tbuckley/cabot-search huggingface dataset:
Transcatheter Repair versus Mitral-Valve Surgery for Secondary Mitral Regurgitation
Authors: Stephan Baldus, Torsten Doenst, Roman Pfister, Jan Gummert, Mirjam Kessler, Peter Boekstegers, Edith Lubos, Jörg Schröder, Holger Thiele, Thomas Walther, Malte Kelm, Jörg Hausleiter, Ingo Eitel, Ulrich Fischer-Rasokat, Alexander Bufe, Alexander Schmeisser, Hüseyin Ince, Philipp Lurz, Ralph Stephan von Bardeleben, Christian Hagl, Thilo Noack, Sebastian Reith, Harald Beucher, Hermann Reichenspurner, Wolfgang Rottbauer, P. Christian Schulze, Wiebke Müller, Julia Frank, Martin Hellmich, Thorsten Wahlers, Volker Rudolph
Journal: New England Journal of Medicine (2024)

BackgroundCurrent treatment recommendations for patients with heart failure and secondary mitral regurgitation include transcatheter edge-to-edge repair and mitral-valve surgery. Data from randomized trials comparing these therapies are lacking in this patient population.MethodsIn this noninferiority trial conducted in Germany, patients with heart failure and secondary mitral regurgitation who continued to have symptoms despite guideline-directed medical therapy were randomly assigned, in a 1:1 ratio, to undergo either transcatheter edge-to-edge repair (intervention group) or surgical mitral-valve repair or replacement (surgery group). The primary efficacy end point was a composite of death, hospitalization for heart failure, mitral-valve reintervention, implantation of an assist device, or stroke within 1 year after the procedure. The primary safety end point was a composite of major adverse events within 30 days after the procedure.ResultsA total of 210 patients underwent randomization. The mean (±SD) age of the patients was 70.5±7.9 years, 39.9% were women, and the mean left ventricular ejection fraction was 43.0±11.7%. Within 1 year, at least one of the components of the primary efficacy end point occurred in 16 of the 96 patients with available data (16.7%) in the intervention group and in 20 of the 89 with available data (22.5%) in the surgery group (estimated mean difference, −6 percentage points; 95% confidence interval [CI], −17 to 6; P<0.001 for noninferiority). A primary safety end-point event occurred in 15 of the 101 patients with available data (14.9%) in the intervention group and in 51 of the 93 patients with available data (54.8%) in the surgery group (estimated mean difference, −40 percentage points; 95% CI, −51 to −27; P<0.001).ConclusionsAmong patients with heart failure and secondary mitral regurgitation, transcatheter edge-to-edge repair was noninferior to mitral-valve surgery with respect to a composite of death, rehospitalization for heart failure, stroke, reintervention, or implantation of an assist device in the left ventricle at 1 year. (Funded by Abbott Vascular; MATTERHORN ClinicalTrials.gov number, NCT02371512.)
Beta‐blocker use and outcomes in patients with heart failure and mildly reduced and preserved ejection fraction
Authors: Shingo Matsumoto, Alasdair D. Henderson, Li Shen, Toru Kondo, Mingming Yang, Ross T. Campbell, Inder S. Anand, Rudolf A. de Boer, Akshay S. Desai, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe A. Martinez, Milton Packer, Margaret M. Redfield, Jean L. Rouleau, Dirk J. Van Veldhuisen, Muthiah Vaduganathan, Faiez Zannad, Michael R. Zile, Pardeep S. Jhund, Scott D. Solomon, John J.V. McMurray
Journal: European Journal of Heart Failure (2024)
Hospitalization of Symptomatic Patients With Heart Failure and Moderate to Severe Functional Mitral Regurgitation Treated With MitraClip
Authors: Piotr Ponikowski, Tim Friede, Ralph Stephan von Bardeleben, Javed Butler, Muhammad Shahzeb Khan, Monika Diek, Jutta Heinrich, Martin Geyer, Marius Placzek, Roberto Ferrari, William T Abraham, Ottavio Alfieri, Angelo Auricchio, Antoni Bayes-Genis, John G F Cleland, Gerasimos Filippatos, Finn Gustafsson, Wilhelm Haverkamp, Malte Kelm, Karl-Heinz Kuck, Ulf Landmesser, Aldo P Maggioni, Marco Metra, Vlasis Ninios, Mark C Petrie, Tienush Rassaf, Frank Ruschitzka, Ulrich Schäfer, P Christian Schulze, Konstantinos Spargias, Alec Vahanian, Jose Luis Zamorano, Andreas Zeiher, Mahir Karakas, Friedrich Koehler, Mitja Lainscak, Alper Öner, Nikolaos Mezilis, Efstratios K Theofilogiannakos, Ilias Ninios, Michael Chrissoheris, Panagiota Kourkoveli, Konstantinos Papadopoulos, Grzegorz Smolka, Wojciech Wojakowski, Krzysztof Reczuch, Fausto J Pinto, Łukasz Wiewiórka, Witold Streb, Marianna Adamo, Evelyn Santiago-Vacas, Tobias Friedrich Ruf, Michael Gross, Joern Tongers, Gerd Hasenfuß, Wolfgang Schillinger, Stefan D Anker
Journal: Journal of the American College of Cardiology (2024)

