tbuckley/cabot-search huggingface dataset:
Physiological versus time based cord clamping in very preterm infants (ABC3): a parallel-group, multicentre, randomised, controlled superiority trial
Authors: Ronny Knol, Emma Brouwer, Thomas van den Akker, Philip L J DeKoninck, Wes Onland, Marijn J Vermeulen, Willem P de Boode, Anton H van Kaam, Enrico Lopriore, Irwin K M Reiss, G Jeroen Hutten, Sandra A Prins, Estelle E M Mulder, Esther J d'Haens, Christian V Hulzebos, Helene A Bouma, Sam J van Sambeeck, Hendrik J Niemarkt, Mayke E van der Putten, Tinta Lebon, Inge A Zonnenberg, Debbie H Nuytemans, Sten P Willemsen, Graeme R Polglase, Sylke J Steggerda, Stuart B Hooper, Arjan B Te Pas
Journal: The Lancet Regional Health - Europe (2024)
Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B
Authors: Jinlin Hou, Wenhong Zhang, Qing Xie, Rui Hua, Hong Tang, Luis Enrique Morano Amado, Sheng-Shun Yang, Cheng-Yuan Peng, Wei-Wen Su, Wan-Long Chuang, Dong Joon Kim, Anchalee Avihingsanon, Jia-Horng Kao, Apinya Leerapun, Man-Fung Yuen, Tarik Asselah, Xieer Liang, Qingyan Bo, Filippo Canducci, Maria Teresa Catanese, Ethan Chen, Cong Cheng, Farouk Chughlay, Sudip Das, Katerina Glavini, Nelson Guerreiro, Yan Huang, Priyanka Kakrana, Rémi Kazma, Avinash Patil, Vedran Pavlovic, Bernadette Surujbally, Miriam Triyatni, Ruchi Upmanyu, Cynthia Wat, Edward Gane
Journal: New England Journal of Medicine (2024)

BackgroundXalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection.MethodsWe conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed.Download a PDF of the Plain Language Summary.ResultsAmong 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level.ConclusionsAmong participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon. (Funded by F. Hoffmann–La Roche; Piranga ClinicalTrials.gov number, NCT04225715.) Quick Take Xalnesiran in Chronic Hepatitis B 2m 55s
Case 38-2024: A 22-Year-Old Woman with Headache, Fever, and Respiratory Failure
Authors: Eleftherios Mylonakis, Eric W Zhang, Philippe B Bertrand, M Edip Gurol, Virginia A Triant, Kristine M Chaudet
Journal: New England Journal of Medicine (2024)

A 22-year-old woman with headache and fever was transferred to the ICU for respiratory failure. Head CT was notable for acute subarachnoid hemorrhage; transthoracic and transesophageal echocardiography was also performed (shown in a video). A diagnosis was made.
Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer
Authors: Amy E Turriff, Christina M Annunziata, Ashkan A Malayeri, Bernadette Redd, Miroslava Pavelova, Ian S Goldlust, Padma Sheila Rajagopal, Jielu Lin, Diana W Bianchi
Journal: New England Journal of Medicine (2024)

BackgroundCell-free DNA (cfDNA) sequence analysis to screen for fetal aneuploidy can incidentally detect maternal cancer. Additional data are needed to identify DNA-sequencing patterns and other biomarkers that can identify pregnant persons who are most likely to have cancer and to determine the best approach for follow-up.MethodsIn this ongoing study we performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (i.e., the fetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories in North America. We used a uniform cancer-screening protocol including rapid whole-body magnetic resonance imaging (MRI), laboratory tests, and standardized cfDNA sequencing for research purposes with the use of a genomewide platform. The primary outcome was the presence of cancer in participants after the initial cancer-screening evaluation. Secondary analyses included test performance.ResultsCancer was present in 52 of the 107 participants in the initial cohort (48.6%). The sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively. Physical examination and laboratory tests were of limited use in identifying participants with cancer. Research sequencing showed that 49 participants had a combination of copy-number gains and losses across multiple (≥3) chromosomes; cancer was present in 47 of the participants (95.9%) with this sequencing pattern. Sequencing patterns of cfDNA in which there were only chromosomal gains (multiple trisomies) or only chromosomal losses (one or more monosomies) were found in participants with nonmalignant conditions, such as fibroids.ConclusionsIn this study, 48.6% of participants who received unusual or nonreportable clinical cfDNA-sequencing results had an occult cancer. Further study of DNA-sequencing patterns that are suggestive of occult cancer during prenatal screening is warranted. (Funded by the NIH Intramural Research Programs; ClinicalTrials.gov number, NCT04049604.)
Cell-free DNA Screening and Maternal Cancer
Authors: Neeta L Vora
Journal: New England Journal of Medicine (2024)

