tbuckley/cabot-search huggingface dataset:
Covid inquiry: communication failures impeded the UK’s pandemic response
Authors: Greg Fell
Journal: BMJ (2024)

Covid inquiry: communication failures impeded the UK's pandemic responseWe must tackle the lack of communication and information sharing between central government and those on the ground when dealing with local outbreaks, writes Greg Fell Greg Fell presidentRecently, the first report of the UK Covid-19 Inquiry was published. 1 The Association of Directors of Public Health (ADPH) were core participants in the first module, which focused on pandemic preparedness.We gave evidence on behalf of directors of public health across all the UK's four countries and dependent territories.
Emerging Perspectives on Neuroprotection
Authors: Gregor Hasler, Dragos Inta
Journal: Psychotherapy and Psychosomatics (2024)

Neuroprotection aims to safeguard neurons from damage caused by various factors like stress, potentially leading to the rescue, recovery, or regeneration of the nervous system and its functions [J Clin Neurosci. 2002;9(1):4–8]. Conversely, neuroplasticity refers to the brain’s ability to adapt and change throughout life, involving structural and functional alterations in cells and synaptic transmission [Neural Plast. 2014;2014:541870]. Neuroprotection is a broad and multidisciplinary field encompassing various approaches and strategies aimed at preserving and promoting neuronal health. It is a critical area of research in neuroscience and neurology, with the potential to lead to new therapies for a wide range of neurological disorders and conditions. Neuroprotection can take various forms and may involve pharmacological agents, lifestyle modifications, or behavioral interventions. Accordingly, also the perspective and the meaning of neuroprotection differs due to different angles of interpretation. The primary interpretation is from the pharmacological point of view since the most consistent data come from this field. In addition, we will discuss also alternative, yet less considered, perspectives on neuroprotection, focusing on specific neuroprotective targets, interactions with surrounding microglia, different levels of neuroprotective effects, the reversive/adaptative dimension, and its use as anticipatory/prophylactic intervention.
Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial
Authors: Peter Grimison, Antony Mersiades, Adrienne Kirby, Annette Tognela, Ian Olver, Rachael L. Morton, Paul Haber, Anna Walsh, Yvonne Lee, Ehtesham Abdi, Stephen Della-Fiorentina, Morteza Aghmesheh, Peter Fox, Karen Briscoe, Jasotha Sanmugarajah, Gavin Marx, Ganessan Kichenadasse, Helen Wheeler, Matthew Chan, Jenny Shannon, Craig Gedye, Stephen Begbie, R. John Simes, Martin R. Stockler
Journal: Journal of Clinical Oncology (2024)

PURPOSE The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components. PATIENTS AND METHODS Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days –1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A). RESULTS We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index—Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD. CONCLUSION THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.
A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease
Authors: Vijaya Raj Bhatt, Valerie K. Shostrom, Hannah K. Choe, Betty K. Hamilton, Krishna Gundabolu, Lori J. Maness, Virender Kumar, Ram I. Mahato, Lynette M. Smith, Taiga Nishihori, Stephanie J. Lee
Journal: Journal of Clinical Oncology (2024)

PURPOSE Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD. PATIENTS AND METHODS In a single-arm multicenter phase II trial (N = 47), adults with sclerotic cGVHD refractory to corticosteroids and ≥one additional line of systemic therapy for cGVHD received ruxolitinib for ≥six months (ClinicalTrials.gov identifier: NCT03616184 ). The primary end point was complete or partial response (PR) in skin and/or joint defined according to the 2014 National Institute of Health cGVHD Consensus Criteria. RESULTS Following the use of ruxolitinib for a median of 11 months, PR in skin and/or joints was noted in 49% (95% CI, 34 to 64) at 6 months, with 45% having joint and fascia response and 19% having skin response. The duration of skin/joint response was 77% (95% CI, 48 to 91) at 12 months. Overall cGVHD PR was noted in 47% (95% CI, 32 to 61). Improvement in Lee Symptom Scale summary and skin subscale scores was noted in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI, 10.0 to 34.1), nonrelapse mortality (NRM) of 2.2% (95% CI, 0.17 to 10.3), and no recurrent malignancy, failure-free survival (FFS) was 77.1% (95% CI, 61.3 to 87.0) at 12 months. Ruxolitinib was overall well tolerated with no new safety signals. CONCLUSION The use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, improvement in patient-reported outcomes, low NRM, and high FFS in patients with refractory sclerotic cGVHD. Ruxolitinib offers an effective treatment option for refractory sclerotic cGVHD.
Context-dependent role of group 3 innate lymphoid cells in mucosal protection
Authors: Leandro P. Araujo, Madeline Edwards, Koichiro Irie, Yiming Huang, Yoshinaga Kawano, Alexander Tran, Simona De Michele, Govind Bhagat, Harris H. Wang, Ivaylo I. Ivanov
Journal: Science Immunology (2024)