For patients with functional mitral regurgitation (FMR) and symptomatic heart failure (HF), randomized trials of mitral transcatheter edge-to-edge repair (M-TEER) have produced conflicting results.
Low-Dose Triple-Pill vs Standard-Care Protocols for Hypertension Treatment in Nigeria
Authors: Dike B. Ojji, Abdul Salam, Mahmoud U. Sani, Okechukwu S. Ogah, Aletta E. Schutte, Mark D. Huffman, Rashmi Pant, Arpita Ghosh, Rupasvi Dhurjati, Josyula K. Lakshmi, Nanna. R. Ripiye, Ikechukwu A. Orji, Shehu A. Kana, Tijjani Abdussalam, Abdulgafar L. Olawumi, Isiaka M. Alfa, Olanike Allison Orimolade, Moses O. Ajayi, Anthony Rodgers
Journal: JAMA (2024)

Importance With the high burden of hypertension in sub-Saharan Africa, there is a need for effective, safe and scalable treatment strategies. Objective To compare, among Black African adults, the effectiveness and safety of a novel low-dose triple-pill protocol compared with a standard-care protocol for blood pressure lowering. Design and Setting Randomized, parallel-group, open-label, multicenter trial conducted in p ublic hospital–based family medicine clinics in Nigeria. Participants Black African adults with uncontrolled hypertension (≥140/90 mm Hg) who were untreated or receiving a single blood pressure–lowering drug. Interventions Participants were randomly allocated to low-dose triple-pill or standard-care protocols. The triple-pill protocol involved a novel combination of telmisartan, amlodipine, and indapamide in triple one-quarter, one-half, and standard doses (ie, 10/1.25/0.625 mg, 20/2.5/1.25 mg, and 40/5/2.5 mg), with accelerated up-titration. The standard-care protocol was the Nigeria hypertension treatment protocol starting with amlodipine (5 mg). Main Outcomes and Measures The primary effectiveness outcome was the reduction in home mean systolic blood pressure, and the primary safety outcome was discontinuation of trial treatment due to adverse events, both from randomization to month 6. Results The first participant was randomized on July 19, 2022, and the last follow-up visit was on July 18, 2024. Among 300 randomized participants (54% female; mean age, 52 years; baseline mean home blood pressure, 151/97 mm Hg; and clinic blood pressure, 156/97 mm Hg), 273 (91%) completed the trial. At month 6, mean home systolic blood pressure was on average 31 mm Hg (95% CI, 28 to 33 mm Hg) lower in the triple-pill protocol group and 26 mm Hg (95% CI, 22 to 28 mm Hg) lower in the standard-care protocol group (adjusted difference, −5.8 mm Hg [95% CI, −8.0 to −3.6]; P &amp;amp;lt; .001]). At month 6, clinic blood pressure control (&amp;amp;lt;140/90 mm Hg) was 82% vs 72% (risk difference, 10% [95% CI, −2% to 20%]) and home blood pressure control (&amp;amp;lt;130/80 mm Hg) was 62% vs 28% (risk difference, 33% [95% CI, 22% to 44%]) in the triple-pill compared with the standard-care protocol group; these were 2 of 21 prespecified secondary effectiveness end points. No participants discontinued trial treatment due to adverse events. Conclusions and Relevance Among Black African adults with uncontrolled hypertension, a low-dose triple-pill protocol achieved better blood pressure lowering and control with good tolerability compared with the standard-care protocol. Trial Registration Pan African Clinical Trials Registry Identifier: PACTR202107579572114
Is a Low-Dose Triple-Drug Combination Pill Protocol the Answer for Hypertension Control in Sub-Saharan Africa?
Authors: George A. Mensah
Journal: JAMA (2024)

