tbuckley/cabot-search huggingface dataset:
Clipper: p-value-free FDR control on high-throughput data from two conditions
Authors: Xinzhou Ge, Yiling Elaine Chen, Dongyuan Song, MeiLu McDermott, Kyla Woyshner, Antigoni Manousopoulou, Ning Wang, Wei Li, Leo D. Wang, Jingyi Jessica Li
Journal: Genome biology (2021)

Abstract High-throughput biological data analysis commonly involves identifying features such as genes, genomic regions, and proteins, whose values differ between two conditions, from numerous features measured simultaneously. The most widely used criterion to ensure the analysis reliability is the false discovery rate (FDR), which is primarily controlled based on p -values. However, obtaining valid p -values relies on either reasonable assumptions of data distribution or large numbers of replicates under both conditions. Clipper is a general statistical framework for FDR control without relying on p -values or specific data distributions. Clipper outperforms existing methods for a broad range of applications in high-throughput data analysis.
80P HER2 expression in primary bladder tumors and paired regional lymph nodes: Relationship to cell cycle profile
Authors: M. Dumitru, M. Mihăilă, C.M. Hotnog, M.E. Panait, M.M. Vasilescu, M.G. Hortopan, L.I. Braşoveanu
Journal: Annals of Oncology (2021)
P50.05 Natural History and Real-World Treatment Outcomes for NSCLC Patients with EGFR Exon 20 Insertion Mutation: An IASLC- ASCO CancerLinQ Study
Authors: M. Behera, R. Jiang, Z. Huang, B. Bunn, M. Wynes, J. Switchenko, G. Scagliotti, C. Belani, S. Ramalingam
Journal: Journal of Thoracic Oncology (2021)
Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior
Authors: Barna Dudok, Miklos Szoboszlay, Anirban Paul, Peter M. Klein, Zhenrui Liao, Ernie Hwaun, Gergely G. Szabo, Tristan Geiller, Bert Vancura, Bor-Shuen Wang, Sam McKenzie, Jesslyn Homidan, Lianne M.F. Klaver, Daniel F. English, Z. Josh Huang, György Buzsáki, Attila Losonczy, Ivan Soltesz
Journal: Neuron (2021)

The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.
Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses
Authors: Jared Feldman, Julia Bals, Clara G. Altomare, Kerri St. Denis, Evan C. Lam, Blake M. Hauser, Larance Ronsard, Maya Sangesland, Thalia Bracamonte Moreno, Vintus Okonkwo, Nathania Hartojo, Alejandro B. Balazs, Goran Bajic, Daniel Lingwood, Aaron G. Schmidt
Journal: Science Immunology (2021)

Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human donors targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). Single-cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as preemergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution, we could select for a higher-affinity RBD interaction, conferred by a single amino acid change. The minimally mutated, affinity-matured antibodies also potently neutralized SARS-CoV-2. Understanding the SARS-CoV-2 RBD–specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses, enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses.
Biosimilar Approved for Wet AMD
Authors: Rebecca Voelker
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Neither Athletic Training nor Detraining Affects LV Hypertrophy in Adult, Low-Risk Patients With HCM
Authors: Antonio Pelliccia, Cristian Borrazzo, Stefano Caselli, Erika Lemme, Maria Beatrice Musumeci, Viviana Maestrini, Pietro Francia, Domitilla Russo, Matteo Pelliccia, Iacopo Olivotto, Camillo Autore
Journal: JACC. Cardiovascular imaging (2021)
Abstract 13147: Association of Electroanatomic Mapping Derived Left Atrial Bipolar Voltage With Clinical Characteristics and Recurrence of Arrhythmia in Patients Undergoing Ablation for Atrial Fibrillation
Authors: Muhammad Haq, Richard Amara, David Yoo, Aaron Kunamalla, Timm Dickfeld, Alejandro Jimenez Restrepo, Andrew Zohlman, Jeffrey Rottman, Stephen Shorofsky, Vincent Y See
Journal: Circulation (2019)

Introduction: Low voltage measured by electroanatomic mapping (EAM) in the left atrium (LA) has been correlated with myocardial fibrosis. Low voltage thresholds of 0.1-0.5mV and 0.2-0.45 have been ...
LGBT+: Indian medical institutions are asked to amend textbooks with unscientific content
Authors: Priti Salian
Journal: BMJ (2021)

Medical institutions in India should not teach from books that contain content that discriminates against LGBT+ people, the Indian National Medical Commission (NMC) has said.

