tbuckley/cabot-search huggingface dataset:
Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial
Authors: Hidehisa Saeki, Kensuke Ito, Daisuke Yokota, Hidetsugu Tsubouchi
Journal: Journal of the American Academy of Dermatology (2021)

BackgroundDifamilast is a selective phosphodiesterase 4 inhibitor. Phosphodiesterase 4 is involved in cytokine production linked with inflammatory disorders, including atopic dermatitis.ObjectiveTo demonstrate the superiority of difamilast ointment 1% to vehicle in adult Japanese patients with atopic dermatitis.MethodsIn this phase 3, randomized, double-blind trial, patients aged 15-70 years with an investigator global assessment score of 2 or 3 received topical difamilast ointment 1% (n = 182) or a vehicle (n = 182) twice daily for 4 weeks.ResultsThe success rate in investigator global assessment score at week 4 (primary endpoint)—the percentage of patients achieving an investigator global assessment score of 0 or 1 with ≥2-grade improvement—was significantly higher with 1% difamilast than with the vehicle (38.46% vs 12.64%, respectively, P < .0001). The success rates in ≥50%, ≥75%, and ≥90% improvement in overall eczema area and severity index score at week 4 followed the same trend. Difamilast at 1% provided significant mean percent improvement from baseline in overall eczema area and severity index score versus vehicle from week 1 to 4. Treatment-emergent adverse events were mostly mild or moderate and less frequent with difamilast.LimitationsStudy treatment was limited to 4 weeks.ConclusionDifamilast ointment 1% demonstrated superiority to the vehicle and favorable safety in adult Japanese patients with atopic dermatitis. Difamilast is a selective phosphodiesterase 4 inhibitor. Phosphodiesterase 4 is involved in cytokine production linked with inflammatory disorders, including atopic dermatitis. To demonstrate the superiority of difamilast ointment 1% to vehicle in adult Japanese patients with atopic dermatitis. In this phase 3, randomized, double-blind trial, patients aged 15-70 years with an investigator global assessment score of 2 or 3 received topical difamilast ointment 1% (n = 182) or a vehicle (n = 182) twice daily for 4 weeks. The success rate in investigator global assessment score at week 4 (primary endpoint)—the percentage of patients achieving an investigator global assessment score of 0 or 1 with ≥2-grade improvement—was significantly higher with 1% difamilast than with the vehicle (38.46% vs 12.64%, respectively, P < .0001). The success rates in ≥50%, ≥75%, and ≥90% improvement in overall eczema area and severity index score at week 4 followed the same trend. Difamilast at 1% provided significant mean percent improvement from baseline in overall eczema area and severity index score versus vehicle from week 1 to 4. Treatment-emergent adverse events were mostly mild or moderate and less frequent with difamilast. Study treatment was limited to 4 weeks. Difamilast ointment 1% demonstrated superiority to the vehicle and favorable safety in adult Japanese patients with atopic dermatitis.
Publisher Correction: Sustainable Development Goals relevant to kidney health: an update on progress
Authors: Valerie A. Luyckx, Ziyad Al-Aly, Aminu K. Bello, Ezequiel Bellorin-Font, Raul G. Carlini, June Fabian, Guillermo Garcia-Garcia, Arpana Iyengar, Mohammed Sekkarie, Wim van Biesen, Ifeoma Ulasi, Karen Yeates, John Stanifer
Journal: Nature Reviews Nephrology (2021)
Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation
Authors: Natalia Reglero-Real, Lorena Pérez-Gutiérrez, Azumi Yoshimura, Loïc Rolas, José Garrido-Mesa, Anna Barkaway, Catherine Pickworth, Rebeca S. Saleeb, Maria Gonzalez-Nuñez, Shani N. Austin-Williams, Dianne Cooper, Laura Vázquez-Martínez, Tao Fu, Giulia De Rossi, Matthew Golding, Mathieu-Benoit Voisin, Chantal M. Boulanger, Yoshiaki Kubota, William A. Muller, Sharon A. Tooze, Thomas D. Nightingale, Lucy Collinson, Mauro Perretti, Ezra Aksoy, Sussan Nourshargh
Journal: Immunity (2021)

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.
Amanda Pritchard becomes first woman to lead NHS England
Authors: Abi Rimmer
Journal: BMJ (2021)

The former chief executive of Guy’s and St Thomas’ NHS Foundation Trust will take up the post of chief executive officer of NHS England on 1 August.