How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (T H 17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of T H 17 and T H 22 cell responses to commensal and pathogenic bacteria, and absence of ILC3s did not affect IL-22 production by CD4 T cells before or during infection. However, despite the presence of IL-22–producing T cells, ILC3s and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell–sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with a low dose of Citrobacter rodentium . However, ILC3s promoted pathogen tolerance at early time points of infection by activating tissue-protective immune pathways. Consequently, ILC3s were indispensable for survival after high-dose infection. Our results demonstrate a context-dependent role for ILC3s in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and T H 17 cell functions.
Deciphering internal and external factors influencing intestinal junctional complexes
Authors: Zachary Markovich, Adriana Abreu, Yi Sheng, Sung Min Han, Rui Xiao
Journal: Gut Microbes (2024)

The intestinal barrier, an indispensable guardian of gastrointestinal health, mediates the intricate exchange between internal and external environments. Anchored by evolutionarily conserved junctional complexes, this barrier meticulously regulates paracellular permeability in essentially all living organisms. Disruptions in intestinal junctional complexes, prevalent in inflammatory bowel diseases and irritable bowel syndrome, compromise barrier integrity and often lead to the notorious "leaky gut" syndrome. Critical to the maintenance of the intestinal barrier is a finely orchestrated network of intrinsic and extrinsic factors that modulate the expression, composition, and functionality of junctional complexes. This review navigates through the composition of key junctional complex components and the common methods used to assess intestinal permeability. It also explores the critical intracellular signaling pathways that modulate these junctional components. Lastly, we delve into the complex dynamics between the junctional complexes, microbial communities, and environmental chemicals in shaping the intestinal barrier function. Comprehending this intricate interplay holds paramount importance in unraveling the pathophysiology of gastrointestinal disorders. Furthermore, it lays the foundation for the development of precise therapeutic interventions targeting barrier dysfunction.
When I use a word . . . Fictional drugs and the benefit to harm balance
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

The benefit to harm balance of any therapeutic intervention depends on three factors: the possible benefits, the possible harms, and the possible harms of not intervening. We have words for the conditions that predispose to harms (hazards) and the chance that harms will occur (risks), but no corresponding words for the benefits, for which I suggest "stragard" and "abscisk." Fictional drugs that feature in novels, typically of the dystopian variety, are used for many different purposes, including prevention and treatment of disease, as love potions, to mimic death, to relieve fears and anxiety and promote social harmony, as hallucinogens, to enhance sexual abilities and pleasure, and to prolong life. The benefit to harm balance varies according to indication. Utopian fictions, however, rarely mention fictional drugs, an exception being Aldous Huxley's late novel <i>Island</i>.
Microbial metabolism marvels: a comprehensive review of microbial drug transformation capabilities
Authors: Filippo Martinelli, Ines Thiele
Journal: Gut Microbes (2024)

