tbuckley/cabot-search huggingface dataset:
International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials
Authors: Marko M. Popovic, Michael Balas, SriniVas R. Sadda, David Sarraf, Ryan Huang, Sophie J. Bakri, Audina Berrocal, Andrew Chang, Chui Ming Gemmy Cheung, Sunir Garg, Roxane J. Hillier, Frank G. Holz, Mark W. Johnson, Peter K. Kaiser, Peter J. Kertes, Timothy Y.Y. Lai, Jason Noble, Susanna S. Park, Yannis M. Paulus, Giuseppe Querques, Aleksandra Rachitskaya, Paisan Ruamviboonsuk, Shohista Saidkasimova, Maria Teresa Sandinha, David H. Steel, Hiroko Terasaki, Christina Y. Weng, Basil K. Williams, Lihteh Wu, Rajeev H. Muni
Journal: Ophthalmology (2024)

OBJECTIVEComplications associated with intravitreal anti-vascular endothelial growth factor (VEGF) therapies are inconsistently reported in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process.DESIGNSystematic review and Delphi consensus process.PARTICIPANTS25 international retinal specialists participated in the Delphi consensus survey.METHODSA systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists that voted on inclusion, exclusion, rephrasing, and addition of complications. As well, surveys determined specifiers for the selected complications. This iterative process helped refine the final classification system.MAIN OUTCOME MEASURESThe proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration.RESULTSAfter screening 18,229 articles, 130 complications were initially categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 (70%) complications after three rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 (52%) complications in the final list. A total of 14 (11%) complications met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds were also excluded from the final classification system after the Delphi process terminated. In addition, 47 out of 75 (63%) proposed complication specifiers were included based on participant agreement.CONCLUSIONUsing the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses.
Genetic-informed proteome-wide scan reveals potential causal plasma proteins for idiopathic pulmonary fibrosis
Authors: Jiahao Zhu, Houpu Liu, Rui Gao, Ruicheng Gong, Jing Wang, Dan Zhou, Min Yu, Yingjun Li
Journal: Thorax (2024)

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which there are no reliable biomarkers or disease-modifying drugs. Here, we integrated human genomics and proteomics to investigate the causal associations between 2769 plasma proteins and IPF. Our Mendelian randomisation analysis identified nine proteins associated with IPF, of which three (FUT3, ADAM15 and USP28) were colocalised. ADAM15 emerged as the top candidate, supported by expression quantitative trait locus analysis in both blood and lung tissue. These findings provide novel insights into the aetiology of IPF and offer translational opportunities in response to the clinical challenges of this devastating disease.
Traffic on the TLR expressway
Authors: Justin Taft, Dusan Bogunovic
Journal: The Journal of Experimental Medicine (2024)

Genetic variation in UNC93B1, a key component in TLR trafficking, can lead to autoinflammation caused by increased TLR activity. Analysis of seven patient variants combined with a comprehensive alanine screen revealed that different regions of UNC93B1 selectively regulate different TLRs (Rael et al. https://doi.org/10.1084/jem.20232005; David et al. https://doi.org/10.1084/jem.20232066).
Feasibility and tolerance of high-dose methotrexate (HDMTX) in older patients with osteosarcoma.
Authors: Aurora Norman, Brittany L Siontis, Thanh P Ho, Matthew T. Houdek, Scott H. Okuno, Steven Ian Robinson
Journal: Journal of Clinical Oncology (2024)

