tbuckley/cabot-search huggingface dataset:
Staphylococcus aureus bacteraemia mortality: a systematic review and meta-analysis
Authors: Anthony D. Bai, Carson K.L. Lo, Adam S. Komorowski, Mallika Suresh, Kevin Guo, Akhil Garg, Pranav Tandon, Julien Senecal, Olivier Del Corpo, Isabella Stefanova, Clare Fogarty, Guillaume Butler-Laporte, Emily G. McDonald, Matthew P. Cheng, Andrew M. Morris, Mark Loeb, Todd C. Lee
Journal: Clinical Microbiology and Infection (2022)
From a Symptom-Based to a Mechanism-Based Pharmacotherapeutic Treatment in Complex Regional Pain Syndrome
Authors: Thomas J. P. Mangnus, Krishna D. Bharwani, Maaike Dirckx, Frank J. P. M. Huygen
Journal: Drugs (2022)

Complex regional pain syndrome (CRPS) is a debilitating painful condition of a distal extremity that can develop after tissue damage. CRPS is thought to be a multimechanism syndrome and ideally the most prominent mechanism(s) should be targeted by drugs in an individually tailored manner. This review gives an overview of the action and evidence of current and future pharmacotherapeutic options for CRPS. The available options are grouped in four categories by their therapeutic actions on the CRPS mechanisms, i.e. inflammation, central sensitisation, vasomotor disturbances and motor disturbances. More knowledge about the underlying mechanisms of CRPS helps to specifically target important CRPS mechanisms. In the future, objective biomarkers could potentially aid in selecting appropriate mechanism-based drugs in order to increase the effectiveness of CRPS treatment. Using this approach, current and future pharmacotherapeutic options for CRPS should be studied in multicentre trials to prove their efficacy. The ultimate goal is to shift the symptom-based selection of therapy into a mechanism-based selection of therapy in CRPS.
Groin and buttocks involvement and methicillin-resistant Staphylococcus aureus nasal swab independently predict cutaneous abscess and methicillin-resistant Staphylococcus aureus infection in inpatient pediatric cellulitis: A retrospective cohort study
Authors: Sidharth Chand, Renajd Rrapi, Colleen K. Gabel, Sarah Song, Radhika Shah, Chadi El Saleeby, Daniela Kroshinsky
Journal: Journal of the American Academy of Dermatology (2022)
High Renin Concentrations in Severe COVID-19 Are Indicative for a Hypo–Renin–Angiotensin-System State
Authors: Sakir Akin, Paula Schriek, Cees van Nieuwkoop, Rugina I. Neuman, Koen Verdonk, A. H. Jan Danser
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

but neglect to contextualize this against a very sick population with comorbidities and on concomitant medications, as evidenced by adverse events in 91.4% of the placebo patients.Similarly, as the authors point out, serious adverse events were reported in 23.3% of the active treatment arm, but once again, the 25.8% incidence of serious adverse events in the placebo arm is omitted.True, there was no survival benefit over 16 weeks, with 12 deaths in the placebo arm versus 10 in the treatment arm; but notably, all of the deaths in the placebo group occurred after a clinical-worsening event, which underscores the need to persist with therapy even in the face of disease progression.This surely then answers the author's question of "to continue or not to continue.
A wireless millimetric magnetoelectric implant for the endovascular stimulation of peripheral nerves
Authors: Joshua C. Chen, Peter Kan, Zhanghao Yu, Fatima Alrashdan, Roberto Garcia, Amanda Singer, C. S. Edwin Lai, Ben Avants, Scott Crosby, Zhongxi Li, Boshuo Wang, Michelle M. Felicella, Ariadna Robledo, Angel V. Peterchev, Stefan M. Goetz, Jeffrey D. Hartgerink, Sunil A. Sheth, Kaiyuan Yang, Jacob T. Robinson
Journal: Nature Biomedical Engineering (2022)