The NMC—India’s regulatory body for medical education and practice—published an advisory1 that medical education should not be taught in a way that is perceived to be derogatory, discriminatory, or insulting to the LGBT+ community.

The commission also said that medical institutions should not approve textbooks until they are amended to remove all discriminatory content after noting that some contain derogatory comments and unscientific information about virginity.

In July 2018, the Indian Psychiatric Society said that homosexuality is not a disease, but a normal variant of sexuality.2 Two months later, India decriminalised same sex relationships.3 But a recent case in the Madras High Court observed that students in India’s 554 medical colleges are …
Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer
Authors: Yuanyuan Zhang, Hongyan Chen, Hongnan Mo, Xueda Hu, Ranran Gao, Yahui Zhao, Baolin Liu, Lijuan Niu, Xiaoying Sun, Xiao Yu, Yong Wang, Qing Chang, Tongyang Gong, Xiuwen Guan, Ting Hu, Tianyi Qian, Binghe Xu, Fei Ma, Zemin Zhang, Zhihua Liu
Journal: Cancer Cell (2021)

In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.
Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial
Authors: Michelle Sholzberg, Grace H Tang, Hassan Rahhal, Musaad AlHamzah, Lisa Baumann Kreuziger, Fionnuala Ní Áinle, Faris Alomran, Khalid Alayed, Mohammed Alsheef, Fahad AlSumait, Carlos Eduardo Pompilio, Catherine Sperlich, Sabrena Tangri, Terence Tang, Peter Jaksa, Deepa Suryanarayan, Mozah Almarshoodi, Lana A Castellucci, Paula D James, David Lillicrap, Marc Carrier, Andrew Beckett, Christos Colovos, Jai Jayakar, Marie-Pier Arsenault, Cynthia Wu, Karine Doyon, E Roseann Andreou, Vera Dounaevskaia, Eric K Tseng, Gloria Lim, Michael Fralick, Saskia Middeldorp, Agnes Y Y Lee, Fei Zuo, Bruno R da Costa, Kevin E Thorpe, Elnara Márcia Negri, Mary Cushman, Peter Jüni
Journal: BMJ (2021)

To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards.
FP09.02 Mobocertinib (TAK-788) in EGFR Exon 20 Insertion+ Metastatic NSCLC: Patient-Reported Outcomes From EXCLAIM Extension Cohort
Authors: M.R. García Campelo, C. Zhou, S. Ramalingam, H. Lin, T. Kim, G. Riely, T. Mekhail, D. Nguyen, E. Goodman, K. Le, M. Mehta, S. Popat, P. Janne
Journal: Journal of Thoracic Oncology (2021)
P10.11 Real-World Experience With Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer at Frankfurt University Hospital
Authors: S. Shaid, J. Stratmann, A. Wolf, N. Niklas, A. Calleja, R. Munro, D. Waldenberger, R. Carroll, M. Daumont, J. Penrod, L. Lacoin, G. Rohde
Journal: Journal of Thoracic Oncology (2021)
Lung Cancer Screening Eligibility and Screening Patterns Among Black and White Adults in the United States
Authors: Jessica W. Lozier, Stacey A. Fedewa, Robert A. Smith, Gerard A. Silvestri
Journal: JAMA Network Open (2021)

This cohort study compares the demographics of US adults who are currently being screened for lung cancer and assesses the potential association between proposed changes to the United States Preventive Services Task Force (USPSTF) screening recommendations and screening rates by race and age.
Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice
Authors: Heidi H. Pak, Spencer A. Haws, Cara L. Green, Mikaela Koller, Mitchell T. Lavarias, Nicole E. Richardson, Shany E. Yang, Sabrina N. Dumas, Michelle Sonsalla, Lindsey Bray, Michelle Johnson, Stephen Barnes, Victor Darley-Usmar, Jianhua Zhang, Chi-Liang Eric Yen, John M. Denu, Dudley W. Lamming
Journal: Nature Metabolism (2021)
Diastolic Blood Pressure and the J-Curve—Causal Effect or Confounding?
Authors: Sydney E. Hartsell, Srinivasan Beddhu
Journal: JAMA Network Open (2021)

Andrew J. Foy, MD; Edward J. Filippone, MD; Eric Schaefer, PhD; Matt Nudy, MD; Mohammed Ruzieh, MD; Anne-Marie Dyer, MS; Vernon M. Chinchilli, PhD; Gerald V. Naccarelli, MD
A novel lncRNA linc-AhRA negatively regulates innate antiviral response in murine microglia upon neurotropic herpesvirus infection
Authors: Yiliang Wang, Weisheng Luo, Lianzhou Huang, Ji Xiao, Xiaowei Song, Feng Li, Yuying Ma, Xiaohui Wang, Fujun Jin, Ping Liu, Yexuan Zhu, Kaio Kitazato, Yifei Wang, Zhe Ren
Journal: Theranostics (2021)