11521 Background: Osteosarcomas (OS) comprise the majority of new primary bone tumors in the US and affect a bimodal distribution of young adults (2nd-3rd decades) and older adults &gt;65 yrs. Most large collaborative studies demonstrating the efficacy of HDMTX-containing chemotherapy regimens in OS limited enrollment to patients &lt;40 yrs. Our study aims to fill the gap of reported clinical outcomes in adult OS patients ≥ 40 yrs by describing the feasibility and tolerability of HDMTX in these patients at Mayo Clinic. Methods: We conducted a retrospective chart review of patients ≥18 yrs with OS seen at our institution between 1/1/1980-9/30/2019 and who received ≥1 dose of HDMTX (12 g/m 2 , max 20 g). Extraosseous OS were excluded. Survival analyses were run for both the entire study population and the subset of patients age ≥40. Patient demographics, disease characteristics, and clinical outcomes were collected. The primary outcome evaluated was 5-year overall survival (5-yr OS). Results: We identified 94 patients whose demographic data are summarized (Table). Twenty-three of 94 (24%) were ≥40 yrs. Both the median number of HDMTX doses received and number of patients who received ≥50% recommended doses were significantly less among patients ≥40 yrs. However, HDMTX-related AKI and median number of hospital days did not differ significantly between the age groups. Among all patients, 5-yr OS was significantly improved (p=0.0025) at 45% (95% CI 35%-58%) for those who received ≥50% doses HDMTX compared to 5-yr OS of 25% (95% CI 12%-53%) for those who did not. Among patients ≥40 yrs, 5-yr OS was significantly improved (p=0.017) at 86% (95% CI 63%-100%) for those who received ≥50% doses HDMTX compared to 5-yr OS of 31% (95% CI 14%-68%) for those who did not. Conclusions: In our cohort, 5-yr OS was superior in those patients who received at least 50% of the planned doses of HDMTX. Older adults were significantly less likely to receive the majority of planned doses, which may be due to clinician bias regarding anticipated toxicity. However, we show that common HDMTX-associated toxicities did not vary significantly by age. If feasible, we recommend referring older patients with osteosarcoma to centers equipped to handle the staffing and supportive care needs of HDMTX administration. [Table: see text]
A phase II study of anlotinib and an anti-PDL1 antibody in patients with alveolar soft part sarcoma: Results of expansion cohorts.
Authors: Zhichao Tan, Yan Wu, Zhengfu Fan, Jiayong Liu, Tian Gao, Chujie Bai, Ruifeng Xue, Shu Li, Lu Zhang, Xinyu Wang
Journal: Journal of Clinical Oncology (2024)

11515 Background: The combination of the anti-angiogenesis tyrosine kinase inhibitor (TKI), anlotinib, with the anti-programmed death-ligand 1 (PDL1) antibody (TQB2450) demonstrated commendable antitumor efficacy in a phase II clinical trial for pan-sarcoma patients, particularly within the alveolar soft part sarcoma (ASPS) cohorts (Liu et al., 2022, PMID: 35675031). An expansion of the ASPS cohort has been underway since 2019. Herein, we present the observed efficacy within this ASPS-specific expansion cohort. Methods: ASPS patients naïve to TKIs or immunotherapy received TQB2450 (1200mg) intravenously on day 1, in combination with oral administration of anlotinib (12mg) from day 1 to 14, repeated every 3 weeks. The primary endpoint was best objective response rate (ORR, per RECIST v1.1). Secondary endpoints comprised median progression free survival (PFS), median overall survival (OS), duration of response (DOR), and adverse events (AEs). Formalin-fixed paraffin-embedded (FFPE) slides were taken for immunohistochemistry and examined for lymphocyte marker expression. Results: Twenty-nine patients were enrolled in the phase II trial. The median age was 29 years (range: 19-46), with female 48.3%. A subset of patients (20.7%) had undergone prior lines of chemotherapy. Twenty-eight patients were evaluable for efficacy (one withdrew). The ORR for evaluable patients reached 79.3%, characterized by 3 complete responses and 20 partial responses. The median PFS (months) was not reached (95%CI: 20.7, not-reached). The median DOR (months) for responders was not reached (95%CI: 18.0, not-reached). No mortalities occurred during the follow-up. Treatment demonstrated favorable tolerability, with predominant grade 1 and 2 AEs. Thirteen patients (44.83%) experienced grade ≥3 AEs, principally hypertriglyceridemia (13.79%), lipase elevation (6.90%), amylase elevation (3.45%), and hypertension (3.45%). A detailed analysis of the tumor microenvironment in 7 patients, including 3 good responders and 4 poor responders, revealed a significant discrepancy in the presence of tertiary lymphoid structures (TLS) between the two groups (refer to Table). Conclusions: The combination of anlotinib and TQB2450 exhibits promising efficacy in ASPS patients, markedly enhancing ORR and extending PFS with favorable tolerability. Notably, TLS emerges as a potential predictive indicator of immunotherapeutic efficacy in ASPS. Clinical trial information: CTR20190938 . [Table: see text]
Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship
Authors: Tibila Kientega, Sophie Marcoux, Jessica Bourbonnais, Jade Montpetit, Maxime Caru, Guillaume B. Cardin, Nathalie Arbour, Valérie Marcil, Daniel Curnier, Caroline Laverdière, Daniel Sinnett, Francis Rodier
Journal: Blood Cancer Journal (2024)

