tbuckley/cabot-search huggingface dataset:
Serology anno 2021—fungal infections: from invasive to chronic
Authors: Cornelia Lass-Flörl, Eldina Samardzic, Miriam Knoll
Journal: Clinical Microbiology and Infection (2021)

BackgroundDiagnosing invasive or chronic fungal infections is a challenge, particularly in the immunocompromised host. Microscopy and culture remain the reference standard, but are insensitive. The use of non-culture-based techniques is recommended in conjunction with conventional methods to improve the diagnostic yield.ObjectivesThe aim was to provide an updated 2021 inventory of fungal antigen and serology tests for diagnosing invasive and chronic fungal infections, the key focus was set on Aspergillus, Candida and Cryptococcus species.SourcesPubmed search for publications with the key words fungal antigen tests, laboratory-based diagnosis of invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, invasive candidiasis, invasive fungal infections and cryptococcal infections published from 2017 to 2020.ContentAntigen assays such as the galactomannan (GM) and β-d-glucan detection systems are frequently used, but these tests vary in sensitivity and specificity, depending on the patient population involved, specimens inspected, cut-offs defined, test strategy applied and inclusion or exclusion of possible fungal case definitions. Multiple different detection systems are available, with recently introduced new point-of-care tests such as the lateral flow device and the lateral flow assay. Despite a wide heterogeneity in populations evaluated, studies indicate a better diagnostic performance of bronchoalveolar lavage GM in comparison with serum GM, and a suboptimal specificity of GM bronchoalveolar lavages (cut-off ≥1) and serum β-d-glucan in non-neutropenic individuals. Point-of-care cryptococcal antigen tests show excellent performance.ImplicationsThere are fungal antigen detection tests available with excellent to reasonable clinical performance to diagnose invasive fungal infections. Only a few assays are useful to monitor therapeutic response. There are multiple marketed IgG antibody tests to detect Aspergillus fumigatus antibodies, the titres vary widely and the performance differs significantly. In general, diagnostic tests are vulnerable to being affected by the host, the microbe and laboratory setting.
Prolonged evolution of the human B cell response to SARS-CoV-2 infection
Authors: Mrunal Sakharkar, C. Garrett Rappazzo, Wendy F. Wieland-Alter, Ching-Lin Hsieh, Daniel Wrapp, Emma S. Esterman, Chengzi I. Kaku, Anna Z. Wec, James C. Geoghegan, Jason S. McLellan, Ruth I. Connor, Peter F. Wright, Laura M. Walker
Journal: Science Immunology (2021)

A comprehensive understanding of the kinetics and evolution of the human B cell response to SARS-CoV-2 infection will facilitate the development of next-generation vaccines and therapies. Here, we longitudinally profiled this response in mild and severe COVID-19 patients over a period of five months. Serum neutralizing antibody (nAb) responses waned rapidly but spike (S)-specific IgG+ memory B cells (MBCs) remained stable or increased over time. Analysis of 1,213 monoclonal antibodies (mAbs) isolated from S-specific MBCs revealed a primarily de novo response that displayed increased somatic hypermutation, binding affinity, and neutralization potency over time, providing evidence for prolonged antibody affinity maturation. B cell immunodominance hierarchies were similar across donor repertoires and remained relatively stable as the immune response progressed. Cross-reactive B cell populations, likely re-called from prior endemic beta-coronavirus exposures, comprised a small but stable fraction of the repertoires and did not contribute to the neutralizing response. The neutralizing antibody response was dominated by public clonotypes that displayed significantly reduced activity against SARS-CoV-2 variants emerging in Brazil and South Africa that harbor mutations at positions 501, 484 and 417 in the S protein. Overall, the results provide insight into the dynamics, durability, and functional properties of the human B cell response to SARS-CoV-2 infection and have implications for the design of immunogens that preferentially stimulate protective B cell responses.
Sex Differences in COVID-19 Hospitalization and Mortality in Chicagoland
Authors: J. M. D. Gomez, J. M. Du-Fay-de-Lavallaz, S. Fugar, J. A. Simmons, A. Sarau, B. Clark, R. Doukky, R. Sanghani, N. Aggarwal, K. A. Williams, A. S. Volgman
Journal: Circulation (2020)
Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10 Splicing
Authors: Anke J. Tijsen, Lucía Cócera Ortega, Yolan J. Reckman, Xiaolei Zhang, Ingeborg van der Made, Simona Aufiero, Jiuru Li, Selina C. Kamps, Anouk van den Bout, Harsha D. Devalla, Karin Y. van Spaendonck-Zwarts, Stefan Engelhardt, Lior Gepstein, James S. Ware, Yigal M. Pinto
Journal: Circulation (2021)