Abstract Implantable bioelectronic devices for the simulation of peripheral nerves could be used to treat disorders that are resistant to traditional pharmacological therapies. However, for many nerve targets, this requires invasive surgeries and the implantation of bulky devices (about a few centimetres in at least one dimension). Here we report the design and in vivo proof-of-concept testing of an endovascular wireless and battery-free millimetric implant for the stimulation of specific peripheral nerves that are difficult to reach via traditional surgeries. The device can be delivered through a percutaneous catheter and leverages magnetoelectric materials to receive data and power through tissue via a digitally programmable 1 mm × 0.8 mm system-on-a-chip. Implantation of the device directly on top of the sciatic nerve in rats and near a femoral artery in pigs (with a stimulation lead introduced into a blood vessel through a catheter) allowed for wireless stimulation of the animals’ sciatic and femoral nerves. Minimally invasive magnetoelectric implants may allow for the stimulation of nerves without the need for open surgery or the implantation of battery-powered pulse generators.
MANAGEMENT OF A LARGE ASCENDING AORTIC PSEUDOANEURYSM: A RARE COMPLICATION OF THORACIC SURGERY AND TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Xinjiang Cai, Negeen Shahandeh, J. Paul Finn, Gregory A Fishbein, Reshma M. Biniwale, Abbas Ardehali, David Sayah, Eric H. Yang
Journal: Journal of the American College of Cardiology (2022)
Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension
Authors: Rowena J. Jones, Eckart M. D. D. De Bie, Emily Groves, Kasia I. Zalewska, Emilia M. Swietlik, Carmen M. Treacy, Jennifer M. Martin, Gary Polwarth, Wei Li, Jingxu Guo, Helen E. Baxendale, Stephen Coleman, Natalia Savinykh, J. Gerry Coghlan, Paul A. Corris, Luke S. Howard, Martin K. Johnson, Colin Church, David G. Kiely, Allan Lawrie, James L. Lordan, Robert V. Mackenzie Ross, Joanna Pepke Zaba, Martin R. Wilkins, S. John Wort, Edoardo Fiorillo, Valeria Orrù, Francesco Cucca, Christopher J. Rhodes, Stefan Gräf, Nicholas W. Morrell, Eoin F. McKinney, Chris Wallace, Mark Toshner, Marta Bleda, Charaka Hadinnapola, Matthias Haimel, Kate Auckland, Tobias Tilly, Jennifer M. Martin, Katherine Yates, Carmen M. Treacy, Margaret Day, Alan Greenhalgh, Debbie Shipley, Val Irvine, Fiona Kennedy, Shahin Moledina, Lynsay MacDonald, Eleni Tamvaki, Anabelle Barnes, Victoria Cookson, Latifa Chentouf, Souad Ali, Shokri Othman, Lavanya Ranganathan, J. Simon, R. Gibbs, Mahitha Gummadi, Rosa DaCosta, Joy Pinguel, Natalie Dormand, Alice Parker, Della Stokes, Dipa Ghedia, Yvonne Tan, Tanaka Ngcozana, Ivy Wanjiku, Gary Polwarth, John Cannon, Karen K. Sheares, Dolores Taboda, Rob V. Mackenzie Ross, Jay Suntharalingam, Mark Grover, Ali Kirby, Richard Trembath
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.
Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD
Authors: Simon Wabitsch, Justin D. McCallen, Olena Kamenyeva, Benjamin Ruf, John C. McVey, Juraj Kabat, Juliane S. Walz, Yaron Rotman, Kylynda C. Bauer, Amanda J. Craig, Marie Pouzolles, Ira Phadke, Vanessa Catania, Benjamin L. Green, Claude Fu, Laurence P. Diggs, Bernd Heinrich, Xin Wei Wang, Chi Ma, Tim F. Greten
Journal: Journal of Hepatology (2022)
Abstract TF2-3: Molecular heterogeneity in HER2+ breast cancer - can outcomes be predicted?
Authors: A Prat
Journal: Cancer Research (2022)

