tbuckley/cabot-search huggingface dataset:
Bias in vaccine effectiveness studies of clinically severe outcomes that are measured with low specificity: the example of COVID-19-related hospitalisation
Authors: Christian Holm Hansen
Journal: Eurosurveillance (2024)

Many vaccine effectiveness (VE) analyses of severe disease outcomes such as hospitalisation and death include ‘false’ cases that are not actually caused by the infection or disease under study. While the inclusion of such false cases inflate outcome rates in both vaccinated and unvaccinated populations, it is less obvious how they affect estimates of VE. Illustrating the main points through simple examples, this article shows how VE is underestimated when false cases are included as outcomes. Depending how the outcome indicator is defined, estimates of VE against severe disease outcomes, whose definition allows for the inclusion of false cases, will be biased downwards and may in certain circumstances approximate the same level as the VE against infection. The bias is particularly pronounced for vaccines that offer high levels of protection against severe disease outcomes but poor protection against infection. Analysing outcomes that are measured with low sensitivity generally does not cause bias in VE studies; defining outcome indicators that minimise the number of false cases rather than the number of missed cases is preferable in VE studies.
Editor's Note: Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment
Authors: Alissa Huston, Xavier Leleu, Xiaoying Jia, Anne-Sophie Moreau, Hai T. Ngo, Judith Runnels, Judy Anderson, Yazan Alsayed, Aldo Roccaro, Sonia Vallet, Evdoxia Hatjiharissi, Yu-Tsu Tai, Peter Sportelli, Nikhil Munshi, Paul Richardson, Teru Hideshima, David G. Roodman, Kenneth C. Anderson, Irene M. Ghobrial
Journal: Clinical Cancer Research (2024)

alert readers to a concern about this article (1): in Fig. 3D, the Western blot for HSP27 has six lanes, which does not match the seven lanes shown in the rest of the runs (p-HSP27, HSP70, HSP90, and alpha tubulin) or the corresponding treatment amounts of perifosine and 17-DMAG.
2023/24 mid-season influenza and Omicron XBB.1.5 vaccine effectiveness estimates from the Canadian Sentinel Practitioner Surveillance Network (SPSN)
Authors: Danuta M Skowronski, Yuping Zhan, Samantha E Kaweski, Suzana Sabaiduc, Ayisha Khalid, Romy Olsha, Sara Carazo, James A Dickinson, Richard G Mather, Hugues Charest, Agatha N Jassem, Inès Levade, Maan Hasso, Nathan Zelyas, Ruimin Gao, Nathalie Bastien
Journal: Eurosurveillance (2024)

The Canadian Sentinel Practitioner Surveillance Network reports mid-season 2023/24 influenza vaccine effectiveness (VE) of 63% (95% CI: 51–72) against influenza A(H1N1)pdm09, lower for clade 5a.2a.1 (56%; 95% CI: 33–71) than clade 5a.2a (67%; 95% CI: 48–80), and lowest against influenza A(H3N2) (40%; 95% CI: 5–61). The Omicron XBB.1.5 vaccine protected comparably well, with VE of 47% (95% CI: 21–65) against medically attended COVID-19, higher among people reporting a prior confirmed SARS-CoV-2 infection at 67% (95% CI: 28–85).
A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial
Authors: Andreas H. Diacon, Clifton E. Barry, Alex Carlton, Ray Y. Chen, Matt Davies, Veronique de Jager, Kim Fletcher, Gavin C. K. W. Koh, Irina Kontsevaya, Jan Heyckendorf, Christoph Lange, Maja Reimann, Sophie L. Penman, Rhona Scott, Gareth Maher-Edwards, Simon Tiberi, Georgios Vlasakakis, Caryn M. Upton, David Barros Aguirre
Journal: Nature Medicine (2024)

Abstract New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis. ClinicalTrials.gov identifier: NCT03557281 .
Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial
Authors: Jeffrey I. Weitz, László B. Tankó, Jürgen Floege, Keith A. A. Fox, Deepak L. Bhatt, Ravi Thadhani, James Hung, Ákos F. Pap, Dagmar Kubitza, Wolfgang C. Winkelmayer
Journal: Nature Medicine (2024)

Abstract Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab—an inhibitory FXIa antibody—is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220 .
Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma
Authors: Johannes R. Björk, Laura A. Bolte, Andrew Maltez Thomas, Karla A. Lee, Niccolo Rossi, Thijs T. Wind, Lotte M. Smit, Federica Armanini, Francesco Asnicar, Aitor Blanco-Miguez, Ruth Board, Neus Calbet-Llopart, Lisa Derosa, Nathalie Dhomen, Kelly Brooks, Mark Harland, Mark Harries, Paul Lorigan, Paolo Manghi, Richard Marais, Julia Newton-Bishop, Luigi Nezi, Federica Pinto, Miriam Potrony, Susana Puig, Patricio Serra-Bellver, Heather M. Shaw, Sabrina Tamburini, Sara Valpione, Levi Waldron, Laurence Zitvogel, Moreno Zolfo, Elisabeth G. E. de Vries, Paul Nathan, Rudolf S. N. Fehrmann, Tim D. Spector, Véronique Bataille, Nicola Segata, Geke A. P. Hospers, Rinse K. Weersma
Journal: Nature Medicine (2024)