This comprehensive review elucidates the pivotal role of microbes in drug metabolism, synthesizing insights from an exhaustive analysis of over two hundred papers. Employing a structural classification system grounded in drug atom involvement, the review categorizes the microbiome-mediated drug-metabolizing capabilities of over 80 drugs. Additionally, it compiles pharmacodynamic and enzymatic details related to these reactions, striving to include information on encoding genes and specific involved microorganisms. Bridging biochemistry, pharmacology, genetics, and microbiology, this review not only serves to consolidate diverse research fields but also highlights the potential impact of microbial drug metabolism on future drug design and
Predicting tissue distribution and tumor delivery of nanoparticles in mice using machine learning models
Authors: Kun Mi, Wei-Chun Chou, Qiran Chen, Long Yuan, Venkata N. Kamineni, Yashas Kuchimanchi, Chunla He, Nancy A. Monteiro-Riviere, Jim E. Riviere, Zhoumeng Lin
Journal: Journal of Controlled Release (2024)

Nanoparticles (NPs) can be designed for targeted delivery in cancer nanomedicine, but the challenge is a low delivery efficiency (DE) to the tumor site. Understanding the impact of NPs' physicochemical properties on target tissue distribution and tumor DE can help improve the design of nanomedicines. Multiple machine learning and artificial intelligence models, including linear regression, support vector machine, random forest, gradient boosting, and deep neural networks (DNN), were trained and validated to predict tissue distribution and tumor delivery based on NPs' physicochemical properties and tumor therapeutic strategies with the dataset from Nano-Tumor Database. Compared to other machine learning models, the DNN model had superior predictions of DE to tumors and major tissues. The determination coefficients (R
Vascular Endothelial Growth Factor (VEGF)-B Blockade with CSL346 in Diabetic Kidney Disease
Authors: Melisa Cooper, David Z.I. Cherney, Tom H. Greene, Hiddo J.L. Heerspink, Meg Jardine, Julia B. Lewis, Muh Geot Wong, Elbalejandra Baquero, Mark Heise, Jeanine Jochems, Diana Lanchoney, Charles Liss, David Reiser, Pierre Scotney, Elena Velkoska, Jamie P. Dwyer
Journal: Journal of the American Society of Nephrology (2024)