In 2013, I, along with other investigators, described a healthy woman with an uncomplicated pregnancy who was referred to maternal fetal medicine and genetic counseling because she received positive results for trisomy 13 and monosomy 18 through a screening assay of cell-free DNA (cfDNA) obtained from a blood sample.1 These results were difficult to explain because the ultrasound showed a structurally normal fetus. An amniocentesis was performed to obtain fetal cells for genetic testing. The results of the fetal karyotype and chromosomal microarray analysis were normal. The pregnancy continued uneventfully and resulted in a normal vaginal delivery of a healthy . . .
Association between periodontal disease and systemic diseases: a cross-sectional analysis of current evidence
Authors: Di Huang, Yun-Yun Wang, Bing-Hui Li, Lan Wu, Wen-Zhong Xie, Xia Zhou, Bin Ma
Journal: Military Medical Research (2024)

Abstract Background Numerous systematic reviews and meta-analyses have been published that evaluate the association between periodontal disease and systemic diseases, many of which address similar topics. Moreover, their quality requires assessment. Therefore, we performed a cross-sectional analysis to examine the evidence on the relationship between periodontal disease and systemic diseases. Methods The PubMed, Embase, Web of Science, and the Cochrane Library databases were systematically searched to identify relevant systematic reviews and meta-analyses. Only studies that considered periodontal disease as the exposure factor and various systemic diseases as the outcome were included. The basic characteristics and pertinent data from the selected studies were extracted. The modified version of A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) was employed for quality assessment, while R software was used for statistical analysis. Results Among the 212 relevant systematic reviews and meta-analyses, 57 were finally included in our analysis. These studies involved 75 diseases and 81 disease-related outcomes, with cancer (19/81) being the most frequently addressed topic. Of the 81 outcomes, 67 demonstrated a significant association. Notably, the highest risk estimate was found for head and neck cancer [odds ratio ( OR ) = 3.17, 95% confidence interval (CI) 1.78 − 5.64], while the lowest was observed for premature rupture of the amniotic sac [relative risk ( RR ) = 1.10, 95% CI 1.08 − 1.12]. The methodological quality ratings indicated that approximately 71.93% of included studies were classified as “Critically low”, with another 17.54% rated as “Low”, and only about 10.53% categorized as “Moderate”. Conclusions Periodontal disease significantly elevates the risks associated with 15 cancer-related, 8 cardiovascular-related, 8 metabolic-related, and 5 neurological-related outcomes. However, the overall methodological quality of existing systematic reviews and meta-analyses is generally suboptimal and requires enhancement to generate higher-quality evidence in the future.
Aging-associated sensory decline and Alzheimer’s disease
Authors: Suji Hong, Seung-Hyun Baek, Mitchell K. P. Lai, Thiruma V. Arumugam, Dong-Gyu Jo
Journal: Molecular Neurodegeneration (2024)

Abstract Multisensory decline is common as people age, and aging is the primary risk of Alzheimer’s Disease (AD). Recent studies have begun to shed light on the possibility that age-related sensory decline could accelerate AD pathogenesis, or be a prodromal indicator of AD. Sensory impairments, specifically in taste and smell, often emerge before cognitive symptoms in AD, indicating their potential as early biomarkers. Olfactory dysfunction has been frequently associated with AD and may offer valuable insights into early detection. Hearing impairment is significantly associated with AD, but its causal impact on AD progression remains unclear. The review also discusses visual and tactile deficits in AD, including retinal thinning and changes in tactile perception, highlighting their links to disease progression. Focusing on molecular mechanisms, the review explores the roles of amyloid-β (Aβ) accumulation and tau protein pathology in sensory decline and their bidirectional relationship with AD. In summary, the evidence presented conclusively supports advocating for an integrated approach to understanding AD and sensory decline, to enhance early detection, implementing preventive strategies, and developing therapeutic interventions for AD. This approach underscores the significance of sensory health in addressing neurodegenerative diseases, particularly AD.
Phase I Trial of MCARH109, a G Protein–Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma: An Updated Analysis
Authors: Eric M. Jurgens, Ross S. Firestone, Jagrutiben Chaudhari, Kinga Hosszu, Sean M. Devlin, Urvi A. Shah, Jonathan Landa, Devin P. McAvoy, Alexander M. Lesokhin, Neha Korde, Hani Hassoun, Carlyn R. Tan, Malin Hultcrantz, Gunjan L. Shah, Heather J. Landau, David J. Chung, Michael Scordo, Ozgur Can Eren, Ahmet Dogan, Sergio A. Giralt, Jae H. Park, Isabelle Rivière, Renier J. Brentjens, Eric L. Smith, Xiuyan Wang, Saad Z. Usmani, Sham Mailankody
Journal: Journal of Clinical Oncology (2024)

