tbuckley/cabot-search huggingface dataset:
A Semimechanistic Model of the Bactericidal Activity of High-Dose Isoniazid against Multidrug-Resistant Tuberculosis: Results from a Randomized Clinical Trial
Authors: Kamunkhwala Gausi, Elisa H. Ignatius, Xin Sun, Soyeon Kim, Laura Moran, Lubbe Wiesner, Florian von Groote-Bidlingmaier, Richard Hafner, Kathleen Donahue, Naadira Vanker, Susan L. Rosenkranz, Susan Swindells, Andreas H. Diacon, Eric L. Nuermberger, Kelly E. Dooley, Paolo Denti
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of Mycobacterium tuberculosis, but the optimal dose remains unknown. Objectives: To characterize the association between isoniazid pharmacokinetics (standard or high dose) and early bactericidal activity against M. tuberculosis (drug sensitive and inhA mutated) and N-acetyltransferase 2 status. Methods: ACTG (AIDS Clinical Trial Group) A5312/INHindsight is a 7-day early bactericidal activity study with isoniazid at a normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary tuberculosis received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (cfu) on solid culture and time to positivity in liquid culture were jointly analyzed using nonlinear mixed-effects modeling. Measurements and Main Results: Fifty-nine adults were included in this analysis. A decline in sputum cfu was described by a one-compartment model, whereas an exponential bacterial growth model was used to interpret time-to-positivity data. The model found that bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship (a model linking the drug concentration to the observed effect). The model predicted lower potency but similar maximum kill of isoniazid against inhA-mutated compared with drug-sensitive isolates. Based on simulations from the pharmacokinetics-pharmacodynamics model, to achieve a drop in bacterial load comparable to 5 mg/kg against drug-sensitive tuberculosis, 10- and 15-mg/kg doses are necessary against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg. Conclusions: Dosing of isoniazid based on N-acetyltransferase 2 acetylator status may help patients attain effective exposures against inhA-mutated isolates. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
Advances in Acute Ischemic Stroke Therapy
Authors: Yunyun Xiong, Ajay K. Wakhloo, Marc Fisher
Journal: Circulation Research (2022)

The treatment of acute ischemic stroke continues to advance. The mainstay of treatment remains intravenous thrombolysis with alteplase. Recent studies demonstrated that later treatment with alteplase is beneficial in patients selected with advanced imaging techniques. Tenecteplase has been evaluated as an alternative thrombolytic drug and evidence suggests that it is as least as effective as alteplase and may lyse large vessel clots more effectively. Endovascular therapy with mechanical thrombectomy has now been shown to be beneficial up to 24 hours after stroke onset in carefully selected patients with proximal, large vessel occlusions. Ongoing studies are evaluating the effectiveness of thrombectomy in patients with more distal vessel occlusions and patients with proximal large vessel occlusions with larger ischemic core volumes and also in patients with milder neurological deficits. Cytoprotection is another potential acute stroke therapy that has not demonstrated efficacy in prior clinical trials. It should be reconsidered as an adjunct to reperfusion and a variety of new clinical trials can be envisioned to evaluate the potential benefits of cytoprotection in patients before and after reperfusion.
Abstract P200: A Polygenic Risk Score Improves Prediction Of Lifetime Risk For Heart Failure
Authors: Taryn Alkis, xi Luo, Katherine Wall, Patricia Chang, Faye L Norby, Ron C Hoogeveen, Christie M Ballantyne, Josef Coresh, Eric Boerwinkle, Amil M Shah, Bing Yu
Journal: Circulation (2022)

