tbuckley/cabot-search huggingface dataset:
BONE DISEASE
Authors: Evangelos Terpos
Journal: HemaSphere (2022)

Osteolytic bone disease is the most common complication of multiple myeloma. Bone targeted agents should be administered in all newly-diagnosed myeloma patients with myeloma-related bone disease. Zoledronic acid should be given even in newly-diagnosed patients without bone disease and it is preferred over other bisphosphonates due to its survival advantage. Zoledronic acid is administered monthly. However, once patients achieve VGPR or better, the treating physician may consider decreasing frequency of dosing to every 3 months or based on osteoporosis recommendations (every 6 months or yearly), or even to discontinue therapy if the patient has received one year of monthly zoledronic acid. Bisphosphonates should be re-administered at a monthly schedule at the time of relapse if new evidence of bone disease is present. Denosumab can also be considered for the treatment of myeloma-related bone disease, particularly in patients with renal impairment. In the largest placebo-controlled trial for myeloma patients to-date, denosumab was compared to zoledronic acid. Although, there was no difference regarding time to first skeletal-related event (SRE), a landmark analysis at 15 months showed a superiority of denosumab. Denosumab may also prolong PFS among newly-diagnosed patients with bone disease, who are eligible for autologous transplantation. Denosumab should be administered as a subcutaneous injection of 120mg at monthly intervals continuously, according to its label. Dosing de-intensification or drug holiday or discontinuation might be considered only after 24 months of treatment and if patient has responded to anti-MM treatment defined as VGPR or better. Discontinuation of denosumab is challenging due to the rebound phenomenon observed in osteoporosis patients. In this case, and until further data is available on myeloma patients, a single dose of iv bisphosphonate (i.e. zoledronic acid) is recommended at least 6 months after the last denosumab dose in order to prevent a potential rebound effect. Balloon kyphoplasty and vertebroplasty are recommended for patients with painful vertebral compression fractures. Radiotherapy should be considered for uncontrolled pain due to impeding or symptomatic spinal cord compression and due to pathological fractures. Surgery should be considered for prevention and restoration of long-bone pathological fractures, vertebral column instability and spinal cord compression with bone fragments within the spinal route.
Abstract P144: Nutritional Intervention May Change Physical Activity Levels In Latino Families: A Cluster Randomized Control Trial
Authors: Tara A Shrout, Colin King, Julie Denenberg, Amelia Eastman, Matthew A Allison
Journal: Circulation (2022)

Introduction: Nutrition and physical activity (PA) are key components for the primary prevention of cardiovascular disease. There remains a paucity of longitudinal data on the role of specific nutritional interventions and how they may impact PA levels, particularly in Latino populations. Hypothesis: We hypothesized that high allocation of avocados in Latino families would result in higher PA levels, measured as metabolic equivalent minutes per week (MET-min/wk) . Methods: A total of 72 Latino families (235 participants, 150 women) in San Diego, CA, were randomized to low- or high-avocado allocation (3/family/wk or 14/family/wk, respectively). A 14-day run-in period was utilized to demonstrate adherence. MET-min/wk PA measures (total, occupational, recreational, transportation) were assessed at baseline, 3-months, and 6-months via the validated global physical activity questionnaire (GPAQ) (moderate PA, 4 METs; vigorous PA, 8 METs). Using ANCOVA, we compared mean differences in longitudinal PA measures. Results: Randomization assigned 35 families to high-allocation (0% attrition throughout) and 37 to low-allocation (8% attrition at 3 months, 16% attrition at 6-months) with no significant difference in baseline PA. While mean total PA in the low-allocation group declined over the 6-month trial period, the inverse appeared true for the high-allocation group (Figure). Compared to low-allocation, the mean total PA between baseline to 6-months was 2,154.75 MET-min/wk higher in the high-allocation group (p=0.001), and specifically that of moderate and vigorous occupational PA being 979.25 and 898.17 MET-min/wk higher in the high-allocation group (p=0.003 and 0.037), respectively. No significant differences were found for recreational or transportation PA. Meaning: In this trial, and compared with a lower allocation, higher allocation of avocados was associated with significant increases in longitudinal PA measures. Further studies are warranted to assess the role of dietary interventions on changes in PA.
Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study
Authors: Annika Fendler, Lewis Au, Scott T. C. Shepherd, Fiona Byrne, Maddalena Cerrone, Laura Amanda Boos, Karolina Rzeniewicz, William Gordon, Benjamin Shum, Camille L. Gerard, Barry Ward, Wenyi Xie, Andreas M. Schmitt, Nalinie Joharatnam-Hogan, Georgina H. Cornish, Martin Pule, Leila Mekkaoui, Kevin W. Ng, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, Sarah Sarker, Karla Lingard, Mary Mangwende, Lucy Holt, Hamid Ahmod, Richard Stone, Camila Gomes, Helen R. Flynn, Ana Agua-Doce, Philip Hobson, Simon Caidan, Michael Howell, Mary Wu, Robert Goldstone, Margaret Crawford, Laura Cubitt, Harshil Patel, Mike Gavrielides, Emma Nye, Ambrosius P. Snijders, James I. MacRae, Jerome Nicod, Firza Gronthoud, Robyn L. Shea, Christina Messiou, David Cunningham, Ian Chau, Naureen Starling, Nicholas Turner, Liam Welsh, Nicholas van As, Robin L. Jones, Joanne Droney, Susana Banerjee, Kate C. Tatham, Shaman Jhanji, Mary O’Brien, Olivia Curtis, Kevin Harrington, Shreerang Bhide, Jessica Bazin, Anna Robinson, Clemency Stephenson, Tim Slattery, Yasir Khan, Zayd Tippu, Isla Leslie, Spyridon Gennatas, Alicia Okines, Alison Reid, Kate Young, Andrew J. S. Furness, Lisa Pickering, Sonia Gandhi, Steve Gamblin, Charles Swanton, Emma Nicholson, Sacheen Kumar, Nadia Yousaf, Katalin A. Wilkinson, Anthony Swerdlow, Ruth Harvey, George Kassiotis, James Larkin, Robert J. Wilkinson, Samra Turajlic
Journal: Nature Cancer (2021)