MCARH109 is a first-in-class G protein–coupled receptor, class C, group 5, member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma. This phase I clinical trial included 17 patients and determined that MCARH109 is safe at a maximum tolerated dose of 150 × 10 6 CAR T cells. In this updated analysis, no new serious adverse events were reported at a median follow-up of 37 months. Overall, 12 (71%) of 17 patients responded, including seven (70%) of 10 patients previously treated with B-cell maturation antigen-targeted therapy. The median duration of response was 8.6 months (95% CI, 5.7 to not reached [NR]) with two patients sustaining a stringent complete response at the time of last follow-up, 32 months and 41 months, respectively. The median overall survival (OS) was NR and the 3-year OS estimate was 59% (95% CI, 40 to 88). Possible GPRC5D loss via immunohistochemistry was observed in 6 (60%) of 10 patients at relapse. High-dimensional spectral cytometry–based immune profiling associated an activated T-cell phenotype at apheresis with a response to MCARH109.
Co-evolution of glioma and immune microenvironment
Authors: Mahmoud M Elguindy, Jacob S Young, Winson S Ho, Rongze O Lu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Glioma evolution is governed by a multitude of dynamic interactions between tumor cells and heterogenous neighboring, non-cancerous cells. This complex ecosystem, termed the tumor microenvironment (TME), includes diverse immune cell types that have gained increasing attention for their critical and paradoxical roles in tumor control and tumorigenesis. Recent work has revealed that the cellular composition and functional state of immune cells in the TME can evolve extensively depending on the tumor stage and intrinsic features of surrounding glioma cells. Concurrently, adaptations to the glioma cellular phenotype, including activation of various cellular states, occur in the context of these immune cell alterations. In this review, we summarize important features of the immune TME that play key roles during each stage of glioma progression, from initiation to immune escape, invasion and recurrence. Understanding the complex interplay between tumor and immune cells is critical for the development of effective immunotherapies for glioma treatment.
Revisiting mutational resistance to ampicillin and cefotaxime in Haemophilus influenzae
Authors: Margo Diricks, Sabine Petersen, Lennart Bartels, Thiên-Trí Lâm, Heike Claus, Maria Paula Bajanca-Lavado, Susanne Hauswaldt, Ricardo Stolze, Omar Jiménez Vázquez, Christian Utpatel, Stefan Niemann, Jan Rupp, Inken Wohlers, Matthias Merker
Journal: Genome Medicine (2024)