Introduction: Heart Failure (HF) has shared genetic architecture with its risk factors, including atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). The risk prediction performance of polygenic risk scores (PRS) for those HF risk factors and HF itself over an established risk equation warrants investigation. Methods: Within the Atherosclerosis Risk in Communities (ARIC) study, six PRSs were constructed for AF, BMI, CHD, SBP, T2D, and HF by summing the product of pre-computed weights from genome-wide association studies and SNP allele dosages in European and African Americans separately. The association between PRSs and incident HF was assessed using cox proportional hazard models, and the 10-, 20-, and 30-year risk prediction performance of PRS over the ARIC HF risk equation was assessed using C-statistics. Associations between AF PRS and HF subtypes, echocardiographic measures, and 4,877 proteins were examined. Results: Over 30 years follow-up, 1,922 (22%) and 735 (29%) HF cases developed in 8,624 European (mean age=54.2, 52% female) and 2,525 African (mean age=53.3, 61% female) Americans. The PRSs for AF and HF were associated with incident HF in both European and African Americans (P&lt;0.05). The AF PRS showed the greatest effect on HF risk in European (HR=1.47, 95% CI: 1.41 to 1.53) and African (HR=1.29, 95% CI: 1.20 to 1.39) Americans. Addition of AF PRS to the ARIC HF risk equation significantly improved the C-statistics for 10-year risk prediction in European (ΔC=0.017, 95% CI: 0.009 to 0.026) and African (ΔC=0.015, 95% CI: 0.004 to 0.026) Americans. The AF PRS was further associated with HF with reduced (HR=1.45, 95% CI: 1.29 to 1.64) and preserved (HR=1.49, 95% CI: 1.34 to 1.66) ejection fraction, and higher left atrial volume index (P=1.67х10 -4 ). Protein analyses revealed that 61 proteins were associated with AF PRS, where NT-proBNP and Coagulation factor X showed the strongest positive and negative associations respectively. Conclusions: The PRS of AF was associated with incident HF, and had significant incremental value over an established HF risk prediction equation. These findings suggest that PRS may be useful in identifying individuals with high risk of HF.
Prognostication and shared decision making in neurocritical care
Authors: Kelsey Goostrey, Susanne Muehlschlegel
Journal: BMJ (2022)

Abstract Prognostication is crucial in the neurological intensive care unit (neuroICU). Patients with severe acute brain injury (SABI) are unable to make their own decisions because of the insult itself or sedation needs. Surrogate decision makers, usually family members, must make decisions on the patient’s behalf. However, many are unprepared for their role as surrogates owing to the sudden and unexpected nature of SABI. Surrogates rely on clinicians in the neuroICU to provide them with an outlook (prognosis) with which to make substituted judgments and decide on treatments and goals of care on behalf of the patient. Therefore, how a prognostic estimate is derived, and then communicated, is extremely important. Prognostication in the neuroICU is highly variable between clinicians and institutions, and evidence based guidelines are lacking. Shared decision making (SDM), where surrogates and clinicians arrive together at an individualized decision based on patient values and preferences, has been proposed as an opportunity to improve clinician-family communication and ensure that patients receive treatments they would choose. This review outlines the importance and current challenges of prognostication in the neuroICU and how prognostication and SDM intersect, based on relevant research and expert opinion.
Metaboloepigenetics in cancer, immunity, and cardiovascular disease
Authors: Samuel T Keating, Assam El-Osta
Journal: Cardiovascular Research (2022)

Abstract The influence of cellular metabolism on epigenetic pathways is well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite S-adenosylmethionine. Technically speaking, there are many other metabolites that drive epigenetic processes that instruct seemingly distant—yet highly connect pathways—and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy links the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism, and immunity in unfamiliar roles—cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism—now recognized as central to proliferation in cancer biology—influences core enzymes that not only control gene expression but are also central to replication, condensation, and the repair of nucleic acid. These nuclear processes rely on metabolism, and with glucose at centre stage, the role of respiration and oxidative metabolism is now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognizable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism, we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation, and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes.
Hepatobiliary Excretion PET/CT With 68Ga-TAoS-DAZA to Evaluate Bile Duct Patency
Authors: Martin Freesmeyer, Robert Drescher, Christian Kühnel, Falk Gühne, Julia Greiser
Journal: Clinical Nuclear Medicine (2021)

Abstract Tri-alkoxysalicyl-1,4-diazepan-6-amine (TAoS-DAZA) ligands, radiolabelled with 68 Ga, have been proposed as PET/CT agents for depiction and quantification of hepatobiliary function and evaluation of bile excretion. In the presented case, a patient with hepatocellulary carcinoma underwent PET/CT with the TAoS-derivate 68 Ga-tri-methoxysalicyl-(TMoS)-DAZA to determine the patency of intrahepatic and extrahepatic bile ducts, in particular of a stent in the common bile duct. The PET/CT was performed without complications. Evaluation of bile excretion over time was possible. 68 Ga-TAoS-DAZA PET/CT may be an option for dynamic imaging of the excretory hepatic function to visualize the biliary tree and to rule out cholestasis.
Abstract MP14: <i>In Utero</i> Exposure To Metals And Trace Elements affects Cord Blood Metabolome Profile: Findings From An Urban Minority Birth Cohort In The United States
Authors: Mingyu Zhang, Jessie Buckley, Liming Liang, Xiumei Hong, Guoying Wang, Mei-Cheng Wang, Marsha Wills-Karp, Xiaobin Wang, Noel T Mueller
Journal: Circulation (2022)