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4
Prolonged SARS-CoV-2 Infection in Patients with Lymphoid Malignancies
Authors: Christina Y. Lee, Monika K. Shah, David Hoyos, Alexander Solovyov, Melanie Douglas, Ying Taur, Peter Maslak, N. Esther Babady, Benjamin Greenbaum, Mini Kamboj, Santosha A. Vardhana
Journal: Cancer Discovery (2021)

Abstract Coronavirus disease 2019 (COVID-19) infection results in both acute mortality and persistent and/or recurrent disease in patients with hematologic malignancies, but the drivers of persistent infection in this population are unknown. We found that B-cell lymphomas were at particularly high risk for persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. Further analysis of these patients identified discrete risk factors for initial disease severity compared with disease chronicity. Active therapy and diminished T-cell counts were drivers of acute mortality in COVID-19–infected patients with lymphoma. Conversely, B cell–depleting therapy was the primary driver of rehospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8+ T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population. Significance: We describe the largest cohort of persistent symptomatic COVID-19 infection in patients with lymphoid malignancies and identify B-cell depletion as the key immunologic driver of persistent infection. Furthermore, we demonstrate ongoing intrahost viral evolution in patients with persistent COVID-19 infection, particularly in patients with impaired CD8+ T-cell immunity. This article is highlighted in the In This Issue feature, p. 1
Vaccine Effectiveness Against SARS-CoV-2 Infection and Severe Outcomes in the Maintenance Dialysis Population in Ontario, Canada
Authors: Matthew J. Oliver, Doneal Thomas, Shabnam Balamchi, Jane Ip, Kyla Naylor, Stephanie N. Dixon, Eric McArthur, Jeff Kwong, Jeffrey Perl, Mohammad Atiquzzaman, Joel Singer, Angie Yeung, Michelle Hladunewich, Kevin Yau, Amit X. Garg, Jerome A. Leis, Adeera Levin, Mel Krajden, Peter G. Blake
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Serology studies of coronavirus disease 2019 vaccines in the maintenance dialysis population have found weak antibody responses to one dose of vaccine and lower responses to two doses than among healthy controls. However, it is undetermined how these serologic responses correlate with the prevention of infection, hospitalization, and mortality in this immunosuppressed population. We identified 13,759 individuals receiving maintenance dialysis in Ontario, Canada. One dose of vaccine reduced the risk of infection and severe outcomes by 41% and 46%, respectively, compared with unvaccinated patients. Two doses of vaccine reduced the risk of infection and severe outcomes by 69% and 83%, respectively. The study confirms that coronavirus disease 2019 vaccination is effective in the maintenance dialysis population. Background Vaccination studies in the hemodialysis population have demonstrated decreased antibody response compared with healthy controls, but vaccine effectiveness for preventing SARS-CoV-2 infection and severe disease is undetermined. Methods We conducted a retrospective cohort study in the province of Ontario, Canada, between December 21, 2020, and June 30, 2021. Receipt of vaccine, SARS-CoV-2 infection, and related severe outcomes (hospitalization or death) were determined from provincial health administrative data. Receipt of one and two doses of vaccine were modeled in a time-varying cause-specific Cox proportional hazards model, adjusting for baseline characteristics, background community infection rates, and censoring for non-COVID death, recovered kidney function, transfer out of province, solid organ transplant, and withdrawal from dialysis. Results Among 13,759 individuals receiving maintenance dialysis, 2403 (17%) were unvaccinated and 11,356 (83%) had received at least one dose by June 30, 2021. Vaccine types were BNT162b2 ( n =8455, 74%) and mRNA-1273 ( n =2901, 26%); median time between the first and second dose was 36 days (IQR 28–51). The adjusted hazard ratio (HR) for SARS-CoV-2 infection and severe outcomes for one dose compared with unvaccinated was 0.59 (95% CI, 0.46 to 0.76) and 0.54 (95% CI, 0.37 to 0.77), respectively, and for two doses compared with unvaccinated was 0.31 (95% CI, 0.22 to 0.42) and 0.17 (95% CI, 0.1 to 0.3), respectively. There were no significant differences in vaccine effectiveness among age groups, dialysis modality, or vaccine type. Conclusions COVID-19 vaccination is effective in the dialysis population to prevent SARS-CoV-2 infection and severe outcomes, despite concerns about suboptimal antibody responses.
A call for advocacy and patient voice to eliminate hepatitis B virus infection
Authors: Philippa C Matthews, Kathryn Jack, Su Wang, Jane Abbott, Kathleen Bryce, Benny Cheng, Indrajit Ghosh, Alistair Story, Jacki Chen, Chris Munoz, John Bell, Steven Riddell, Amanda Goldring, Chun Goddard, Kate Moraras, Chari Cohen, Kenneth Brown, Jeffrey V Lazarus, Ahmed M Elsharkawy
Journal: The Lancet. Gastroenterology & hepatology (2022)
Autocrine Canonical Wnt Signaling Primes Noncanonical Signaling through ROR1 in Metastatic Castration-Resistant Prostate Cancer
Authors: Fen Ma, Seiji Arai, Keshan Wang, Carla Calagua, Amanda R. Yuan, Larysa Poluben, Zhongkai Gu, Joshua W. Russo, David J. Einstein, Huihui Ye, Meng Xiao He, Yu Liu, Eliezer Van Allen, Adam G. Sowalsky, Manoj K. Bhasin, Xin Yuan, Steven P. Balk
Journal: Cancer Research (2022)