Abstract Background Haemophilus influenzae is an opportunistic bacterial pathogen that can cause severe respiratory tract and invasive infections. The emergence of β-lactamase-negative ampicillin-resistant (BLNAR) strains and unclear correlations between genotypic (i.e., gBLNAR) and phenotypic resistance are challenging empirical treatments and patient management. Thus, we sought to revisit molecular resistance mechanisms and to identify new resistance determinants of H. influenzae . Methods We performed a systematic meta-analysis of H. influenzae isolates ( n = 291) to quantify the association of phenotypic ampicillin and cefotaxime resistance with previously defined resistance groups, i.e., specific substitution patterns of the penicillin binding protein PBP3, encoded by ftsI . Using phylogenomics and a genome-wide association study (GWAS), we investigated evolutionary trajectories and novel resistance determinants in a public global cohort ( n = 555) and a new clinical cohort from three European centers ( n = 298), respectively. Results Our meta-analysis confirmed that PBP3 group II- and group III-related isolates were significantly associated with phenotypic resistance to ampicillin ( p &lt; 0.001), while only group III-related isolates were associated with resistance to cefotaxime ( p = 0.02). The vast majority of H. influenzae isolates not classified into a PBP3 resistance group were ampicillin and cefotaxime susceptible. However, particularly group II isolates had low specificities (&lt; 16%) to rule in ampicillin resistance due to clinical breakpoints classifying many of them as phenotypically susceptible. We found indications for positive selection of multiple PBP3 substitutions, which evolved independently and often step-wise in different phylogenetic clades. Beyond ftsI , other possible candidate genes (e.g., oppA, ridA, and ompP2 ) were moderately associated with ampicillin resistance in the GWAS. The PBP3 substitutions M377I, A502V, N526K, V547I, and N569S were most strongly related to ampicillin resistance and occurred in combination in the most prevalent resistant haplotype H1 in our clinical cohort. Conclusions Gradient agar diffusion strips and broth microdilution assays do not consistently classify isolates from PBP3 groups as phenotypically resistant . Consequently, when the minimum inhibitory concentration is close to the clinical breakpoints, and genotypic data is available, PBP3 resistance groups should be prioritized over susceptible phenotypic results for ampicillin. The implications on treatment outcome and bacterial fitness of other extended PBP3 substitution patterns and novel candidate genes need to be determined.
Minimal Residual Disease as an Early Endpoint for Accelerated Drug Approval in Myeloma: A Roadmap
Authors: Ola Landgren, Sean M. Devlin
Journal: Blood Cancer Discovery (2024)

Abstract Improvements in multiple myeloma (MM) treatments have extended patient survival to a decade or more. Treatment response rates &amp;gt;90% have introduced new challenges for drug development, including a need for early endpoints with greater sensitivity. The FDA, based on data from two academic research groups and industry, evaluated minimal residual disease (MRD) negativity as an intermediate endpoint for progression-free and overall survival, culminating in a unanimous vote by the Oncology Drugs Advisory Committee in April 2024 supporting MRD-negative complete response as an early endpoint reasonably likely to predict clinical benefit in MM that may be used to support accelerated approval.
Feasibility of a Biomarker‐Based Screening for Pre‐Symptomatic <scp>AL</scp> Amyloidosis in Patients With Intermediate/High‐Risk <scp>MGUS</scp>
Authors: Silvia Mangiacavalli, Paolo Milani, Claudio Salvatore Cartia, Marzia Varettoni, Michele Palumbo, Marco Basset, Valeria Masoni, Mario Nuvolone, Andrea Foli, Virginia Valeria Ferretti, Giampaolo Merlini, Luca Arcaini, Giovanni Palladini
Journal: American Journal of Hematology (2024)

Biomarker-based screening enables early detection of AL amyloidosis in intermediate/high-risk MGUS patients. Our study shows that identifying pre-symptomatic AL through biomarker longitudinal monitoring allows early treatment, leading to significant organ function recovery.
Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment
Authors: Tomoyuki Minowa, Kenji Murata, Yuka Mizue, Aiko Murai, Munehide Nakatsugawa, Kenta Sasaki, Serina Tokita, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Toshiya Handa, Sayuri Sato, Kohei Horimoto, Junji Kato, Tokimasa Hida, Yoshihiko Hirohashi, Hisashi Uhara, Toshihiko Torigoe
Journal: Science Translational Medicine (2024)

Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.
Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease
Authors: Lina Dinkel, Selina Hummel, Valerio Zenatti, Mariagiovanna Malara, Yannik Tillmann, Alessio Colombo, Laura Sebastian Monasor, Jung H. Suh, Todd Logan, Stefan Roth, Lars Paeger, Patricia Hoffelner, Oliver Bludau, Andree Schmidt, Stephan A. Müller, Martina Schifferer, Brigitte Nuscher, Jasenka Rudan Njavro, Matthias Prestel, Laura M. Bartos, Karin Wind-Mark, Luna Slemann, Leonie Hoermann, Sebastian T. Kunte, Johannes Gnörich, Simon Lindner, Mikael Simons, Jochen Herms, Dominik Paquet, Stefan F. Lichtenthaler, Peter Bartenstein, Nicolai Franzmeier, Arthur Liesz, Antje Grosche, Tatiana Bremova-Ertl, Claudia Catarino, Skadi Beblo, Caroline Bergner, Susanne A. Schneider, Michael Strupp, Gilbert Di Paolo, Matthias Brendel, Sabina Tahirovic
Journal: Science Translational Medicine (2024)

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N-acetyl-l-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.