Key Points The vascular endothelial growth factor B inhibitor CSL346 (8 or 16 mg/kg q4w) did not reduce urinary albumin-creatinine ratio at week 16 versus placebo in patients with type 2 diabetes mellitus and diabetic kidney disease. CSL346 was generally well tolerated at both doses; however, CSL346 (16 mg/kg) significantly increased diastolic BP versus placebo. Background Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes. Reducing VEGF-B activity in animal models of DKD using an anti–VEGF-B antibody improved histological evidence of glomerular injury and reduced albuminuria, effects attributed to prevention of ectopic lipid deposition in the kidney. CSL346 is a novel humanized monoclonal antibody that binds VEGF-B with high affinity. Targeting VEGF-B in patients with type 2 diabetes mellitus may improve DKD progression markers. Methods An international, randomized, double-blind, placebo-controlled, phase 2a study (NCT04419467) assessed CSL346 (8 or 16 mg/kg subcutaneously every 4 weeks for 12 weeks) in participants with type 2 diabetes mellitus and a urinary albumin-creatinine ratio (UACR) ≥150 mg/g (17.0 mg/mmol), and eGFR &gt;20 ml/min per 1.73 m 2 . Efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of CSL346 were evaluated. The primary analysis compared the change from baseline in log-transformed UACR between the two CSL346 dose groups combined versus placebo at week 16. Results In total, 114 participants were randomized. CSL346 did not significantly reduce UACR compared with placebo at week 16 (combined CSL346 group difference from placebo [95% confidence interval], 4.0% [−14.7 to 26.8]). Furthermore, no effect was seen in participant subgroups (degree of kidney impairment or sodium-glucose cotransporter 2 inhibitor use) or on urinary biomarkers reflecting proximal tubular injury. CSL346 was generally well tolerated; however, diastolic BP was significantly higher with CSL346 16 mg/kg versus placebo from week 2 onward, with differences ranging from +3.8 to +5.3 mm Hg ( P = 0.002 at week 16). Conclusions CSL346 did not reduce UACR compared with placebo at 16 weeks in participants with type 2 diabetes mellitus and DKD and was associated with an increase in diastolic BP. Clinical Trial registry name and registration number: VEGF-B Blockade with the Monoclonal Antibody CSL346 in Subjects with DKD, NCT04419467.
Evaluation of NCI-Designated Cancer Center and Comprehensive Cancer Center Survivorship-Focused Websites: Information Provided and Accessibility
Authors: Rachel T. Kurtzman, Lisa Mikesell, Benjamin F. Crabtree
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Individuals with a history of cancer increasingly seek health information from online resources, including NCI-designated Cancer Center websites. Centers receive NCI designation because they provide excellent care and engage in cutting-edge research. However, the information presented on these webpages and their accessibility is unknown. An evaluation of the survivorship-focused webpages from NCI-designated Cancer Centers is needed to assess survivorship information and accessibility of these webpages. Methods: We conducted an evaluation of the survivorship-focused webpages from 64 NCI-designated Cancer Centers. We evaluated where survivorship-focused webpages were housed, if there was a survivorship clinic or program, target audience of the webpage, how cancer survivor was defined, contact methods, and available resources. Accessibility outcomes included readability, font type, font size, color scheme, and alternative text (alt text) descriptors. An artificial intelligence (AI) audit was conducted to assess if the webpage was compliant with national accessibility guidelines. Results: Most cancer centers had a survivorship-focused webpage, with 72% located on the cancer center’s website and 28% on a health system website. Survivorship information available varied considerably and was often lacking in detail. Although three-quarters of webpages targeted patients only, variable definitions of cancer survivor were observed. Accessibility issues identified included inconsistent use of alt text descriptors, font size smaller than 15 points, and color schemes without adequate contrast. The average reading-level of information presented was above 12th grade. Only 9% of webpages were compliant with online accessibility guidelines; 72% semicompliant and 21% were noncompliant. Conclusions: Information presented on NCI-designated Cancer Center survivorship-focused webpages was inconsistent, often lacking, and inaccessible. NCI-designated Cancer Centers are role models for cancer research in the United States and have an obligation to provide survivorship information. Changes to content and website design are needed to provide better information for individuals seeking resources and health information relative to their cancer and care.
Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
Authors: Hui Wang, Timothy S Chang, Beth A Dombroski, Po-Liang Cheng, Vishakha Patil, Leopoldo Valiente-Banuet, Kurt Farrell, Catriona Mclean, Laura Molina-Porcel, Alex Rajput, Peter Paul De Deyn, Nathalie Le Bastard, Marla Gearing, Laura Donker Kaat, John C Van Swieten, Elise Dopper, Bernardino F Ghetti, Kathy L Newell, Claire Troakes, Justo G de Yébenes, Alberto Rábano-Gutierrez, Tina Meller, Wolfgang H Oertel, Gesine Respondek, Maria Stamelou, Thomas Arzberger, Sigrun Roeber, Ulrich Müller, Franziska Hopfner, Pau Pastor, Alexis Brice, Alexandra Durr, Isabelle Le Ber, Thomas G Beach, Geidy E Serrano, Lili-Naz Hazrati, Irene Litvan, Rosa Rademakers, Owen A Ross, Douglas Galasko, Adam L Boxer, Bruce L Miller, Willian W Seeley, Vivanna M Van Deerlin, Edward B Lee, Charles L White, Huw Morris, Rohan de Silva, John F Crary, Alison M Goate, Jeffrey S Friedman, Yuk Yee Leung, Giovanni Coppola, Adam C Naj, Li-San Wang, Clifton Dalgard, Dennis W Dickson, Günter U Höglinger, Gerard D Schellenberg, Daniel H Geschwind, Wan-Ping Lee
Journal: Molecular Neurodegeneration (2024)

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT , MOBP , S TX6 , SLCO1A2 , DUSP10 , and SP1 , and further uncovered novel signals in APOE , FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1 . Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH , PCMT1 , CYP2A13 , and SMCP . In the H1/H2 haplotype region, there is a burden of rare deletions and duplications ( P = 6.73 × 10 –3 ) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.