Abstract Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling–mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth. Significance: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.
Modeling Benefits, Costs, and Affordability of a Novel Gene Therapy in Hemophilia A
Authors: Renske M.T. ten Ham, Simon M. Walker, Marta O. Soares, Geert W.J. Frederix, Frank W.G. Leebeek, Kathelijn Fischer, Michiel Coppens, Stephen J. Palmer
Journal: HemaSphere (2022)

The objective was to undertake an early cost-effectiveness assessment of valoctocogene roxaparvovec (valrox; Roctavian) compared to factor (F)VIII prophylaxis or emicizumab (Hemlibra; Roche HQ, Bazel, Switzerland) in patients with severe Hemophilia A (HA) without FVIII-antibodies. We also aimed to incorporate and quantify novel measures of value such as treatment durability, maximum value-based price (MVBP) and break-even time (ie, time until benefits begin to offset upfront payment). We constructed a Markov model to model bleeds over time which were linked to costs and quality-of-life decrements. In the valrox arm, FVIII over time was estimated combining initial effect and treatment waning and then linked to bleeds. In FVIII and emicizumab arms, bleeds were based on trial evidence. Evidence and assumptions were validated using expert elicitation. Model robustness was tested via sensitivity analyses. A Dutch societal perspective was applied with a 10-year time horizon. Valrox in comparison to FVIII, and emicizumab showed small increases in quality-adjusted life years at lower costs, and were therefore dominant. Valrox' base case MVBP was estimated at €2.65 million/treatment compared to FVIII and €3.5 million/treatment versus emicizumab. Mean break-even time was 8.03 years compared to FVIII and 5.68 years to emicizumab. Early modeling of patients with HA in The Netherlands treated with valrox resulted in estimated improved health and lower cost compared to prophylactic FVIII and emicizumab. We also demonstrated feasibility of incorporation of treatment durability and novel outcomes such as value-based pricing scenarios and break-even time. Future work should aim to better characterize uncertainties and increase translation of early modeling to direct research efforts.
Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction
Authors: Antoinette F. van Ouwerkerk, Fernanda M. Bosada, Karel van Duijvenboden, Arjan C. Houweling, Koen T. Scholman, Vincent Wakker, Cornelis P. Allaart, Jae-Sun Uhm, Inge B. Mathijssen, Ton Baartscheer, Alex V. Postma, Phil Barnett, Arie O. Verkerk, Bastiaan J. Boukens, Vincent M. Christoffels
Journal: Circulation (2022)

