tbuckley/cabot-search huggingface dataset:
Diagnostic accuracy of portable sleep monitors in pediatric sleep apnea: A systematic review
Authors: Vivianne Landry, Koorosh Semsar-Kazerooni, Tanya Chen, Joshua Gurberg, Lily H.P. Nguyen, Evelyn Constantin
Journal: Sleep Medicine Reviews (2024)

In recent years, a plethora of new type III and IV portable sleep monitors (PSM) have been developed, although evidence regarding their diagnostic accuracy for use in children remains heterogeneous. This study systematically reviews the literature addressing the diagnostic accuracies of type III and IV PSM for pediatric sleep apnea. Publications indexed in Medline, Embase, or Web of Science were reviewed using the PRISMA framework. Of 1054 studies, 62 fulfilled the inclusion criteria. Of the studies evaluating oximetry-based type IV PSM, one (6.25 %) demonstrated a balanced set of high (≥80 %) sensitivities and specificities for the diagnosis of any pediatric sleep apnea, while five studies (27.8 %) showed similar accuracies for moderate-to-severe sleep apnea. For non-oximetry-based type IV PSM, two studies (40 %) reported a balanced set of high diagnostic accuracies for moderate-to-severe sleep apnea. Type III PSM repeatedly demonstrated higher diagnostic accuracies, with six studies (66.7 %) reporting a balanced set of high diagnostic accuracies for moderate-to-severe sleep apnea. This review highlights the potential of type III PSM to detect moderate-to-severe pediatric sleep apnea, although current evidence is limited to support the stand-alone use of type IV PSM for the diagnosis of sleep apnea in most children.
Targeting the FGFR Pathway in Patients with Advanced Solid Tumors
Authors: Chadi Hage Chehade, Zeynep Irem Ozay, Neeraj Agarwal
Journal: Clinical Cancer Research (2024)

In the phase II FUZE trial targeting the FGFR pathway, Debio 1347 showed limited antitumor activity and manageable toxicity in patients with advanced solid tumors. Results from transcriptome-based analysis enhanced our understanding of the genomic landscape of FGFR fusion-driven tumors, informing clinical trial design and generating hypotheses for resistance mechanisms. See related article by Grivas et al., p. 4572.
Mepolizumab depletes inflammatory but preserves homeostatic eosinophils in severe asthma
Authors: Michael Fricker, John Harrington, Sarah A. Hiles, Peter G. Gibson
Journal: Allergy (2024)

Abstract Background Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response. Methods We performed a cross‐sectional observational study of severe asthma (eosinophilic n = 32, non‐eosinophilic n = 23, mepolizumab‐treated n = 25), with longitudinal follow‐up of 30 eosinophilic participants at two timepoints (4–24 weeks, &gt;24 weeks) post‐commencement of mepolizumab ( n = 20) or benralizumab ( n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein. Results iEO proportion was significantly lower in mepolizumab‐treated participants in both the cross‐sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow‐up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non‐eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab‐treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab‐treated participants, which was associated with significantly better asthma control and spirometry. Conclusions Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab‐treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.
T-cell specific in vivo gene delivery with DART-AAVs targeted to CD8
Authors: Muhammed Burak Demircan, Luca J. Zinser, Alexander Michels, Mar Guaza-Lasheras, Fabian John, Johanna M. Gorol, Samuel A. Theuerkauf, Dorothee M. Günther, Dirk Grimm, Florian R. Greten, Petr Chlanda, Frederic B. Thalheimer, Christian J. Buchholz
Journal: Molecular Therapy (2024)