Microglia are the primary cellular source of type I interferons (I-IFNs) in the brain upon neurotropic virus infection. Although the I-IFN-based antiviral innate immune response is crucial for eliminating viruses, overproduction led to immune disorders. Therefore, the relatively long-lasting I-IFNs must be precisely controlled, but the regulatory mechanism for the innate antiviral response in microglia remains largely unknown. Long non-coding RNAs (lncRNAs) are being recognized as crucial factors in numerous diseases, but their regulatory roles in the innate antiviral response in microglia are undefined. Methods: The high-throughput RNA sequencing was performed to obtain differentially expressed lncRNAs (DELs) in primary microglia infected with or without the neurotropic herpes simplex virus type 1 (HSV-1). We selected four DELs ranked in the top 15 in basic level and their fold change induced by HSV-1, i.e., FPKMHSV-1/FPKMCells.We subsequently found a key lncRNA affecting the innate antiviral response of microglia significantly. We next used dual-luciferase reporter assays, bioinformatical tools, and truncation mutants of both lncRNA and targeted proteins to elucidate the downstream and upstream mechanism of action of lncRNA. Further, we established microglia-specific knock-in (KI) mice to investigate the role of lncRNA in vivo. Results: We identified a long intergenic non-coding RNA, linc-AhRA, involved in regulating the innate antiviral response in murine microglia. linc-AhRA is activated by aryl hydrocarbon receptor (AhR) and restricts I-IFN production in microglia upon neurotropic herpesvirus infection and innate immune stimulation. Mechanistically, linc-AhRA binds to both tripartite motif-containing 27 (TRIM27) and TANK-binding kinase 1 (TBK1) through its conserved 117nt fragment as a molecular scaffold to enhance TRIM27-TBK1 interaction. This interaction facilitates the TRIM27-mediated ubiquitination of TBK1 and results in ubiquitin-proteasome-dependent degradation of TBK1. Consequently, linc-AhRA suppresses I-IFN production through facilitating TBK1 degradation and limits the microglial innate immune response against neurotropic herpesvirus infection. Microglia-specific KI of linc-AhRA mice shows a weakened antiviral immune response upon neurotropic herpesvirus challenge due to a reduction of TBK1 in microglia. Conclusion: Our findings indicate that linc-AhRA is a negative regulator of I-IFN production in microglia to avoid excessive autoimmune responses. These findings uncover a previously unappreciated role for lncRNA conserved fragments in the innate antiviral response, providing a strong foundation for developing nucleotide drugs based on conserved functional fragments within lncRNAs.
3TR: a pan-European cross-disease research consortium aimed at improving personalised biological treatment of asthma and COPD
Authors: Celeste Porsbjerg, Anke H. Maitland-van der Zee, Guy Brusselle, Giorgio Walter Canonica, Alvar Agusti, Rosa Faner, Claus F. Vogelmeier, Martijn Nawijn, Maarten van den Berge, Franca Rusconi, Charles Pilette, Valeria Ramiconi, Courtney Coleman, Rekha Chaudhuri, Kian Fan Chung, Jadwiga Wedzicha, Sejla Saglani, Marc P. Van der Schee, Liam Heaney, Arnaud Bourdin, Graham Roberts, Ratko Djukanovic, Piotr Kuna, Maciej Kupczyk, Judith Axmann, Heribert Staudinger, Graham W. Clarke, Sven Erik Dahlen, Chris Brightling
Journal: European Respiratory Journal (2021)

<b>3TR, the largest IMI consortium ever in immune diseases, brings clinical researchers and scientists from several disease areas together, in an endeavour to increase the clinical impact of targeted immune-mediated therapies, including asthma and COPD</b>https://bit.ly/3kPq0xI
Banff consensus recommendations for steatosis assessment in donor livers
Authors: Desley A. H. Neil, Marta Minervini, Maxwell L. Smith, Stefan G. Hubscher, Elizabeth M. Brunt, A. Jake Demetris
Journal: Hepatology (2021)