Background: TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the TTN transcript are the most frequent cause of hereditary heart failure. We showed before that TTN produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20. Methods: We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes. Results: Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as MEF2A and CASQ2 . Strikingly, loss of cTTN1 also caused abnormal splicing of TTN itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20. Conclusions: We demonstrate that circRNAs formed from the TTN transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the TTN transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.
Tackling nasal symptoms in athletes: Moving towards personalized medicine
Authors: Valerie Hox, Simon Beyaert, Dominique Bullens, Mariana Couto, Daniel Langer, Peter‐Willem Hellings, Caroline Huart, Philippe Rombaux, Sven F. Seys, Pavol Surda, Abigail Walker, Brecht Steelant
Journal: Allergy (2021)

Abstract Adequate nasal breathing is indispensable for athletes, and nasal symptoms have been shown to interfere with their subjective feeling of comfortable breathing and quality of life. Nasal symptoms are caused by either structural abnormalities or mucosal pathology. Structural pathologies are managed differently from mucosal disease, and therefore, adequate diagnosis is of utmost importance in athletes in order to choose the correct treatment option for the individual. Literature suggests that nasal symptoms are more prevalent in athletes compared to the general population and certain sports environments might even trigger the development of symptoms. Given the high demands of respiratory function in athletes, insight into triggering factors is of high importance for disease prevention. Also, it has been suggested that athletes are more neglectful to their symptoms and hence remain undertreated, meaning that special attention should be paid to education of athletes and their caregivers. This review aims at giving an overview of nasal physiology in exercise as well as the possible types of nasal pathology. Additionally, diagnostic and treatment options are discussed and we focus on unmet needs for the management and prevention of these symptoms in athletes within the concept of precision medicine.
Re-emphasizing early Alzheimer’s disease pathology starting in select entorhinal neurons, with a special focus on mitophagy
Authors: Asgeir Kobro-Flatmoen, Maria Jose Lagartos-Donate, Yahyah Aman, Paul Edison, Menno P. Witter, Evandro F. Fang
Journal: Ageing Research Reviews (2021)

The entorhinal-hippocampal system contains distinct networks subserving declarative memory. This system is selectively vulnerable to changes of ageing and pathological processes. The entorhinal cortex (EC) is a pivotal component of this memory system since it serves as the interface between the neocortex and the hippocampus. EC is heavily affected by the proteinopathies of Alzheimer's disease (AD). These appear in a stereotypical spatiotemporal manner and include increased levels of intracellular amyloid-beta Aβ (iAβ), parenchymal deposition of Aβ plaques, and neurofibrillary tangles (NFTs) containing abnormally processed Tau. Increased levels of iAβ and the formation of NFTs are seen very early on in a population of neurons belonging to EC layer II (EC LII), and recent evidence leads us to believe that this population is made up of highly energy-demanding reelin-positive (RE+) projection neurons. Mitochondria are fundamental to the energy supply, metabolism, and plasticity of neurons. Evidence from AD postmortem brain tissues supports the notion that mitochondrial dysfunction is one of the initial pathological events in AD, and this is likely to take place in the vulnerable RE + EC LII neurons. Here we review and discuss these notions, anchored to the anatomy of AD, and formulate a hypothesis attempting to explain the vulnerability of RE + EC LII neurons to the formation of NFTs. We attempt to link impaired mitochondrial clearance to iAβ and signaling involving both apolipoprotein 4 and reelin, and argue for their relevance to the formation of NFTs specifically in RE + EC LII neurons during the prodromal stages of AD. We believe future studies on these interactions holds promise to advance our understanding of AD etiology and provide new ideas for drug development.
Household Transmission of SARS-CoV-2
Authors: Joshua P. Metlay, Jennifer S. Haas, Alexander E. Soltoff, Katrina A. Armstrong
Journal: JAMA Network Open (2021)