Dike B. Ojji, PhD; Abdul Salam, PhD; Mahmoud U. Sani, PhD; Okechukwu S. Ogah, PhD; Aletta E. Schutte, PhD; Mark D. Huffman, MD; Rashmi Pant, PhD; Arpita Ghosh, PhD; Rupasvi Dhurjati, PharmD; Josyula K. Lakshmi, PhD; Nanna. R. Ripiye, MBBS; Ikechukwu A. Orji, PhD; Shehu A. Kana, MSCI; Tijjani Abdussalam, MBBS; Abdulgafar L. Olawumi, MPH; Isiaka M. Alfa, MBBS; Olanike Allison Orimolade, MBBS; Moses O. Ajayi, BPHARM; Anthony Rodgers, PhD
Higher survival following transplantation with a mismatched unrelated donor with posttransplant cyclophosphamide‐based graft‐versus‐host disease prophylaxis than with double unit umbilical cord blood in patients with acute myeloid leukemia in first complete remission: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Frédéric Baron, Myriam Labopin, Jurjen Versluis, Jan Vydra, Peter A. von dem Borne, Emma Nicholson, Didier Blaise, Rachel Protheroe, Alexander Kulagin, Claude Eric Bulabois, Montserrat Rovira, Patrice Chevallier, Edouard Forcade, Jenny Byrne, Jaime Sanz, Annalisa Ruggeri, Mohamad Mohty, Fabio Ciceri
Journal: American Journal of Hematology (2024)

Abstract The best donor option for acute myeloid leukemia (AML) patients lacking an HLA‐matched donor has remained intensively debated. We herein report the results of a large retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between double‐unit umbilical cord blood transplantation (dCBT, n = 209) versus 9/10 HLA‐matched unrelated donor (UD) with posttransplant cyclophosphamide (PTCy)‐based graft‐versus‐host disease (GVHD) prophylaxis (UD 9/10, n = 270) in patients with AML in first complete remission (CR1). Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT without PTCy, transplantation between 2013 and 2021, and no in vivo T‐cell depletion. The 180‐day cumulative incidence of grade II‐IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients ( p = .001). After adjustment for covariates, dCBT recipients had a higher non‐relapse mortality (HR = 2.35, 95% CI: 1.23–4.48; p = .01), comparable relapse incidence (HR = 1.12, 95% CI: 0.67–1.86; p = .66), lower leukemia‐free survival (HR = 1.5, 95% CI: 1.01–2.23; p = .047), and lower overall survival (HR = 1.66, 95% CI: 1.08–2.55; p = .02) compared with patients receiving UD 9/10 HCT. In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy‐based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy‐based GVHD prophylaxis over dCBT in AML patients lacking an HLA‐matched donor.
Digital consults in heart failure care: a randomized controlled trial
Authors: Jelle P. Man, Maarten A. C. Koole, Paola G. Meregalli, M. Louis Handoko, Susan Stienen, Frederik J. de Lange, Michiel M. Winter, Marlies P. Schijven, Wouter E. M. Kok, Dorianne I. Kuipers, Pim van der Harst, Folkert W. Asselbergs, Aeilko H. Zwinderman, Marcel G. W. Dijkgraaf, Steven A. J. Chamuleau, Mark J. Schuuring
Journal: Nature Medicine (2024)