Abstract HER2+ breast cancer is clinically and biologically heterogenous. In the last 10 years, translational research in this disease has deciphered many biological features, which are associated with clinical outcomes both in early and metastatic disease. Among them, RNA-based gene expression has identified 4 main molecular subtypes (HER2-enriched, Basal-like, Luminal A and Luminal B), and HER2-enriched tumors within HER2+ breast cancer show high HER2 activation and response to anti-HER2 therapy. At the same time, ERBB2 mRNA levels by itself have also been linked to a higher response to anti-HER2 therapy, including T-DM1. Whether these 2 biological features will predict response to novel anti-HER2 therapies such as DS8201a is currently unknown. One important aspect is that levels of the target (i.e., HER2/ERBB2) and the activation of the downstream signaling pathway (i.e., HER2-enriched) are related but different at the same time. In other words, higher levels of ERBB2 mRNA are associated with a HER2-enriched phenotype; however, a substantial proportion of HER2+ tumors with low levels of ERBB2 are also HER2-enriched. Thus, they should not be considered the same, and this could have clinical implications. Similarly, hormone receptor negative HER2+ breast cancer has higher levels of ERBB2 and higher proportion of HER2-enriched disease than hormone receptor-positive. The high sensitivity of hormone receptor-negative and HER2-enriched disease to anti-HER2 therapy has been demonstrated in the neoadjuvant setting as well as studies looking at on-treatment biology after short-course of anti-HER2 treatment. Indeed, in advanced HER2+ breast cancer, the major gains in overall survival with new anti-HER2-based therapies are seen in hormone receptor-negative disease. Finally, tumor microenvironment plays a critical role. Indeed, tumor-infiltrating lymphocytes and immune gene expression signatures are associated with treatment response and better survival outcome. Whether this immune-related variables predict response to antiPD1/PDL1 is currently unknown, although translational studies do suggest that there might be a link. To conclude, the biological heterogeneity that exists within HER2+ disease is now well-known, and these variables, together with clinical-pathological features, should allow the design of new biomarkers to help answer critical clinical questions. Citation Format: A Prat. Molecular heterogeneity in HER2+ breast cancer - can outcomes be predicted? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr TF2-3.
Exercise and Resistant Hypertension—Is Exercise Enough?—Reply
Authors: Fernando Ribeiro, Linda S. Pescatello, Alberto J. Alves
Journal: JAMA Cardiology (2022)

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 Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Cardiology journal
Comparison of 3 Randomized Clinical Trials of Frontline Therapies for Malignant Pleural Mesothelioma
Authors: Tomer Meirson, Francesca Pentimalli, Francesco Cerza, Giovanni Baglio, Steven G. Gray, Pierpaolo Correale, Marija Krstic-Demonacos, Gal Markel, Antonio Giordano, David Bomze, Luciano Mutti
Journal: JAMA Network Open (2022)

Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments.To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003.This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021.Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT.A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048).This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.
HSR22-160: An Assessment of the Association Between Patient Race and Prior Authorization Program Determinations in the Context of Radiation Therapy for Breast Cancer
Authors: Adam C. Powell, Christopher T Lugo, Jeremy T Pickerell, James W Long, Amin J Mirhadi, Bryan A Loy
Journal: Journal of the National Comprehensive Cancer Network (2022)

"HSR22-160: An Assessment of the Association Between Patient Race and Prior Authorization Program Determinations in the Context of Radiation Therapy for Breast Cancer" published on 31 Mar 2022 by National Comprehensive Cancer Network.
Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort
Authors: Rachel C. Newsome, Raad Z. Gharaibeh, Christine M. Pierce, Wildson Vieira da Silva, Shirlene Paul, Stephanie R. Hogue, Qin Yu, Scott Antonia, Jose R. Conejo-Garcia, Lary A. Robinson, Christian Jobin
Journal: Genome Medicine (2022)

Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored.
DESMOPLAKIN RELATED ARRHYTHMOGENIC CARDIOMYOPATHY PRESENTING AS ACUTE LYMPHOCYTIC MYOCARDITIS
Authors: Nakeya Dewaswala, Huzefa Bhopalwala, Kirtan Patolia, Ahmed Noor, Steve Leung, Andrew Kolodziej, Gaurang N. Vaidya
Journal: Journal of the American College of Cardiology (2022)
LEFT ATRIAL DIAMETER IS ASSOCIATED WITH THE PRESENCE OF NEW ONSET ATRIAL FIBRILLATION AT 30-DAY FOLLOW-UP IN TRANSCATHETER AORTIC VALVE REPLACEMENT PATIENTS
Authors: Shwetha Kochi, Mark Brahier, Julia Huang, Athanasios Thomaides, Ron Waksman, Lowell F. Satler, Peter J. Bergquist, Monvadi B. Srichai, Jose D. Vargas
Journal: Journal of the American College of Cardiology (2022)
DOES ANXIETY IMPACT ABLATION-OUTCOME AND QUALITY OF LIFE IN ATRIAL FIBRILLATION PATIENTS UNDERGOING CATHETER ABLATION?
Authors: Sanghamitra Mohanty, Prasant Mohanty, Carola Gianni, Domenico Giovanni Della Rocca, SaiShishir Shetty, John Burkhardt, Rodney P. Horton, Gerald J. Gallinghouse, Luigi Di Biase, Andrea Natale
Journal: Journal of the American College of Cardiology (2022)
ASSOCIATION BETWEEN SYMPTOM DURATION AND CLINICAL OUTCOMES IN PATIENTS WITH NON-ST ELEVATION MYOCARDIAL INFARCTION
Authors: Jung-Joon Cha, SungA Bae, Hyung Joon Joo, Jae Hyoung Park, Seong-Mi Park, Soon Jun Hong, Cheol Woong Yu, Do-Sun Lim, Tae Hoon Ahn
Journal: Journal of the American College of Cardiology (2022)
RACIAL AND SEX DIFFERENCES IN OUTCOMES AFTER OUT-OF-HOSPITAL CARDIAC ARREST: A GLIMPSE OF THE LARGEST MUNICIPAL HEALTHCARE SYSTEM IN THE UNITED STATES
Authors: Sanjana Nagraj, Hiba Narvel, Sheetal V. Mathai, Amrin Kharawala, Dimitrios Varrias, Rosy Thachil
Journal: Journal of the American College of Cardiology (2022)
ADMISSION TO A CARDIOLOGY SERVICE IS ASSOCIATED WITH DECREASED LENGTH OF STAY WITHOUT CHANGES IN OUTCOMES IN PATIENTS WITH HEART FAILURE: A SINGLE-CENTER EXPERIENCE
Authors: Jose S. Aguilar-Gallardo, Javier A. Arreaza, Ga Hee Kim, Andrew Kim, Jeewendra Dulal, Alaa Omar, Johanna Paola Contreras
Journal: Journal of the American College of Cardiology (2022)
BPI22-014: Independent Validation of the PREDICT Prognostication Tool in U.S. Breast Cancer Patients Using the National Cancer Database (NCDB)
Authors: Lifen Cao, Nickolas Stabellini, Christopher W Towe, Megan E Miller, Robert Shenk, Amanda L Amin, Alberto J Montero
Journal: Journal of the National Comprehensive Cancer Network (2022)

"BPI22-014: Independent Validation of the PREDICT Prognostication Tool in U.S. Breast Cancer Patients Using the National Cancer Database (NCDB)" published on 31 Mar 2022 by National Comprehensive Cancer Network.
Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation
Authors: Kristofor E. Glinton, Wanshu Ma, Connor Lantz, Lubov S. Grigoryeva, Matthew DeBerge, Xiaolei Liu, Maria Febbraio, Mark Kahn, Guillermo Oliver, Edward B. Thorp
Journal: Journal of Clinical Investigation (2022)

Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.
Transcriptional kinetics and molecular functions of long noncoding RNAs
Authors: Per Johnsson, Christoph Ziegenhain, Leonard Hartmanis, Gert-Jan Hendriks, Michael Hagemann-Jensen, Björn Reinius, Rickard Sandberg
Journal: Nature Genetics (2022)

An increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene's transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.
Sustained delivery of rhMG53 promotes diabetic wound healing and hair follicle development
Authors: Hong Niu, Haichang Li, Ya Guan, Xin Zhou, Zhongguang Li, Serana Li Zhao, Peng Chen, Tao Tan, Hua Zhu, Valerie Bergdall, Xuehong Xu, Jianjie Ma, Jianjun Guan
Journal: Bioactive Materials (2022)
Elections loom large in France’s pandemic policies
Authors: Barbara Casassus
Journal: BMJ (2022)

the government has managed covid-19, writes Barbara Casassus Barbara Casassus freelance journalist Doctors in France have mixed views about the government's handling of the covid-19 pandemic, but they agree that the presidential and parliamentary elections-to be held in April and June-are key factors in setting pandemic policy.President Emmanuel Macron said in his new year wishes that the pandemic could end in 2022.Public health took precedence at the beginning of the crisis, but since the second wave of covid-19 in August 2020, the economy and social pressures have become the focus.