Amanda Pritchard has been chief operating officer of NHS England and chief executive of NHS Improvement since 2019. She has worked for the NHS for almost 25 years since joining through the NHS graduate management training scheme.1

Commenting on her appointment, Pritchard said she had always been very proud to work in the health service “but never more so than over the last 18 months as nurses, doctors, therapists, paramedics, pharmacists, porters, cleaners, and other staff have responded so magnificently to the covid-19 pandemic.”

The appointment of Pritchard, who was health team leader for the prime minister’s delivery unit in 2005, was welcomed by Boris Johnson. “Amanda’s experience and expertise mean she is perfectly placed to address these issues and more, and I look forward to working closely with her,” the prime minister said.

During her tenure Pritchard is likely to feel the impact of the Health and Care Bill 2021-22,2 which the government wants in place by April 2022. …
Association of Diphtheria-Tetanus–Acellular Pertussis Vaccine Timeliness and Number of Doses With Age-Specific Pertussis Risk in Infants and Young Children
Authors: Madhura S. Rane, Pejman Rohani, M. Elizabeth Halloran
Journal: JAMA Network Open (2021)

<h3>Importance</h3> In most countries, the diphtheria-tetanus–acellular pertussis (DTaP) vaccine is administered as a 3-dose infant series followed by additional booster doses in the first 5 years of life. Short-term immunity from the DTaP vaccine can depend on the number, timing, and interval between doses. Not receiving doses in a timely manner might be associated with a higher pertussis risk. <h3>Objective</h3> To examine the association between number and timeliness of vaccine doses and age-specific pertussis risk. <h3>Design, Setting, and Participants</h3> This population-based, retrospective cohort study used Washington State Immunization Information System data and pertussis surveillance data from Public Health Seattle and King County, Washington. Included participants were children aged 3 months to 9 years born or living in King County, Washington, between January 1, 2008, and December 31, 2017. Data were analyzed from June 30 to December 1, 2019. <h3>Exposures</h3> Being undervaccinated (receiving fewer than recommended doses at a given age) or delayed vaccination (not receiving doses within time frames recommended by Centers for Disease Control and Prevention). <h3>Main Outcomes and Measures</h3> Suspected, probable, and confirmed pertussis diagnosis. <h3>Results</h3> A total of 316 404 children (median age, 65.2 months [interquartile range, 35.3-94.1 months]; 162 025 boys [51.2%]) as of December 31, 2017, with 17.4 million person-months of follow-up were included in the analysis. A total of 19 943 children (6.3%) had no vaccines recorded in the Immunization Information System, 116 193 (36.7%) received a vaccine with a delay, and 180 268 (56.9%) were fully vaccinated with no delay. Delayed vaccination and undervaccination rates were higher for older children (17.6% delayed or undervaccinated at age 2 months for dose 1 at 3 months vs 41.6% at age 5 years for dose 5) but improved for successive birth cohorts (52.2% for 2008 birth cohort vs 32.3% for 2017 birth cohort). Undervaccination was significantly associated with higher risk of pertussis for the 3-dose primary series (adjusted relative risk [aRR], 4.8; 95% CI, 3.1-7.6), the first booster (aRR, 3.2; 95% CI, 2.3-4.5), and the second booster (aRR, 4.6; 95% CI, 2.6-8.2). However, delay in vaccination among children who received the recommended number of vaccine doses was not associated with pertussis risk. <h3>Conclusions and Relevance</h3> The results of this cohort study suggest that undervaccination is associated with higher pertussis risk. Short delays in vaccine receipt may be less important if the age-appropriate number of doses is administered, but delaying doses is not recommended. Ensuring that children receive all doses of pertussis vaccine, even if there is some delay, is important.
A High‐Throughput Distal Lung Air–Blood Barrier Model Enabled By Density‐Driven Underside Epithelium Seeding (Adv. Healthcare Mater. 15/2021)
Authors: Hannah Viola, Kendra Washington, Cauviya Selva, Jocelyn Grunwell, Rabindra Tirouvanziam, Shuichi Takayama
Journal: Advanced Healthcare Materials (2021)