Background: Exposure to metals lead (Pb), mercury (Hg), and cadmium (Cd) and trace elements selenium (Se) and manganese (Mn) has been linked to the developmental origins of cardiometabolic diseases, but the mechanisms are not well-understood. Objective: Conduct a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn affects the metabolic programming of fetuses. Methods: We used data from mother-infant pairs in the Boston Birth Cohort. We measured metals and trace elements in maternal red blood cells (RBCs) collected 24-72 hours after delivery, and metabolites in cord blood collected at birth. We used multivariable linear regression to examine associations of metals and trace elements with metabolites and Bonferroni correction to account for multiple comparisons. We assessed non-linear associations of metals and trace elements with metabolites using restricted cubic spline plots. Results: This analysis included 690 mother-infant pairs (57% Black and 24% Hispanic). After Bonferroni correction, 25 cord metabolites were associated with at least one metal or trace element (Figure). Pb was negatively associated with the xenobiotic piperine, Cd was positively associated with xenobiotics cotinine and hydroxycotinine, and Hg was associated with 8 lipid metabolites (in both directions). Mn and Se shared associations with 6 metabolites (in both directions), which mostly included nucleotides and amino acids; Mn was additionally associated C36:4 hydroxy phosphatidylcholine and Se was additionally associated with 7 metabolites (mostly amino acids, nucleotides, and carnitines). Most associations were linear. Discussion: Maternal RBC metal and trace element concentrations were associated in a dose-dependent fashion with cord blood metabolites. What remains to be determined is whether these metals- and trace elements-associated changes in cord metabolites can influence a child’s future risk of cardiometabolic diseases.
Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use
Authors: Rebecca Rockett, Kerri Basile, Susan Maddocks, Winkie Fong, Jessica E. Agius, Jessica Johnson-Mackinnon, Alicia Arnott, Shona Chandra, Mailie Gall, Jenny Draper, Elena Martinez, Eby M. Sim, Clement Lee, Christine Ngo, Marc Ramsperger, Andrew N. Ginn, Qinning Wang, Michael Fennell, Danny Ko, H. Ling Lim, Nicky Gilroy, Matthew V.N. O’Sullivan, Sharon C.-A. Chen, Jen Kok, Dominic E. Dwyer, Vitali Sintchenko
Journal: New England Journal of Medicine (2022)
A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy
Authors: Yu Hirata, Kazuhiro Nomura, Daisuke Kato, Yoshihisa Tachibana, Takahiro Niikura, Kana Uchiyama, Tetsuya Hosooka, Tomoaki Fukui, Keisuke Oe, Ryosuke Kuroda, Yuji Hara, Takahiro Adachi, Koji Shibasaki, Hiroaki Wake, Wataru Ogawa
Journal: Journal of Clinical Investigation (2022)

Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.
Yellow Urticaria
Authors: R. Matthew McLarney, Warren R. Heymann
Journal: JAMA Dermatology (2022)

This case report describes a man in his 70s with dark urine in the setting of increased acetaminophen use, a pruritic rash, scleral icterus, jaundice, and well-circumscribed, bright yellow papules and plaques on his lateral abdomen.
Transoral Surgery With Neck Dissection Is an Excellent Treatment for the Appropriately Selected Patient With Early-Stage Oropharyngeal Cancer
Authors: Adam S. Garden
Journal: Journal of Clinical Oncology (2022)

Ferris et al 1 have conducted and published the results of the E3311 trial.In the 2000s, RTOG performed phase II trials testing intensity-modulated radiotherapy in multiinstitutional settings, and now, intensity-modulated radiotherapy is the standard form of radiation for treating head and neck cancer.Similarly, gathering 68 surgeons to operate 500 patients with transoral surgery and have 3-year overall survival .90% is a major accomplishment.Yet, several questions are raised:1. Which patients is this strategy targeting?The inclusion was limited to stage I patients, presentations no longer considered locally advanced.Matted nodes were excluded explicitly, and the high proportion of tonsil tumors, , 2 cm primaries, and , 3 cm nodes suggests implicit selection bias for the most favorable patients within stage I. 2. Is this truly a treatment de-escalation strategy?All patients had surgery, including a neck dissection.Grade 3-5 toxicities associated with surgery were .15%.More importantly, in this highly selected population, 90% had adjuvant radiation and .30% (including 45% of cN2b patients) had treatment intensification-surgery, high-dose radiation, and chemotherapy.We never get a sense of the overall toxicities of the strategy as the authors only provide subgroup analysis by modality and arms. How relevant is a reduction of 15% in radiationdose?There is more to radiation dose than just dose.Overall treatment time, fraction size, and what tissues are treated and the volume of these tissues are as important (if not more so).The cited studies from M.D. Anderson demonstrated that 57.6 Gy in 32 fractions is efficacious for intermediate-risk disease. [2]3][4] This is clearly , 60 Gy in 30 fractions and more likely equivalent to the experimental 50 Gy in 25 fractions.Furthermore, these patients' tissues at risk were relatively small with , 4 cm primary tumors and modest nodal burden.The authors 1 did not provide differences in ipsilateral versus bilateral therapy in each arm, and arm C did have more tongue tumors where bilateral therapy is the standard.Without the overall toxicity profile and only a , 10% difference in grade .3 acute toxicities, the relevance of the dose reduction is questionable.
FDG PET/CT Showing a Primary Vaginal NK/T Cell Lymphoma
Authors: Pan Tang, Rang Wang, Minggang Su, Guohua Shen, Rong Tian
Journal: Clinical Nuclear Medicine (2021)

