated incident HF events (1). We appreciate the critical appraisal of WATCH-DM by Fonseca and colleagues (2).

Our integer score was developed similarly to the well-established method popularized by the Framingham framework, in which the points associated with each level of each risk factor are relative to the points associated with an increase in age (3). Briefly, continuous variables were first converted to dichotomous variables. Cutoffs for the continuous variables were either determined by established guidelines (for example, the normal, overweight, and obese cutoffs for …
Recurrence Is Rare Following Complete Eradication of Intestinal Metaplasia in Patients With Barrett’s Esophagus and Peaks at 18 Months
Authors: Sachin Wani, Samuel Han, Vladimir Kushnir, Dayna Early, Daniel Mullady, Hazem Hammad, Brian Brauer, Adarsh Thaker, Violette Simon, Eze Ezekwe, Thomas Hollander, Mariah Wood, Amit Rastogi, Steven Edmundowicz, V. Raman Muthusamy, Srinadh Komanduri
Journal: Clinical Gastroenterology and Hepatology (2020)
Downregulation of the Arg/N-degron Pathway Sensitizes Cancer Cells to Chemotherapy In Vivo
Authors: Dominique Leboeuf, Tatiana Abakumova, Tatiana Prikazchikova, Luke Rhym, Daniel G. Anderson, Timofei S. Zatsepin, Konstantin I. Piatkov
Journal: Molecular Therapy (2020)

The N-degron pathway is an emerging target for anti-tumor therapies, because of its capacity to positively regulate many hallmarks of cancer, including angiogenesis, cell proliferation, motility, and survival. Thus, inhibition of the N-degron pathway offers the potential to be a highly effective anti-cancer treatment. With the use of a small interfering RNA (siRNA)-mediated approach for selective downregulation of the four Arg/N-degron-dependent ubiquitin ligases, UBR1, UBR2, UBR4, and UBR5, we demonstrated decreased cell migration and proliferation and increased spontaneous apoptosis in cancer cells. Chronic treatment with lipid nanoparticles (LNPs) loaded with siRNA in mice efficiently downregulates the expression of UBR-ubiquitin ligases in the liver without any significant toxic effects but engages the immune system and causes inflammation. However, when used in a lower dose, in combination with a chemotherapeutic drug, downregulation of the Arg/N-degron pathway E3 ligases successfully reduced tumor load by decreasing proliferation and increasing apoptosis in a mouse model of hepatocellular carcinoma, while avoiding the inflammatory response. Our study demonstrates that UBR-ubiquitin ligases of the Arg/N-degron pathway are promising targets for the development of improved therapies for many cancer types. The N-degron pathway is an emerging target for anti-tumor therapies, because of its capacity to positively regulate many hallmarks of cancer, including angiogenesis, cell proliferation, motility, and survival. Thus, inhibition of the N-degron pathway offers the potential to be a highly effective anti-cancer treatment. With the use of a small interfering RNA (siRNA)-mediated approach for selective downregulation of the four Arg/N-degron-dependent ubiquitin ligases, UBR1, UBR2, UBR4, and UBR5, we demonstrated decreased cell migration and proliferation and increased spontaneous apoptosis in cancer cells. Chronic treatment with lipid nanoparticles (LNPs) loaded with siRNA in mice efficiently downregulates the expression of UBR-ubiquitin ligases in the liver without any significant toxic effects but engages the immune system and causes inflammation. However, when used in a lower dose, in combination with a chemotherapeutic drug, downregulation of the Arg/N-degron pathway E3 ligases successfully reduced tumor load by decreasing proliferation and increasing apoptosis in a mouse model of hepatocellular carcinoma, while avoiding the inflammatory response. Our study demonstrates that UBR-ubiquitin ligases of the Arg/N-degron pathway are promising targets for the development of improved therapies for many cancer types.