Childhood acute lymphoblastic leukemia (cALL) survivors suffer early-onset chronic diseases classically associated with aging. Normal aging is accompanied by organ dysfunctions, including immunological ones. We hypothesize that thymic immunosenescence occurs in cALL survivors and that its severity may correlate with early-onset chronic diseases. The PETALE study is a cALL survivor cohort with an extensive cardiovascular and metabolic evaluation. The thymic immunosenescence biomarker, signal joint T-cell receptor excision circles (TREC), was evaluated and was highly correlated with age in healthy participants (n = 281) and cALL survivors (n = 248). We observed a systematic thymic immunoage accentuation in each cALL survivor compared to controls ranging from 5.9 to 88.3 years. The immunoage gain was independent of age at diagnosis and treatment modalities and was more severe for females. Thymic aging was associated with several pathophysiological parameters, was greater in survivors suffering from metabolic syndrome, but there was no significant association with global physical condition. The decrease in TREC was independent from blood cell counts, which were normal, suggesting a segmental aging of the thymic compartment. Indeed, increased plasmatic T cell regulatory cytokines IL-6, IL-7 and GM-CSF accompanied high immunoage gain. Our data reveal that cALL or its treatment trigger a rapid immunoage gain followed by further gradual thymic immunosenescence, similar to normal aging. This leads to an enduring shift in accentuated immunoage compared to chronological age. Thus, accentuated thymic immunosenescence is a hallmark of cALL survivorship and TREC levels could be useful immunosenescence biomarkers to help monitoring the health of cancer survivors.
Comprehensive analysis of resilience of human airway epithelial barrier against short‐term PM2.5 inorganic dust exposure using in vitro microfluidic chip and ex vivo human airway models
Authors: Ozlem Goksel, Meryem Irem Sipahi, Sena Yanasik, Pelin Saglam‐Metiner, Sema Benzer, Leila Sabour‐Takanlou, Maryam Sabour‐Takanlou, Cigir Biray‐Avci, Ozlem Yesil‐Celiktas
Journal: Allergy (2024)