A 28-year-old woman with vaginal discharge was admitted to the hospital. Colposcopy examination found several ulcers with pus in the vagina. Biopsy demonstrated extranodal natural killer/T-cell lymphoma. PET/CT scan was subsequently performed for staging. It revealed intense FDG uptake in the vagina. No FDG-avid lesion was seen in the rest of the body. A primary vaginal extranodal natural killer/T-cell lymphoma was diagnosed.
Role of 68Ga-DOTATOC PET/CT in Insulinoma According to 3 Different Contexts: A Retrospective Study
Authors: Pierre-Louis Moreau, Cyrielle Aveline, Sophie Christin-Maitre, Philippe Chanson, Olivier Dubreuil, Timofei Rusu, Françoise Montravers
Journal: Clinical Nuclear Medicine (2022)

Objective The aim of this study was to assess the performance of 68 Ga-DOTATOC PET/CT in the detection and extension of insulinomas according to 3 different contexts: sporadic benign, sporadic metastatic, and multiple endocrine neoplasia type 1 (MEN1). Patients and Methods The data of 71 adult patients who underwent 68 Ga-DOTATOC PET/CT for suspected or confirmed sporadic insulinoma, suspicion of insulinoma in the context of MEN1, follow-up of metastatic insulinoma, or suspicion of recurrence of insulinoma were retrospectively analyzed. Pathological examination or strong clinical and biological findings were used as standards of truth. Results For the assessment of a confirmed sporadic insulinoma in 17 patients, the sensitivity of SR-PET was 75%, including 2 patients for whom metastatic lesions had been revealed by SR-PET. For 35 patients with a suspicion of insulinoma, the sensitivity was 39%. In 10 patients followed up for metastatic insulinoma, the sensitivity was 100%. For 5 patients with a history of MEN1, interpretation of SR-PET was difficult, as 3 of them presented with multiple pancreatic uptake foci. The global sensitivity of SR-PET in all insulinomas excluding those with a MEN1 story was 64% (100% for metastatic insulinomas, 62% for benign insulinomas), with a specificity of 89%. Conclusions 68 Ga-DOTATOC PET/CT is a useful examination tool for the assessment of insulinomas in selected contexts, with very high performance for the detection and extension workup of metastatic insulinomas and high specificity for the detection of sporadic benign insulinomas. The examination should be completed with GLP-1 receptor PET when it is negative or in a MEN1 context.
The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma
Authors: Stephen Opat, Alessandra Tedeschi, Kim Linton, Pamela McKay, Bei Hu, Henry Chan, Jie Jin, Magdalena Sobieraj-Teague, Pier Luigi Zinzani, Morton Coleman, Catherine Thieblemont, Peter Browett, Xiaoyan Ke, Mingyuan Sun, Robert Marcus, Craig A. Portell, Kirit Ardeshna, Fontanet Bijou, Patricia Walker, Eliza A. Hawkes, Sally Mapp, Shir-Jing Ho, Dipti Talaulikar, Ke-Shu Zhou, Melannie Co, Xiaotong Li, Wenxiao Zhou, Massimo Cappellini, Chris Tankersley, Jane Huang, Judith Trotman
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Marginal zone lymphoma (MZL) is an uncommon non–Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111–214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Conclusions: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.
An Atypical Case of Meckel's Diverticulum Assessed by SPECT/CT Imaging
Authors: Gregory S. Mittl, Sabah-e-Noor Servaes, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2021)

Abstract A 17-year-old adolescent boy presented with multiple episodes of hematochezia. After a negative 99m TcO 4 scan, upper endoscopy, colonoscopy, and CT angiography, the patient underwent a second 99m TcO 4 scan with ranitidine. The anterior images demonstrated a faint, delayed focus of uptake in the midabdomen without correlate on lateral projections. SPECT/CT was performed for localization with the focus of activity seen in an anterior loop of distal small bowel adjacent to the umbilicus. The patient subsequently underwent diagnostic laparoscopy and resection of the diverticulum with postoperative resolution of the symptoms.