Acute Liver Failure A confocal image (60x) shows a higher resolution of work in article number 2100879 by Shuichi Takayama and co-workers. Epithelial cells are stimulated with poly(I:C) resulting in endothelial release of von Willebrand Factor (green), demonstrating the culture model allows propagation of inflammatory signals from epithelium to endothelium.
A role for the cortex in sleep–wake regulation
Authors: Lukas B. Krone, Tomoko Yamagata, Cristina Blanco-Duque, Mathilde C. C. Guillaumin, Martin C. Kahn, Vincent van der Vinne, Laura E. McKillop, Shu K. E. Tam, Stuart N. Peirson, Colin J. Akerman, Anna Hoerder-Suabedissen, Zoltán Molnár, Vladyslav V. Vyazovskiy
Journal: Nature Neuroscience (2021)
P-152 Sarcopenia in advanced colorectal cancer patients treated with trifluridine/tipiracil
Authors: M. Malik, M. Michalak, B. Radecka, M. Gełej, A. Jackowska, E. Filipczyk-Cisarż, K. Hetman, M. Foszczynska-Kloda, B. Kania-Zembaczynska, D. Mańka, M. Orlikowska, H. Rogowska-Droś, L. Bodnar
Journal: Annals of Oncology (2021)
T2B or not to B: Calming neutrophils offshore
Authors: Hafsa Munir, Theresa T. Lu
Journal: The Journal of Experimental Medicine (2021)

In this issue of JEM, Podstawka et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210409) show that B cells can limit neutrophil responses within the lung microvasculature by marginating and acting on marginated neutrophils. This study provides a new view of B cells and reveals a novel mechanism of cell-mediated intravascular regulation.
LBA-3 Integrated analysis of cell-free DNA (cfDNA) BRAF mutant allele fraction (MAF) and whole exome sequencing in BRAFV600E metastatic colorectal cancer (mCRC) treated with BRAF-antiEGFR +/- MEK inhibitors
Authors: E. Élez, J. Ros, G. Martini, J. Matito, G. Villacampa, F. Salva, I. Baraibar, N. Saoudi, A. Garcia, R. Comas, D. Ciardiello, E. Martinelli, P. Nuciforo, H. Pálmer, R. Dienstmann, R. Toledo, F. Ciardiello, J. Tabernero, A. Vivancos
Journal: Annals of Oncology (2021)
Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland)
Authors: D Hayes-Ryan, A S Khashan, K Hemming, C Easter, D Devane, D J Murphy, A Hunter, A Cotter, F M McAuliffe, J J Morrison, F M Breathnach, E Dempsey, L C Kenny, K O’Donoghue
Journal: BMJ (2021)

Abstract Objective To determine whether the addition of placental growth factor (PlGF) measurement to current clinical assessment of women with suspected pre-eclampsia before 37 weeks' gestation would reduce maternal morbidity without increasing neonatal morbidity. Design Stepped wedge cluster randomised control trial from 29 June 2017 to 26 April 2019. Setting National multisite trial in seven maternity hospitals throughout the island of Ireland Participants Women with a singleton pregnancy between 20 +0 to 36 +6 weeks’ gestation, with signs or symptoms suggestive of evolving pre-eclampsia. Of the 5718 women screened, 2583 were eligible and 2313 elected to participate. Intervention Participants were assigned randomly to either usual care or to usual care plus the addition of point-of-care PlGF testing based on the randomisation status of their maternity hospital at the time point of enrolment. Main outcomes measures Co-primary outcomes of composite maternal morbidity and composite neonatal morbidity. Analysis was on an individual participant level using mixed-effects Poisson regression adjusted for time effects (with robust standard errors) by intention-to-treat. Results Of the 4000 anticipated recruitment target, 2313 eligible participants (57%) were enrolled, of whom 2219 (96%) were included in the primary analysis. Of these, 1202 (54%) participants were assigned to the usual care group, and 1017 (46%) were assigned the intervention of additional point-of-care PlGF testing. The results demonstrate that the integration of point-of-care PlGF testing resulted in no evidence of a difference in maternal morbidity—457/1202 (38%) of women in the control group versus 330/1017 (32%) of women in the intervention group (adjusted risk ratio (RR) 1.01 (95% CI 0.76 to 1.36), P=0.92)—or in neonatal morbidity—527/1202 (43%) of neonates in the control group versus 484/1017 (47%) in the intervention group (adjusted RR 1.03 (0.89 to 1.21), P=0.67). Conclusions This was a pragmatic evaluation of an interventional diagnostic test, conducted nationally across multiple sites. These results do not support the incorporation of PlGF testing into routine clinical investigations for women presenting with suspected preterm pre-eclampsia, but nor do they exclude its potential benefit. Trial registration ClinicalTrials.gov NCT02881073 .
<i>Lrig1</i> expression identifies airway basal cells with high proliferative capacity and restricts lung squamous cell carcinoma growth
Authors: Laura Succony, Sandra Gómez-López, Adam Pennycuick, Ahmed S.N. Alhendi, Derek Davies, Sarah E. Clarke, Kate H.C. Gowers, Nicholas A. Wright, Kim B. Jensen, Sam M. Janes
Journal: European Respiratory Journal (2021)