Abstract Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS &lt;12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and &lt;12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.
<scp>APCs</scp> in sinus floor augmentation
Authors: Pascal Valentini, Elena Calciolari, Sebastien Monlezun, Aliye Akcalı, Nikos Donos, Marc Quirynen
Journal: Periodontology 2000 (2024)

Abstract After tooth loss in the posterior area of the maxilla, sinus floor elevation is often required to compensate the vertical bone loss due to sinus pneumatization. This narrative review reports on the potential benefits of autologous platelet concentrates (APCs) during this procedure. As for transcrestal approach, APCs have been used as “sole” substitute/graft. However, because of the low number of clinical trials available with PRGF, and even none for PRP, no definitive conclusions can be made regarding their efficacy. The number of studies on the use of L‐PRF were outnumbered indicating good feasibility for vertical bone gain, with a high implant survival rate and a low degree of complications. PRP and PRGF have not been studied as a “single/sole” substitute for a one‐stage lateral window approach, probably because of the weak physical characteristics of the membranes. L‐PRF alone appears to be a predictable grafting material for lateral maxillary sinus grafting and a reduced RBH should not be considered as a risk factor. Compared to a “standard” bone substitute L‐PRF shows slightly less vertical bone gain (consider enough membrane application and use of bony window as new sinus floor roof over the implant apices), enhanced early resorption (first 6 months after application), but a similar stable bone gain afterward. For a two‐stage lateral window approach, APCs “alone” cannot be recommended, due to their weak withstand to the sinus pneumatization forces. APCs combined with bone substitutes seem to accelerate bone formation, without any additional benefits on the long‐term new bone gain. The use of L‐PRF membranes for the treatment of perforations appears to be an effective treatment option, but further clinical studies are needed to confirm this. Even though the abovementioned statements are based on large numbers of studies, additional RCTs comparing APCs with different types of grafting procedures for sinus elevation are needed.
Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19
Authors: Josefine Radke, Jenny Meinhardt, Tom Aschman, Robert Lorenz Chua, Vadim Farztdinov, Sören Lukassen, Foo Wei Ten, Ekaterina Friebel, Naveed Ishaque, Jonas Franz, Valerie Helena Huhle, Ronja Mothes, Kristin Peters, Carolina Thomas, Shirin Schneeberger, Elisa Schumann, Leona Kawelke, Julia Jünger, Viktor Horst, Simon Streit, Regina von Manitius, Péter Körtvélyessy, Stefan Vielhaber, Dirk Reinhold, Anja E. Hauser, Anja Osterloh, Philipp Enghard, Jana Ihlow, Sefer Elezkurtaj, David Horst, Florian Kurth, Marcel A. Müller, Nils C. Gassen, Julia Melchert, Katharina Jechow, Bernd Timmermann, Camila Fernandez-Zapata, Chotima Böttcher, Werner Stenzel, Elke Krüger, Markus Landthaler, Emanuel Wyler, Victor Corman, Christine Stadelmann, Markus Ralser, Roland Eils, Frank L. Heppner, Michael Mülleder, Christian Conrad, Helena Radbruch
Journal: Nature Neuroscience (2024)
RUBICON: a framework for designing efficient deep learning-based genomic basecallers
Authors: Gagandeep Singh, Mohammed Alser, Kristof Denolf, Can Firtina, Alireza Khodamoradi, Meryem Banu Cavlak, Henk Corporaal, Onur Mutlu
Journal: Genome biology (2024)

Nanopore sequencing generates noisy electrical signals that need to be converted into a standard string of DNA nucleotide bases using a computational step called basecalling. The performance of basecalling has critical implications for all later steps in genome analysis. Therefore, there is a need to reduce the computation and memory cost of basecalling while maintaining accuracy. We present RUBICON, a framework to develop efficient hardware-optimized basecallers. We demonstrate the effectiveness of RUBICON by developing RUBICALL, the first hardware-optimized mixed-precision basecaller that performs efficient basecalling, outperforming the state-of-the-art basecallers. We believe RUBICON offers a promising path to develop future hardware-optimized basecallers.
Ripple-locked coactivity of stimulus-specific neurons and human associative memory
Authors: Lukas Kunz, Bernhard P. Staresina, Peter C. Reinacher, Armin Brandt, Tim A. Guth, Andreas Schulze-Bonhage, Joshua Jacobs
Journal: Nature Neuroscience (2024)