One of the biggest challenges for in vivo gene therapy are vectors mediating highly selective gene transfer into a defined population of therapy-relevant cells. Here we present DARPin-targeted AAVs (DART-AAVs) displaying DARPins specific for human and murine CD8. Insertion of DARPins into the GH2/GH3 loop of the capsid protein 1 (VP1) of AAV2 and AAV6 resulted in high selectivity for CD8-positive T cells with unimpaired gene delivery activity. Remarkably, the capsid core structure was unaltered with protruding DARPins detectable. In complex primary cell mixtures, including donor blood or systemic injections into mice, the CD8-targeted AAVs were by far superior to unmodified AAV2 and AAV6 in terms of selectivity, target cell viability, and gene transfer rates. In vivo, up to 80% of activated CD8+ T cells were hit upon a single vector injection into conditioned humanized or immunocompetent mice. While gene transfer rates decreased significantly under non-activated conditions, genomic modification selectively in CD8+ T cells was still detectable upon Cre delivery into indicator mice. In both mouse models, selectivity for CD8+ T cells was close to absolute with exceptional detargeting from liver. The CD8-AAVs described here expand strategies for immunological research and in vivo gene therapy options. One of the biggest challenges for in vivo gene therapy are vectors mediating highly selective gene transfer into a defined population of therapy-relevant cells. Here we present DARPin-targeted AAVs (DART-AAVs) displaying DARPins specific for human and murine CD8. Insertion of DARPins into the GH2/GH3 loop of the capsid protein 1 (VP1) of AAV2 and AAV6 resulted in high selectivity for CD8-positive T cells with unimpaired gene delivery activity. Remarkably, the capsid core structure was unaltered with protruding DARPins detectable. In complex primary cell mixtures, including donor blood or systemic injections into mice, the CD8-targeted AAVs were by far superior to unmodified AAV2 and AAV6 in terms of selectivity, target cell viability, and gene transfer rates. In vivo, up to 80% of activated CD8+ T cells were hit upon a single vector injection into conditioned humanized or immunocompetent mice. While gene transfer rates decreased significantly under non-activated conditions, genomic modification selectively in CD8+ T cells was still detectable upon Cre delivery into indicator mice. In both mouse models, selectivity for CD8+ T cells was close to absolute with exceptional detargeting from liver. The CD8-AAVs described here expand strategies for immunological research and in vivo gene therapy options.
Host–microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency
Authors: Yong-Uk Lee, Bennett W. Fox, Rui Guo, Brian J. Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L. Safak Yilmaz, Cole M. Haynes, Frank C. Schroeder, Albertha J. M. Walhout
Journal: Nature Metabolism (2024)
Age-associated clonal B cells drive B cell lymphoma in mice
Authors: José P. Castro, Anastasia V. Shindyapina, Alessandro Barbieri, Kejun Ying, Olga S. Strelkova, João A. Paulo, Alexander Tyshkovskiy, Rico Meinl, Csaba Kerepesi, Anna P. Petrashen, Marco Mariotti, Margarita V. Meer, Yan Hu, Alexander Karamyshev, Grigoriy Losyev, Mafalda Galhardo, Elsa Logarinho, Artur A. Indzhykulian, Steven P. Gygi, John M. Sedivy, John P. Manis, Vadim N. Gladyshev
Journal: Nature Aging (2024)
Not all are the same: the power of registries in defining genotype–phenotype relationships in primary ciliary dyskinesia
Authors: Amjad Horani, Pleasantine Mill
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The study by J. Raidt and co-workers in this issue of the <i>European Respiratory Journal</i> exemplifies the power and importance of rare disease registries, with such large multiscale clinical datasets with linked genotypes, in stratifying patients with PCD.</b>https://bit.ly/4eEWVjz
Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations
Authors: M. Austin Argentieri, Sihao Xiao, Derrick Bennett, Laura Winchester, Alejo J. Nevado-Holgado, Upamanyu Ghose, Ashwag Albukhari, Pang Yao, Mohsen Mazidi, Jun Lv, Iona Millwood, Hannah Fry, Rodosthenis S. Rodosthenous, Jukka Partanen, Zhili Zheng, Mitja Kurki, Mark J. Daly, Aarno Palotie, Cassandra J. Adams, Liming Li, Robert Clarke, Najaf Amin, Zhengming Chen, Cornelia M. van Duijn
Journal: Nature Medicine (2024)

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations.
Advances in the mechanism of small nucleolar RNA and its role in DNA damage response
Authors: Li-Ping Shen, Wen-Cheng Zhang, Jia-Rong Deng, Zhen-Hua Qi, Zhong-Wu Lin, Zhi-Dong Wang
Journal: Military Medical Research (2024)

Abstract Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.
Game of microbes: the battle within – gut microbiota and multiple sclerosis
Authors: Ti-Ara Turner, Peter Lehman, Sudeep Ghimire, Shailesh K. Shahi, Ashutosh Mangalam
Journal: Gut Microbes (2024)