No consensus criteria or approaches exist regarding assessment of steatosis in the setting of human donor liver suitability for transplantation. The Banff Working Group on Liver Allograft Pathology undertook a study to determine the consistency with which steatosis is assessed and reported in frozen sections of potential donor livers.
Endothelin-1 overexpression inhibits prostate cancer growth in vivo through vasoconstriction of tumor-feeding arterioles
Authors: Christine Weydert, Alison Esser, Ruth Mejia, Justin Drake, James Barnes, Michael Henry
Journal: Cancer Research (2008)

2063  The vasoactive peptide ET-1 has been implicated in the progression of prostate and other cancers. To explore this further, we generated prostate cancer cell lines (PC-3 and 22Rv1) overexpressing ET-1 from a retroviral vector. Using this approach, we achieved 127- and 88-fold overexpression of ET-1 in PC-3 and 22Rv1 cells, respectively, compared to vector controls. This level of ET-1 secretion was comparable to that secreted by primary human lung microvascular endothelial cells. Overexpression of ET-1 leads to a modest increase in PC-3 cell growth in vitro (~2 fold). This occurred through an endothelin receptor A (ETA)-dependent autocrine mechanism. ET-1 overexpression did not affect growth of ETA-deficient 22Rv1 cells. Surprisingly, both 22Rv1 and PC-3 ET-1 overexpressing cells produced significantly smaller subcutaneous tumors compared to controls. Furthermore 22Rv1 ET-1 overexpressing cells delivered via intracardiac route failed to grow in liver, adrenal gland, or bone though viable tumor cells did colonize these organs as assessed by bioluminescence imaging. Based on these data, wehypothesized that overexpression of ET-1 may have an effect on the tumor microenvironment that inhibits tumor growth. Initially, we investigated angiogenesis in PC-3 and 22Rv1 ET-1 overexpressing subcutaneous tumors. We determined that PC-3 ET-1 overexpressing tumors demonstrated decreased microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression compared to vector control. However, 22Rv1 ET-1 overexpressing tumors did not exhibit alterations in MVD or VEGF expression compared to controls suggesting other mechanisms are involved in poor tumor growth. Indeed, preliminary microCT analysis following Microfil resin infusion suggested vasoconstriction of tumor-feeding arterioles within and near the ET-1 overexpressing tumors. Furthermore, growth of subcutaneous ET-1 overexpressing tumors was partially restored by an orally administered systemic vasodilator, hydralazine. Taken together, these data suggest that localized ET-1 concentration in vivo is critical for determining the balance between suppression of tumor growth (vasoconstriction) and growth promotion (mitogenesis and angiogenesis).
FP04.04 A Phase Ib/II Study of Imprime PGG and Pembrolizumab in Pretreated Patients With Advanced Stage Non-Small Cell Lung Cancer: BTCRC-LUN15-017
Authors: M. Furqan, J. Malhotra, L. Liu, H. Wang, M. Pasquinelli, E. Sisel, K. Kennedy, A. Shergill, L. Feldman
Journal: Journal of Thoracic Oncology (2021)
Identification of Novel Risk Loci for Behçet's Disease–Related Uveitis in a Chinese Population in a <scp>Genome‐Wide</scp> Association Study
Authors: Guannan Su, Zhenyu Zhong, Qingyun Zhou, Liping Du, Zi Ye, Fuzhen Li, Wenjuan Zhuang, Chaokui Wang, Liang Liang, Yan Ji, Qingfeng Cao, Qingfeng Wang, Rui Chang, Handan Tan, Shenglan Yi, Yujing Li, Xiaojie Feng, Weiting Liao, Wanyun Zhang, Jia Shu, Shiyao Tan, Jing Xu, Su Pan, Hongxi Li, Jing Shi, Zhijun Chen, Ying Zhu, Xingsheng Ye, Xiao Tan, Jun Zhang, Zhangluxi Liu, Fanfan Huang, Gangxiang Yuan, Tingting Pang, Yizong Liu, Jiadong Ding, Yingnan Gao, Meifen Zhang, Wei Chi, Xiaoli Liu, Yuqin Wang, Ling Chen, Akira Meguro, Masaki Takeuchi, Nobuhisa Mizuki, Shigeaki Ohno, Xianbo Zuo, Aize Kijlstra, Peizeng Yang
Journal: Arthritis & Rheumatology (2021)

To explore susceptibility loci associated with uveitis in Behçet's disease (BD).We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.
A Modern Approach to Dyslipidemia
Authors: Amanda J Berberich, Robert A Hegele
Journal: Endocrine Reviews (2021)

Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents-especially antisense RNA and monoclonal antibodies-targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.