The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt-Oram syndrome (also known as hand-heart syndrome) and early onset of atrial fibrillation. Revealing how an altered key developmental transcription factor modulates cardiac physiology in vivo will provide unique insights into the mechanisms underlying atrial fibrillation in these patients.We analyzed ECGs of an extended family pedigree of Holt-Oram syndrome patients. Next, we introduced the TBX5-p.G125R variant in the mouse genome (Tbx5G125R) and performed electrophysiologic analyses (ECG, optical mapping, patch clamp, intracellular calcium measurements), transcriptomics (single-nuclei and tissue RNA sequencing), and epigenetic profiling (assay for transposase-accessible chromatin using sequencing, H3K27ac [histone H3 lysine 27 acetylation] CUT&RUN [cleavage under targets and release under nuclease sequencing]).We discovered high incidence of atrial extra systoles and atrioventricular conduction disturbances in Holt-Oram syndrome patients. Tbx5G125R/+ mice were morphologically unaffected and displayed variable RR intervals, atrial extra systoles, and susceptibility to atrial fibrillation, reminiscent of TBX5-p.G125R patients. Atrial conduction velocity was not affected but systolic and diastolic intracellular calcium concentrations were decreased and action potentials were prolonged in isolated cardiomyocytes of Tbx5G125R/+ mice compared with controls. Transcriptional profiling of atria revealed the most profound transcriptional changes in cardiomyocytes versus other cell types, and identified over a thousand coding and noncoding transcripts that were differentially expressed. Epigenetic profiling uncovered thousands of TBX5-p.G125R-sensitive, putative regulatory elements (including enhancers) that gained accessibility in atrial cardiomyocytes. The majority of sites with increased accessibility were occupied by Tbx5. The small group of sites with reduced accessibility was enriched for DNA-binding motifs of members of the SP (specificity protein) and KLF (Krüppel-like factor) families of transcription factors. These data show that Tbx5-p.G125R induces changes in regulatory element activity, alters transcriptional regulation, and changes cardiomyocyte behavior, possibly caused by altered DNA binding and cooperativity properties.Our data reveal that a disease-causing missense variant in TBX5 induces profound changes in the atrial transcriptional regulatory network and epigenetic state in vivo, leading to arrhythmia reminiscent of those seen in human TBX5-p.G125R variant carriers.
Do knowledge representations facilitate learning under epistemic uncertainty?
Authors: Isaac J. Handley-Miner, Liane Young
Journal: Behavioral and Brain Sciences (2021)

Abstract Phillips and colleagues argue that knowledge representations are more fundamental than belief representations because they better facilitate social learning. We suggest that existing theory of mind paradigms may be ill-equipped to adequately evaluate this claim. Future study should explore learning in situations where there is uncertainty about one's own and others’ knowledge, which better mirror real-world social learning contexts.
80% of patients with COVID-19 have ≥1 long-term effect at 14 to 110 d after initial symptoms
Authors: Matthew Kaczynski, Eleftherios Mylonakis
Journal: Annals of Internal Medicine (2022)

ACP Journal ClubJanuary 202280% of patients with COVID-19 have ≥1 long-term effect at 14 to 110 d after initial symptomsMatthew Kaczynski, BS, Eleftherios Mylonakis, MD, PhDMatthew Kaczynski, BSRhode Island Hospital and The Miriam Hospital/Brown University, Providence, Rhode Island, USA (M.K., E.M.), Eleftherios Mylonakis, MD, PhDRhode Island Hospital and The Miriam Hospital/Brown University, Providence, Rhode Island, USA (M.K., E.M.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/J21-0007 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021;11:16144. https://pubmed.ncbi.nlm.nih.gov/34373540Clinical Impact RatingsGIM/FP/GP: Hospitalists: Infectious Disease: References1. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601-15. [PMID: 33753937] Google Scholar2. Lerner AM, Robinson DA, Yang L, et al. Toward understanding COVID-19 recovery: National Institutes of Health workshop on postacute COVID-19. Ann Intern Med. 2021;174:999-1003. [PMID: 33780290] Google Scholar Author, Article, and Disclosure InformationAffiliations: Rhode Island Hospital and The Miriam Hospital/Brown University, Providence, Rhode Island, USA (M.K., E.M.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J21-0007.This article was published at Annals.org on 4 January 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byPost-viral fatigue in COVID-19: A review of symptom assessment methods, mental, cognitive, and physical impairment January 2022Volume 175, Issue 1Page: JC10KeywordsCOVID-19Computed axial tomographyPosttraumatic stress disorderProspective studiesPulmonary diseasesResearch fundingResearch laboratoriesSigns and symptomsSleep disordersSystematic reviews ePublished: 4 January 2022 Issue Published: January 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...