Abstract Associative memory enables the encoding and retrieval of relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves temporally correlated spiking of medial temporal lobe (MTL) neurons that exhibit stimulus-specific tuning. Using single-neuron recordings from patients with epilepsy performing an associative object–location memory task, we identified the object-specific and place-specific neurons that represented the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object-specific and place-specific neurons activated together during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients’ associative learning progressed. Between encoding and retrieval, the ripple-locked timing of coactivity shifted, suggesting flexibility in the interaction between MTL neurons and hippocampal ripples according to behavioral demands. Our results are consistent with a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli.
3D Printing of Cobalt‐Incorporated Chloroapatite Bioceramic Composite Scaffolds with Antioxidative Activity for Enhanced Osteochondral Regeneration
Authors: Chaoqin Shu, Chen Qin, Aijun Wu, Yufeng Wang, Chaoqian Zhao, Zhe Shi, Huicong Niu, Jiajie Chen, Jimin Huang, Xinxin Zhang, Zhiguang Huan, Lei Chen, Min Zhu, Yufang Zhu
Journal: Advanced Healthcare Materials (2024)

Osteochondral defects are often accompanied by excessive reactive oxygen species (ROS) caused by osteoarthritis or acute surgical inflammation. An inflammatory environment containing excess ROS will not only hinder tissue regeneration but also impact the quality of newly formed tissues. Therefore, there is an urgent need to develop scaffolds with both ROS scavenging and osteochondral repair functions to promote and protect osteochondral tissue regeneration. In this work, by using 3D printing technology, a composite scaffold based on cobalt-incorporated chloroapatite (Co-ClAP) bioceramics, which possesses ROS-scavenging activity and can support cell proliferation, adhesion, and differentiation, is developed. Benefiting from the catalytic activity of Co-ClAP bioceramics, the composite scaffold can protect cells from oxidative damage under ROS-excessive conditions, support their directional differentiation, and simultaneously mediate an anti-inflammatory microenvironment. In addition, it is also confirmed by using rabbit osteochondral defect model that the Co-ClAP/poly(lactic-co-glycolic acid) scaffold can effectively promote the integrated regeneration of cartilage and subchondral bone, exhibiting an ideal repair effect in vivo. This study provides a promising strategy for the treatment of defects with excess ROS and inflammatory microenvironments.
A TNF-IL-1 circuit controls <i>Yersinia</i> within intestinal pyogranulomas
Authors: Rina Matsuda, Daniel Sorobetea, Jenna Zhang, Stefan T. Peterson, James P. Grayczyk, Winslow Yost, Nicolai Apenes, Maria E. Kovalik, Beatrice Herrmann, Rosemary J. O’Neill, Andrea C. Bohrer, Matthew Lanza, Charles-Antoine Assenmacher, Katrin D. Mayer-Barber, Sunny Shin, Igor E. Brodsky
Journal: The Journal of Experimental Medicine (2024)

Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. We previously reported that Yersinia pseudotuberculosis colonizes the intestinal mucosa and induces the recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas (PG) that control Yersinia infection. Inflammatory monocytes are essential for the control and clearance of Yersinia within intestinal PG, but how monocytes mediate Yersinia restriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following enteric Yersinia infection. We further show that monocyte-intrinsic TNFR1 signaling drives the production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptors on non-hematopoietic cells to enable PG-mediated control of intestinal Yersinia infection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative inflammatory circuit that restricts intestinal Yersinia infection.
Causal phase-dependent control of non-spatial attention in human prefrontal cortex
Authors: Jeroen Brus, Joseph A. Heng, Valeriia Beliaeva, Fabian Gonzalez Pinto, Antonino Mario Cassarà, Esra Neufeld, Marcus Grueschow, Lukas Imbach, Rafael Polanía
Journal: Nature Human Behaviour (2024)

Abstract Non-spatial attention is a fundamental cognitive mechanism that allows organisms to orient the focus of conscious awareness towards sensory information that is relevant to a behavioural goal while shifting it away from irrelevant stimuli. It has been suggested that attention is regulated by the ongoing phase of slow excitability fluctuations of neural activity in the prefrontal cortex, a hypothesis that has been challenged with no consensus. Here we developed a behavioural and non-invasive stimulation paradigm aiming at modulating slow excitability fluctuations of the inferior frontal junction. Using this approach, we show that non-spatial attention can be selectively modulated as a function of the ongoing phase of exogenously modulated excitability states of this brain structure. These results demonstrate that non-spatial attention relies on ongoing prefrontal excitability states, which are probably regulated by slow oscillatory dynamics, that orchestrate goal-oriented behaviour.
The grey area of “fertility tech” being mis-sold as contraception
Authors: Mun-Keat Looi
Journal: BMJ (2024)

Chelsea Polis, who won the 2023 Maddox prize early career award, explains how she was sued for identifying a mis-sold medical device—and why, in an age of disinformation, researchers and clinicians must call out wrongdoing when they see it. <b>Mun-Keat Looi</b> reports
Clinical Activity of TGF-β Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study
Authors: Jin-Hee Ahn, Jeeyun Lee, Changhee Park, Seung-Hoon Beom, Seung Hyun Kim, Young Han Lee, Kum-Hee Yun, Jeung Eun Kim, Wooyeol Baek, Yoon Dae Han, Sang Kyum Kim, Hyang Joo Ryu, Inkyung Jung, JooHee Lee, Hong In Yoon, Hyo Song Kim
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The study was to determine the activity and safety of the TGF-β inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. Patients and Methods: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level −1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. Results: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). Conclusions: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-β inhibitor, in this rare and difficult-to-treat desmoid tumor.