disease 437 91 (20.8) <.001 Chronic obstructive pulmonary disease 798 116 (14.5) <.001 Dementia 85 15 (17.7) .02
Preventing Opioid-Induced Constipation
Authors: Chaker Ben Salem, Asma Ben Abdelkrim, Bouraoui Ouni
Journal: JAMA Internal Medicine (2021)

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Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis
Authors: Giovanni Palladini, Bruno Paiva, Ashutosh Wechalekar, Margherita Massa, Paolo Milani, Marta Lasa, Sriram Ravichandran, Isabel Krsnik, Marco Basset, Leire Burgos, Mario Nuvolone, Ramón Lecumberri, Andrea Foli, Noemi Puig, Melania Antonietta Sesta, Margherita Bozzola, Pasquale Cascino, Alice Nevone, Jessica Ripepi, Pierpaolo Berti, Simona Casarini, Ombretta Annibali, Alberto Orfao, Jesus San-Miguel, Giampaolo Merlini
Journal: Blood Cancer Journal (2021)

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.
Patient-Reported Outcomes and Long-Term Nonadherence to Aromatase Inhibitors
Authors: Dawn L Hershman, Alfred I Neugut, Anna Moseley, Kathryn B Arnold, Julie R Gralow, N Lynn Henry, Grace Clarke Hillyer, Scott D Ramsey, Joseph M Unger
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Nonadherence to aromatase inhibitors (AIs) is common and increases risk of breast cancer (BC) recurrence. We analyzed factors associated with nonadherence among patients enrolled in S1105, a randomized trial of text messaging. Methods At enrollment, patients were required to have been on an adjuvant AI for at least 30 days and were asked about financial, medication, and demographic factors. They completed patient-reported outcomes (PROs) representing pain (Brief Pain Inventory), endocrine symptoms (Functional Assessment of Cancer Therapy–Endocrine Symptoms), and beliefs about medications (Treatment Satisfaction Questionnaire for Medicine; Brief Medication Questionnaire). Our primary endpoint was AI nonadherence at 36 months, defined as urine AI metabolite assay of less than 10 ng/mL or no submitted specimen. We evaluated the association between individual baseline characteristics and nonadherence with logistic regression. A composite risk score reflecting the number of statistically significant baseline characteristics was examined. Results We analyzed data from 702 patients; median age was 60.9 years. Overall, 35.9% patients were nonadherent at 36 months. Younger patients (younger than age 65 years) were more nonadherent (38.8% vs 28.6%, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.05 to 2.16; P = .02). Fourteen baseline PRO scales were each statistically significantly associated with nonadherence. In a composite risk model categorized into quartile levels, each increase in risk level was associated with a 46.5% increase in the odds of nonadherence (OR = 1.47, 95% CI =1.26 to 1.70; P &amp;lt; .001). The highest-risk patients were more than 3 times more likely to be nonadherent than the lowest-risk patients (OR = 3.14, 95% CI = 1.97 to 5.02; P &amp;lt; .001). Conclusions The presence of multiple baseline PRO-specified risk factors was statistically significantly associated with AI nonadherence. The use of these assessments can help identify patients for targeted interventions to improve adherence.
Hemophilia Gene Therapy: Approaching the First Licensed Product
Authors: Paul Batty, David Lillicrap
Journal: HemaSphere (2021)

The clinical potential of hemophilia gene therapy has now been pursued for the past 30 years, and there is a realistic expectation that this goal will be achieved within the next couple of years with the licensing of a gene therapy product. While recent late phase clinical trials of hemophilia gene therapy have shown promising results, there remain a number of issues that require further attention with regard to both efficacy and safety of this therapeutic approach. In this review, we present information relating to the current status of the field and focus attention on the unanswered questions for hemophilia gene therapy and the future challenges that need to be overcome to enable the widespread application of this treatment paradigm.
Patient education for colonoscopy in the time of computers: are you ready, player one?
Authors: Leonardo Frazzoni
Journal: Endoscopy (2021)