Multiple sclerosis (MS) is a chronic and progressive autoimmune disease of the central nervous system (CNS), with both genetic and environmental factors contributing to the pathobiology of the disease. While human leukocyte antigen (HLA) genes have emerged as the strongest genetic factor, consensus on environmental risk factors are lacking. Recently, trillions of microbes residing in our gut (microbiome) have emerged as a potential environmental factor linked with the pathobiology of MS as PwMS show gut microbial dysbiosis (altered gut microbiome). Thus, there has been a strong emphasis on understanding the factors (host and environmental) regulating the composition of the gut microbiota and the mechanism(s) through which gut microbes contribute to MS disease, especially through immune system modulation. A better understanding of these interactions will help harness the enormous potential of the gut microbiota as a therapeutic approach to treating MS.
Long-term survival comparison of patients admitted to the intensive care unit following in-hospital cardiac arrest in perioperative and ward settings. A multicentre retrospective cohort study
Authors: Ryo Ueno, Rachel Chan, Mallikarjuna Ponnapa Reddy, Daryl Jones, David Pilcher, Ashwin Subramaniam
Journal: Intensive Care Medicine (2024)

Perioperative in-hospital cardiac arrests (Perioperative IHCAs) may have better outcomes than IHCAs in the ward (Ward IHCAs), due to enhanced monitoring and faster response. However, quantitative comparisons of their long-term outcomes are lacking, posing challenges for prognostication. This retrospective multicentre study included adult intensive care unit (ICU) admissions from theatre/recovery or wards with a diagnosis of cardiac arrest between January 2018 and March 2022. We used data from 175 ICUs in the ANZICS adult patient database. The primary outcome was a survival time of up to 4 years. We used the Cox proportional hazards model adjusted for Sequential Organ Failure Assessment (SOFA) score, age, sex, comorbidities, hospital type, treatment limitation on admission to the ICU, and ICU treatments. Subgroup analyses examined age (≥ 65 years), intubation within the first 24 h, elective vs. emergency admission, and survival on discharge. Of 702,675 ICU admissions, 5,659 IHCAs were included (Perioperative IHCA 38%; Ward IHCA 62%). Perioperative IHCA group were younger, less frail, and less comorbid. Perioperative IHCA were most frequent in patients admitted to ICU after cardiovascular, gastrointestinal, or trauma surgeries. Perioperative IHCA group had longer 4-year survival (59.9% vs. 33.0%, p < 0.001) than the Ward IHCA group, even after adjustments (adjusted hazard ratio [HR]: 0.63, 95% confidence interval [CI] 0.57–0.69). This was concordant across all subgroups. Of note, older patients with Perioperative IHCA survived longer than both younger and older patients with Ward IHCA. Patients admitted to the ICU following Perioperative IHCA had longer survival than Ward IHCA. Future studies on IHCA should distinguish these patients.
Recommendations for clinical trial design in acute kidney injury from the 31st acute disease quality initiative consensus conference. A consensus statement
Authors: Alexander Zarbock, Lui G. Forni, Jay L. Koyner, Samira Bell, Thiago Reis, Melanie Meersch, Sean M. Bagshaw, Dana Y. Fuhmann, Kathleen D. Liu, Neesh Pannu, Ayse Akcan Arikan, Derek C. Angus, D‘Arcy Duquette, Stuart L. Goldstein, Eric Hoste, Michael Joannidis, Niels Jongs, Matthieu Legrand, Ravindra L. Mehta, Patrick T. Murray, Mitra K. Nadim, Marlies Ostermann, John Prowle, Emily J. See, Nicholas M. Selby, Andrew D. Shaw, Nattachai Srisawat, Claudio Ronco, John A. Kellum
Journal: Intensive Care Medicine (2024)

Novel interventions for the prevention or treatment of acute kidney injury (AKI) are currently lacking. To facilitate the evaluation and adoption of new treatments, the use of the most appropriate design and endpoints for clinical trials in AKI is critical and yet there is little consensus regarding these issues. We aimed to develop recommendations on endpoints and trial design for studies of AKI prevention and treatment interventions based on existing data and expert consensus. At the 31st Acute Disease Quality Initiative (ADQI) meeting, international experts in critical care, nephrology, involving adults and pediatrics, biostatistics and people with lived experience (PWLE) were assembled. We focused on four main areas: (1) patient enrichment strategies, (2) prevention and attenuation studies, (3) treatment studies, and (4) innovative trial designs of studies other than traditional (parallel arm or cluster) randomized controlled trials. Using a modified Delphi process, recommendations and consensus statements were developed based on existing data, with > 90% agreement among panel members required for final adoption. The panel developed 12 consensus statements for clinical trial endpoints, application of enrichment strategies where appropriate, and inclusion of PWLE to inform trial designs. Innovative trial designs were also considered. The current lack of specific therapy for prevention or treatment of AKI demands refinement of future clinical trial design. Here we report the consensus findings of the 31st ADQI group meeting which has attempted to address these issues including the use of predictive and prognostic enrichment strategies to enable appropriate patient selection.
Living with peripartum cardiomyopathy: A statement from the Heart Failure Association and the Association of Cardiovascular Nursing and Allied Professions of the European Society of Cardiology
Authors: Karen Sliwa, Amina Rakisheva, Charle Viljoen, Tobias Pfeffer, Maggie Simpson, Alice M. Jackson, Mark C. Petrie, Peter van der Meer, Hasan Al Farhan, Silvana Jovanova, Amam Mbakwem, Gianfranco Sinagra, Emeline Van Craenenbroeck, Julian Hoevelmann, Mark R. Johnson, Richard Mindham, Ovidiu Chioncel, Kai G. Kahl, Giuseppe Rosano, Carsten Tschöpe, Alexandre Mebazaa, Petar Seferovic, Johann Bauersachs
Journal: European Journal of Heart Failure (2024)