Abstract Background and Objective The updated World Health Organization (WHO) air quality guideline recommends an annual mean concentration of fine particulate matter (PM2.5) not exceeding 5 or 15 μg/m 3 in the short‐term (24 h) for no more than 3–4 days annually. However, more than 90% of the global population is currently exposed to daily concentrations surpassing these limits, especially during extreme weather conditions and due to transboundary dust transport influenced by climate change. Herein, the effect of respirable &lt;PM2.5 inorganic silica particle exposures on epithelial barrier integrity was simultaneously evaluated within the biomimetic microfluidic platform‐based airway epithelial barrier (AEB)‐on‐a‐chip and human bronchoscopic ex vivo airway tissue models, comparatively. Methods Silica particles at an average size of 1 μm, referred to as &lt;PM2.5, dose‐dependently tested by MTT and LDH analyses. The elicited dose of 800 μg/mL was applied to human airway epithelial cells (Calu‐3) seeded to the membrane at air–liquid interface in the AEB‐on‐a‐chip platform, which is operated under static and dynamic conditions and to ex vivo human bronchoscopy bronchial tissue slices for 72 h. For both models, healthy and exposed groups were comparatively investigated. Computational fluid dynamics simulations were performed to assess shear stress profiles under different flow conditions. Qualitative and quantitative analyses were carried out to evaluate the resilience of the epithelial barrier via cell survivability, morphology, barrier integrity, permeability, and inflammation. Results In the AEB‐on‐a‐chip platform, short‐term exposure to 800 μg/mL PM2.5 disrupted AEB integrity via increasing barrier permeability, decreasing cell adhesion‐barrier markers such as ZO‐1 , Vinculin , ACE2 , and CD31 , impaired cell viability and increased the expression levels of proinflammatory markers; IFNs , IL‐6 , IL‐1s , TNF‐α , CD68 , CD80 , and Inos , mostly under dynamic conditions. Besides, decreased tissue viability, impaired tissue integrity via decreasing of Vinculin , ACE2 , β‐catenin , and E‐cadherin , and also proinflammatory response with elevated CD68 , IL‐1 α, IL‐6 , IFN‐Ɣ , Inos , and CD80 markers, were observed after PM2.5 exposure in ex vivo tissue. Conclusion The duration and concentration of PM2.5 that can be exposed during extreme weather conditions and natural events aligns with our exposure model (0–800 μg/mL 72 h). At this level of exposure, the resilience of the epithelial barrier is demonstrated by both AEB‐on‐a‐chip platform emulating dynamic forces in the body and ex vivo bronchial biopsy slices. Lung‐on‐a‐chip models will serve as reliable exposure models in this context.
Challenges in pig-to-human kidney xenotransplantation
Authors: Yu-An Liu, Chih-Yu Yang, Der-Cherng Tarng
Journal: The Lancet (2024)

Alexandre Loupy and colleagues1Loupy A Goutaudier V Giarraputo A et al.Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study.Lancet. 2023; 402: 1158-1169Summary Full Text Full Text PDF PubMed Google Scholar reported an exciting breakthrough in porcine kidney xenotransplantation into human recipients. The results in figures 3 and 4 have drawn our attention. The authors observed increased expression of multiple HLA genes by next-generation sequencing. Since the xenografts before implantation (the control group in figure 3A) were taken directly from pigs and had not been perfused with human blood, they are expected to express swine leukocyte antigen (SLA), not HLA. The possibility of cross-reaction between different species is slim because the number of SLA-expressing cells (pig kidney) substantially outweighs any trace of human cells in the transplanted kidney (the experimental group in figure 3A). Because the volcano plots of differentially expressed genes in figures 3 and 4 are presented as fold changes, we wonder how the fold changes were calculated if the numbers used for comparison are zero (human genes are not detectable in the control group). We declare no competing interests. Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping studyDespite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results. Full-Text PDF Challenges in pig-to-human kidney xenotransplantation – Authors' replyThe Correspondence from Liming Cheng and Kai Liu on our Article1 contains several comments that deserve further discussion. The decision to use thymokidneys from pigs with only the alpha-1, 3-galactosyltransferase antigen knocked out (Gal-KO) was made for several reasons.2 First, this herd is being successfully bred, making it easy to rapidly produce Gal-KO pigs at the large scale that is needed if xenotransplantation is to effectively address the shortage of organs for human transplantation. To consistently breed pigs with a substantial number of genetic edits is currently challenging. Full-Text PDF
Offline: Japan's hidden secret
Authors: Richard Horton
Journal: The Lancet (2024)