Abstract Guideline-directed medical therapy (GDMT) has clear benefits on morbidity and mortality in patients with heart failure; however, GDMT use remains low. In the multicenter, open-label, investigator-initiated ADMINISTER trial, patients ( n = 150) diagnosed with heart failure and reduced ejection fraction (HFrEF) were randomized (1:1) to receive usual care or a strategy using digital consults (DCs). DCs contained (1) digital data sharing from patient to clinician (pharmacotherapy use, home-measured vital signs and Kansas City Cardiomyopathy Questionnaires); (2) patient education via a text-based e-learning; and (3) guideline recommendations to all treating clinicians. All remotely gathered information was processed into a digital summary that was available to clinicians in the electronic health record before every consult. All patient interactions were standardly conducted remotely. The primary endpoint was change in GDMT score over 12 weeks (ΔGDMT); this GDMT score directly incorporated all non-conditional class 1 indications for HFrEF therapy with equal weights. The ADMINISTER trial met its primary outcome of achieving a higher GDMT in the DC group after a follow-up of 12 weeks (ΔGDMT score in the DC group: median 1.19, interquartile range (0.25, 2.3) arbitrary units versus 0.08 (0.00, 1.00) in usual care; P &lt; 0.001). To our knowledge, this is the first multicenter randomized controlled trial that proves a DC strategy is effective to achieve GDMT optimization. ClinicalTrials.gov registration: NCT05413447 .
Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women
Authors: Paul M Ridker, M Vinayaga Moorthy, Nancy R Cook, Nader Rifai, I-Min Lee, Julie E Buring
Journal: New England Journal of Medicine (2024)

BackgroundHigh-sensitivity C-reactive protein (CRP), low-density lipoprotein (LDL) cholesterol, and lipoprotein(a) levels contribute to 5-year and 10-year predictions of cardiovascular risk and represent distinct pathways for pharmacologic intervention. More information about the usefulness of these biomarkers for predicting cardiovascular risk over longer periods of time in women is needed because early-life intervention represents an important risk-reduction method.MethodsWe measured high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels at baseline in 27,939 initially healthy U.S. women who were subsequently followed for 30 years. The primary end point was a first major adverse cardiovascular event, which was a composite of myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. We calculated the adjusted hazard ratios and 95% confidence intervals across quintiles of each biomarker, along with 30-year cumulative incidence curves adjusted for age and competing risks.ResultsThe mean age of the participants at baseline was 54.7 years. During the 30-year follow-up, 3662 first major cardiovascular events occurred. Quintiles of increasing baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) all predicted 30-year risks. Covariable-adjusted hazard ratios for the primary end point in a comparison of the top with the bottom quintile were 1.70 (95% confidence interval [CI], 1.52 to 1.90) for high-sensitivity CRP, 1.36 (95% CI, 1.23 to 1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21 to 1.47) for lipoprotein(a). Findings for coronary heart disease and stroke appeared to be consistent with those for the primary end point. Each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers.ConclusionsA single combined measure of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels among initially healthy U.S. women was predictive of incident cardiovascular events during a 30-year period. These data support efforts to extend strategies for the primary prevention of atherosclerotic events beyond traditional 10-year estimates of risk. (Funded by the National Institutes of Health; Women's Health Study ClinicalTrials.gov number, NCT00000479.)
Patient satisfaction with teledermatology: a systematic review and meta-analysis
Authors: Michael J Diaz, Jasmine T Tran, Isabella M Mark, Dang Nguyen, Mahtab Forouzandeh, Shari R Lipner, Jane M Grant-Kels, Abel Torres, Kiran Motaparthi, Marjorie E Montanez-Wiscovich, Benjamin H Kaffenberger
Journal: Journal of the American Academy of Dermatology (2024)
Targeted gene therapy for rare genetic kidney diseases
Authors: Veenita Khare, Stephanie Cherqui
Journal: Kidney International (2024)