Background Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival. Methods and results Using an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression. Conclusion Together, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes.
多発性硬化症における病理学的所見とMRI所見との関連【JST・京大機械翻訳】
Authors: Filippi Massimo, Brueck Wolfgang, Chard Declan, Fazekas Franz, Geurts Jeroen J G, Enzinger Christian, Hametner Simon, Kuhlmann Tanja, Preziosa Paolo, Rovira Alex, Schmierer Klaus, Stadelmann Christine, Rocca Maria A
Journal: The Lancet Neurology (2019)
Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis
Authors: Alicia G. Gómez-Valadés, Macarena Pozo, Luis Varela, Mehdi Boutagouga Boudjadja, Sara Ramírez, Iñigo Chivite, Elena Eyre, Roberta Haddad-Tóvolli, Arnaud Obri, Maria Milà-Guasch, Jordi Altirriba, Marc Schneeberger, Mónica Imbernón, Angela R. Garcia-Rendueles, Pau Gama-Perez, Jonathan Rojo-Ruiz, Bence Rácz, Maria Teresa Alonso, Ramon Gomis, Antonio Zorzano, Giuseppe D’Agostino, Clara V. Alvarez, Rubén Nogueiras, Pablo M. Garcia-Roves, Tamas L. Horvath, Marc Claret
Journal: Cell Metabolism (2021)

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.
In moderately severe CAP stable after 3 d of β-lactam, stopping therapy was noninferior to 5 additional d
Authors: Thomas Fekete
Journal: Annals of Internal Medicine (2021)

Source Citation Dinh A, Ropers J, Duran C, et al. Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial. Lancet. 2021;397:1195-1203. 33773631
Abstract 15025: E-NTPDase Gene Eluting Stent Prevents In-stent Restenosis in Injured Artery; Optical Coherence Tomography Evaluation
Authors: Ji Hee Sung, Hiroyuki Kawata, Tsunenari Soeda, Satoshi Somekawa, Shiro Uemura, Masanori Matsumoto, Yoshihiro Fujimura, Yoshihiko Saito
Journal: Circulation (2011)

Backgrounds Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) rapidly hydrolyzes ADP, which is well known to induce smooth muscle cell proliferation, to AMP at arterial wall. We had report...
BECLOMETHASONE DIPROPIONATE INHALATION (BDI) THERAPY INFLUENCE ON BRONCHIAL HYPERRESPONSIVENESS
Authors: Iikura Y, Hahm Yb, Ebisawa M, Tsubaki T, Miura K, Sakaguchi N, Katsunuma T, Sugimoto H, Matsuda S
Journal: Journal of Allergy and Clinical Immunology (1995)
Cognitive Functioning and Hippocampal Connectivity in Patients With Longstanding Type 1 Diabetes and Apolipoprotein E ε4
Authors: Eelco van Duinkerken, Richard G. IJzerman, Frederik Barkhof, Annette C. Moll, Michaela Diamant, Frank J. Snoek, Martin Klein
Journal: Diabetes Care (2021)

OBJECTIVE While the apolipoprotein E ε4 allele (ApoE-ε4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-ε4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-ε4 effects in adult patients with T1DM. RESEARCH DESIGN AND METHODS Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-ε4 presence was investigated and adjusted for age and mean systolic blood pressure. RESULTS ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-ε4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-ε4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-ε4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. CONCLUSIONS The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies.
Prognostic Importance of Health Status Versus Functional Status in Heart Failure and Secondary Mitral Regurgitation
Authors: Suzanne V. Arnold, Gregg W. Stone, Sneha S. Jain, Michael J. Mack, John T. Saxon, Zixuan Zhang, JoAnn Lindenfeld, William T. Abraham, David J. Cohen
Journal: JACC Heart Failure (2021)
The resect and discard strategy: a new kid on the block?
Authors: Yark Hazewinkel
Journal: Endoscopy (2021)

Approximately 90 % of polyps detected and removed during screening colonoscopy are smaller than 10 mm [1]. The vast majority of these lesions, especially diminutive polyps (1–5 mm), do not contain colorectal cancer (CRC) or advanced histology, such as villous histology or high grade dysplasia. Yet, in most of our practices, all resected polyps, including diminutive lesions, are routinely sent for histological analysis.
P33.03 Alteration of Circulating Blood Lymphocyte Subtypes Reveal Therapy Effect in Non-small Cell Lung Cancer
Authors: L. Xu, J. Zhang, L. Yang, G. Shao, T. Liuru, W. Xu, Z. Liang, W. Chen, Y. Zhang, C. Zhao, L. Ma, F. Zhang, M. Luo, S. Li, D. Pang, F.(. Kong
Journal: Journal of Thoracic Oncology (2021)