Japan deserves a great deal of admiration and respect for the way in which, after the nuclear devastation of World War 2, it rebuilt its health system, delivered universal health coverage within a generation, and implemented innovative social protections for vulnerable groups in society, such as its older citizens. The country's political leaders have been principled voices in global health advocacy. Keizo Takemi has been a particular champion of equity and health system strengthening, roles he continues to develop as a member of the House of Councillors in the National Diet of Japan.
Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial
Authors: Mark W Parsons, Vignan Yogendrakumar, Leonid Churilov, Carlos Garcia-Esperon, Bruce C V Campbell, Michelle L Russell, Gagan Sharma, Chushuang Chen, Longting Lin, Beng Lim Chew, Felix C Ng, Akshay Deepak, Philip M C Choi, Timothy J Kleinig, Dennis J Cordato, Teddy Y Wu, John N Fink, Henry Ma, Thanh G Phan, Hugh S Markus, Carlos A Molina, Chon-Haw Tsai, Jiunn-Tay Lee, Jiann-Shing Jeng, Daniel Strbian, Atte Meretoja, Juan F Arenillas, Brian H Buck, Michael J Devlin, Helen Brown, Ken S Butcher, Billy O'Brien, Arman Sabet, Tissa Wijeratne, Andrew Bivard, Rohan S Grimley, Smriti Agarwal, Sunil K Munshi, Geoffrey A Donnan, Stephen M Davis, Ferdinand Miteff, Neil J Spratt, Christopher R Levi
Journal: The Lancet Neurology (2024)
Depleting profibrotic macrophages using bioactivated in vivo assembly peptides ameliorates kidney fibrosis
Authors: Qing Ouyang, Chao Wang, Tian Sang, Yan Tong, Jian Zhang, Yulan Chen, Xue Wang, Lingling Wu, Xu Wang, Ran Liu, Pu Chen, Jiaona Liu, Wanjun Shen, Zhe Feng, Li Zhang, Xuefeng Sun, Guangyan Cai, Li-Li Li, Xiangmei Chen
Journal: Cellular and Molecular Immunology (2024)
Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial
Authors: Sarah E Silk, Wilmina F Kalinga, Jo Salkeld, Ivanny M Mtaka, Saumu Ahmed, Florence Milando, Ababacar Diouf, Caroline K Bundi, Neema Balige, Omar Hassan, Catherine G Mkindi, Stella Rwezaula, Thabit Athumani, Sarah Mswata, Nasoro S Lilolime, Beatus Simon, Hania Msami, Mohamed Mohamed, Damiano M David, Latipha Mohammed, Gloria Nyaulingo, Bakari Mwalimu, Omary Juma, Tunu G Mwamlima, Ibrahim A Sasamalo, Rose P Mkumbange, Janeth J Kamage, Jordan R Barrett, Lloyd D W King, Mimi M Hou, David Pulido, Cecilia Carnrot, Alison M Lawrie, Rachel E Cowan, Fay L Nugent, Rachel Roberts, Jee-Sun Cho, Carole A Long, Carolyn M Nielsen, Kazutoyo Miura, Simon J Draper, Ally I Olotu, Angela M Minassian
Journal: The Lancet Infectious Diseases (2024)

A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time.
Psychological and psychosocial interventions for treatment-resistant schizophrenia: a systematic review and network meta-analysis
Authors: Nurul Husna Salahuddin, Alexandra Schütz, Gabi Pitschel-Walz, Susanna Franziska Mayer, Anna Chaimani, Spyridon Siafis, Josef Priller, Stefan Leucht, Irene Bighelli
Journal: The Lancet Psychiatry (2024)

Many patients with schizophrenia have symptoms that do not respond to antipsychotics. This condition is called treatment-resistant schizophrenia and has not received specific attention as opposed to general schizophrenia. Psychological and psychosocial interventions as an add-on treatment to pharmacotherapy could be useful, but their role and comparative efficacy to each other and to standard care in this population are not known. We investigated the efficacy, acceptability, and tolerability of psychological and psychosocial interventions for patients with treatment-resistant schizophrenia.
No accident: the UK infected blood scandal
Authors: None The Lancet Gastroenterology & Hepatology
Journal: The Lancet. Gastroenterology & hepatology (2024)

"This disaster was not an accident", remarked Sir Brian Langstaff at the publication of the Infected Blood Inquiry's report on May 20. In seven volumes, the report that Langstaff chairs details the institutional and individual failures that led to the infection of more than 30 000 people in the UK with viral hepatitis and HIV between 1970 and 1991. The audience at the launch met Langstaff's long-awaited conclusion with applause. For decades and against a culture of denial and resistance they have campaigned for justice in the wake of a scandal that has left 3000 dead and many more sick, grieving, and traumatised.