:Chronic kidney disease (CKD) is one of the leading causes of mortality worldwide because of kidney failure and the associated challenges of its treatment including dialysis and kidney transplantation. About one-third of CKD cases are linked to inherited monogenic factors, making them suitable for potential gene therapy interventions. However, the intricate anatomical structure of the kidney poses a challenge, limiting the effectiveness of targeted gene delivery to the renal system. In this review, we explore the progress made in the field of targeted gene therapy approaches and their implications for rare genetic kidney disorders, examining preclinical studies and prospects for clinical application. In vivo gene therapy is most commonly used for kidney-targeted gene delivery and involves administering viral and non-viral vectors through various routes such as systemic, renal vein and renal arterial injections. Small nucleic acids have also been used in preclinical and clinical studies for treating certain kidney disorders. Unexpectedly, hematopoietic stem and progenitor cells have been used as an ex vivo gene therapy vehicle for kidney gene delivery, highlighting their ability to differentiate into macrophages within the kidney, forming tunneling nanotubes that can deliver genetic material and organelles to adjacent kidney cells, even across the basement membrane to target the proximal tubular cells. As gene therapy technologies continue to advance and our understanding of kidney biology deepens, there is hope for patients with genetic kidney disorders to eventually avoid kidney transplantation.
Identification and functional validation of miR-190b-5p and miR-296-3p as novel therapeutic attenuators of liver fibrosis
Authors: Jovana Markovic, Ruomeng Li, Rajendra Khanal, Qi Peng, Selina Möbus, Qinggong Yuan, Bastian Engel, Richard Taubert, Florian W.R. Vondran, Heike Bantel, Manvendra K. Singh, Tobias Cantz, Hildegard Büning, Heiner Wedemeyer, Michael Ott, Asha Balakrishnan, Amar Deep Sharma
Journal: Journal of Hepatology (2024)
Potential and limitations of the human mast cell activation test in amoxicillin hypersensitivity
Authors: Didier G. Ebo, Rajia Bahri, Chiara Tontini, Michel Van Houdt, Michiel Beyens, Alessandro Toscano, Margo M. Hagendorens, Athina L. Van Gasse, Christel Mertens, Jessy Elst, Vito Sabato
Journal: Allergy (2024)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Bidirectional association between inflammatory bowel disease and type 1 diabetes: a nationwide matched cohort and case-control study
Authors: Jiangwei Sun, Jialu Yao, Ola Olén, Jonas Halfvarsson, David Bergman, Fahim Ebrahimi, Sofia Carlsson, Johnny Ludvigsson, Jonas F. Ludvigsson
Journal: The Lancet Regional Health - Europe (2024)
Joint single-cell genetic and transcriptomic analysis reveal pre-malignant SCP-like subclones in human neuroblastoma
Authors: Thale K. Olsen, Jörg Otte, Shenglin Mei, Bethel Tesfai Embaie, Polina Kameneva, Huaitao Cheng, Teng Gao, Vasilios Zachariadis, Ioanna Tsea, Åsa Björklund, Emil Kryukov, Ziyi Hou, Anna Johansson, Erik Sundström, Tommy Martinsson, Susanne Fransson, Jakob Stenman, Shahrzad Shirazi Fard, John Inge Johnsen, Per Kogner, Igor Adameyko, Martin Enge, Peter V. Kharchenko, Ninib Baryawno
Journal: Molecular Cancer (2024)

Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element.
Statins, but not proprotein convertase subtilisin‐kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low‐density lipoprotein receptor upregulation
Authors: Lunbo Tan, Na Wang, Annet M. H. Galema‐Boers, Leonie van Vark‐van der Zee, Jeanine Roeters van Lennep, Monique T. Mulder, Xifeng Lu, A. H. Jan Danser, Koen Verdonk
Journal: MedComm (2024)

Abstract Hypercholesterolemia is characterized by elevated low‐density lipoprotein (LDL)‐cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol‐lowering with statins or proprotein convertase subtilisin‐kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL‐cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high‐density lipoprotein (HDL)‐cholesterol. Yet, only statins additionally reduced chemerin and high‐sensitivity C‐reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL 2 /HDL 3 fractions, while &gt;75% was free. Statins lowered both HDL‐bound and free chemerin. Pull‐down assays revealed that chemerin binds to the HDL‐component Apolipoprotein A‐I (ApoA‐I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL‐mediated cholesterol efflux via its chemerin chemokine‐like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA‐I and inhibits HDL‐mediated cholesterol efflux. Statins prevent this by lowering HDL‐bound chemerin. Combined with their anti‐inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.
Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way Comparison of RADICALS-HD (NCT00541047)
Authors: Chris C. Parker, Noel W. Clarke, Adrian D. Cook, Peter M. Petersen, Charles N. Catton, William R. Cross, Howard Kynaston, Raj A. Persad, Fred Saad, John Logue, Heather Payne, Claire Amos, Lorna Bower, Rakesh Raman, Ian Sayers, Jane Worlding, Wendy R. Parulekar, Mahesh K.B. Parmar, Matthew R. Sydes
Journal: European Urology (2024)

The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term.