This statement focuses on the fact that women with peripartum cardiomyopathy (PPCM) have a substantial mortality and morbidity rate. Less than 50% of patients have full recovery of their cardiac function within 6 months of diagnosis. Also, patients with recovered cardiac function often suffer from comorbidities, such as hypertension or arrhythmias, which require long‐term treatment. This has major implications which extend beyond the life of the patient, as it may also substantially impact her family. Women with a new diagnosis of PPCM should be involved in the decision‐making processes regarding therapies, e.g. the recommendation to abstain from breastfeeding, or the use of cardiac implantable electronic devices. Women living with PPCM face the uncertainty of not knowing for some time whether their cardiac function will recover to allow them a near‐to‐normal life expectancy. This not only impacts their ability to work, which may have financial implications, but may also affect mental health and quality of life for the extended family. Women living with PPCM must be informed that a future pregnancy always carries a substantial risk and, in case of poor cardiac recovery, is associated with a high morbidity and mortality. Patients with PPCM are best managed by an interdisciplinary and multiprofessional approach including e.g. a cardiologist, a gynaecologist, nurses, a psychologist, and social workers. The scope of this document encompasses contemporary challenges and approaches for the management of women diagnosed with PPCM.
The burden of zoster in asthma: what is left to learn?
Authors: Chloe Bloom
Journal: European Respiratory Journal (2024)

Herpes zoster (HZ) is caused by the reactivation of latent varicella zoster virus and typically manifests as painful erythematous vesicles erupted along a single dermatome. The pain is often excruciating, occurring alongside constitutional symptoms such as headache, fever and malaise. It is fortunately, usually, self-limiting to around 2–3 weeks, but up to 10% suffer with debilitating, postherpetic neuralgia. Treatment options are limited, so for those at increased threat, HZ vaccination may be the most effective option (figure 1). Asthma is a global risk factor for herpes zoster, increasing with older age and use of oral corticosteroids https://bit.ly/3WiCyAk
Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts
Authors: Jannie Marie Bülow Sand, Henrik Jessen, Diana Julie Leeming, Sheeline Yu, Chris J Lee, Buqu Hu, Ying Sun, Taylor Adams, Taylor Pivarnik, Angela Liu, Samuel Woo, John R McGovern, Vitória Fiorini, Tina Saber, Jean Paul Higuero-Sevilla, Mridu Gulati, Naftali Kaminski, William Damsky, Albert C Shaw, Subhasis Mohanty, Gillian Goobie, Yingze Zhang, Erica Lyndrup Herzog, Changwan Ryu
Journal: Thorax (2024)

Introduction The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. Methods We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. Results Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. Discussion In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease.
Urban metabolic and airway immune profiles increase the risk of infections in early childhood
Authors: Nicklas Brustad, Jonathan Thorsen, Casper Emil Tingskov Pedersen, Mina Ali, Julie Kyvsgaard, Sarah Brandt, Jenni Lehtimäki, Nicole Prince, Nilofar V Følsgaard, Jessica Lasky-Su, Jakob Stokholm, Klaus Bønnelykke, Bo Chawes
Journal: Thorax (2024)

Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms.
Animal experiments of a new through-the-scope full-thickness endoscopic suturing device
Authors: Mati Shnell, Erez Scapa, Maria Valeria Matteo, Hideyuki Chiba, Yohei Minato, Leon M G Moons, Vincenzo Bove, Shelby Sullivan, Ken Ohata, Ivo Boskoski
Journal: Gut (2024)