Patient education has been recognized as an important quality parameter for colonoscopy [1], as the preparation for this examination is not straightforward and encompasses several steps: patients have to follow a recommended diet and correctly take the bowel prep, generally in a split-dose or same-day regimen, which may be difficult to follow without proper instructions. In general terms, communicating something to a person means making that person understand the content of your speech, which is generally possible if the other person can relate to the object of understanding. This relies on the capability to mentally figure it, or at least to compare it to a past experience [2]. In human history, as well as in medicine, the written word has been the basis for the process of education, through books and their much leaner, modern versions, such as leaflets. However, paralleling what is currently happening with social networks, the written word has been progressively replaced by images, and these latter by videos. This is not unexpected, if we consider that a video engages both the sense of sight and hearing, and has in its motion another reason for its superiority over still images and words.
TWIST1 preserves hematopoietic stem cell function via CACNA1B/Ca2+/mitochondria axis
Authors: Nan Wang, Jing Yin, Na You, Shangda Yang, Dan Guo, Yangyang Zhao, Yongxin Ru, Xiaoyan Liu, Hui Cheng, Qian Ren, Tao Cheng, Xiaotong Ma
Journal: Blood (2021)

Mitochondria of hematopoietic stem cells (HSCs) play crucial roles in regulating cell fate and preserving HSC functionality and survival. However, the mechanism underlying its regulation remains poorly understood. Here, we identify transcription factor TWIST1 as a novel regulator of HSC maintenance through modulating mitochondrial function. We demonstrate that Twist1 deletion results in a significantly decreased lymphoid-biased (Ly-biased) HSC frequency, markedly reduced HSC dormancy and self-renewal capacities, and skewed myeloid differentiation in steady-state hematopoiesis. Twist1-deficient HSCs are more compromised in tolerance of irradiation and 5-fluorouracil-induced stresses, and exhibit typical phenotypes of senescence. Mechanistically, Twist1 deletion induces transactivation of voltage-gated calcium channel (VGCC) Cacna1b which exhausts Ly-biased HSCs, impairs genotoxic hematopoietic recovery, and enhances mitochondrial calcium levels, metabolic activity, and reactive oxygen species production. Suppression of VGCC by a calcium channel blocker largely rescues the phenotypic and functional defects in Twist1-deleted HSCs under both steady-state and stress conditions. Collectively, our data, for the first time, characterize TWIST1 as a critical regulator of HSC function acting through the CACNA1B/Ca2+/mitochondria axis, and highlight the importance of Ca2+ in HSC maintenance. These observations provide new insights into the mechanisms for the control of HSC fate.
Joint ESCMID, FEMS, IDSA, ISID and SSI position paper on the fair handling of career breaks among physicians and scientists when assessing eligibility for early-career awards
Authors: Angela Huttner, Alice Bricheux, Carianne J.M. Buurmeijer-van Dijk, Matthew Harvey, Alison Holmes, Britta Lassmann, Valéry Lavergne, Alexandra Mailles, Marc Mendelson, Nicolas Muller, Maurizio Sanguinetti, Cynthia Sears, Chrysanthi Skevaki, Uzma Syed, Salandra Thomas, Talia H. Swartz
Journal: Clinical Microbiology and Infection (2021)

Though women increasingly make up the majority of medical-school and other science graduates, they remain a minority in academic biomedical settings, where they are less likely to hold leadership positions or be awarded research funding. A major factor is the career breaks that women disproportionately take to see to familial duties. They experience a related, but overlooked, hurdle upon their return: they are often too old to be eligible for 'early-career researcher' grants and 'career-development' awards, which are stepping stones to leadership positions in many institutions and which determine the demographics of their hierarchies for decades to come. Though age limits are imposed to protect young applicants from more experienced seniors, they have an unintended side effect of excluding returning workers, still disproportionately women, from the running.