tbuckley/cabot-search huggingface dataset:
Differentiation of Active Corneal Infections from Healed Scars Using Deep Learning
Authors: Mo Tiwari, Chris Piech, Medina Baitemirova, Namperumalsamy V. Prajna, Muthiah Srinivasan, Prajna Lalitha, Natacha Villegas, Niranjan Balachandar, Janice T. Chua, Travis Redd, Thomas M. Lietman, Sebastian Thrun, Charles C. Lin
Journal: Ophthalmology (2021)
Abstract 9663: Sirt7 Contributes to Proper Wound Healing After Murine Model of Myocardial Infarction by Modulating the Fibroblast Differentiation
Authors: Satoshi Araki, Yasuhiro Izumiya, Takafumi Senokuchi, Taku Rokutanda, Shinsuke Hanatani, Eva Bober, Thomas Braun, Kazuya Yamagata, Hisao Ogawa
Journal: Circulation (2011)

Introduction: Sirt7 is the only mammalian sirtuin which is localized predominantly in the nucleoli. To date, little is known about the role of Sirt7 in wound healing in the setting of acute cardiac insult. Hypothesis: Sirt7 contributes to proper wound healing processes after myocardial infarction (MI) by modulating cardiac fibroblast function. Methods: MI was created in 10-week-old male homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery. Cardiac function and structure were assessed by micromanometer catheter, echocardiography, histology and gene expression analyses. Sirt7 knockdown experiments were performed with rat neonatal cardiac fibroblast and human skin fibroblast. Results: Sirt7 transcript expression was increased by 2.5-fold in the border zone (BZ) of myocardial tissues at 3 days after MI in WT mice. Body weight, heart rate, systolic blood pressure, echocardiographic and hemodynamic parameters did not differ between Sirt7-/- and WT mice at 3 days after MI. However, the number of mice that died of cardiac rupture within 1 weeks after MI was significantly higher in Sirt7-/- mice (63%, 12 of 19 mice) than in WT mice (21%, 5 of 24 mice) (P&lt;0.01). Histological analysis revealed that interstitial fibrosis and α-SMA positive fibroblast in the BZ of myocardium was significantly decreased in Sirt7-/- mice, despite the same infarct size between both groups. These changes were accompanied by the reduction in collagen I and α-SMA gene expression. In vitro, Sirt7 transcripts expression was readily detectable in total RNA isolated from rat neonatal cardiac fibroblast and human skin fibroblast. Knockdown of endogenous Sirt7 expression by small interfering RNA attenuated TGF-β1-induced PAI-1 and α-SMA expression. Conversely, adenovirus-mediated overexpression of Sirt7 augmented TGF-β1-induced α-SMA gene expression. TGF-β1-induced ERK phosphorylation was blocked by Sirt7 knockdown. However, phosphorylation and translocation of smad2 was not changed by Sirt7 knockdown. Conclusions: Sirt7 modulates cardiac fibroblast differentiation which is dependent on ERK signaling. Sirt7 contributes to proper wound healing process after experimental myocardial infarction.
Metabolism
Authors: L. Lind, H. Bricchi, M. Gemma, C. Ariano, F. Fiacchino, M. M. Berger, C. Cavadini, S. Guinchard, S. Krupp, H. Dirren, A. Dive, M. Maulart, Ph. Jonart, J. Jamart, P. Mahieu, T. Müller, A. Müller, H. Lange, Jiménez J. Jiménez, Leyba C. Ortiz, Peres M. Barros, Montero J. Garnacho, Lopez P. Porras, Menendez K. Gonzales, F. Staïkowsky, B. Guidet, T. Vassal, G. Offenstadt, P. Amstutz, A. N. Roos, R. G. J. Westendorp, M. Frölich, A. E. Meinders, P. Guglia, H. Steltzer, W. Petricek, A. Balassa, P. Germann, A. F. Hammerle, S. Celaya, P. Luque, C. Homs, J. Lopez, A. Guallart, F. Pardo, M. Navarro, X. Sarriento, M. Soler, J. J. Guardiola, R. Tomas, P. Velasco, K. Esquirol, A. Tonasia, G. Marecaux, M. R. Pinsky, E. Dupont, J. L. Vincent, P. Botsis, M. Eforakopoulou, G. Stamatiou, H. Ioannidou, S. Tragaras, Ch. Madianou, D. Radrizzani, M. Savioli, D. Codazzi, G. Ronzoni, G. Iapichino, F. Brivet, M. Bernardin, P. Chérin, J. Chalas, P. Galanaud, J. Dormont, L. S. Brandi, D. Santoro, F. Altomonte, A. Natali, G. Buzzigoli, E. Ferrannini, A. C. Timmins, A. M. Cotterill, J. M. P. Holly, C. J. Hinds, G. Vignali, A. Guadagriucci, A. Baratta, G. Rogato, G. Tulli, F. Leonardi, A. R. Moral, A. Turhan, B. Ersöz, F. Girgin, M. Tryba, K. Kurz-Müller, H. Thole, M. Wilhelm, F. Bobbio Pallavicini, G. Verde, M. Bonizzoni, G. Bichisao, F. Cassini
Journal: Intensive Care Medicine (1992)
Polygenic Risk Scores for Breast Cancer—Can They Deliver on the Promise of Precision Medicine?
Authors: Payal D. Shah
Journal: JAMA Network Open (2021)

Cong Liu, PhD; Nur Zeinomar, PhD; Wendy K. Chung, MD, PhD; Krzysztof Kiryluk, MD; Ali G. Gharavi, MD; George Hripcsak, MD; Katherine D. Crew, MD; Ning Shang, PhD; Atlas Khan, PhD; David Fasel, BS; Teri A. Manolio, MD, PhD; Gail P. Jarvik, MD, PhD; Robb Rowley, MD; Ann E. Justice, PhD; Alanna K. Rahm, PhD; Stephanie M. Fullerton, DPhil; Jordan W. Smoller, MD, ScD; Eric B. Larson, MD; Paul K. Crane, MD; Ozan Dikilitas, MD; Georgia L. Wiesner, MD; Alexander G. Bick, MD, PhD; Mary Beth Terry, PhD; Chunhua Weng, PhD
<i>The Doctors Blackwell</i>—Biography of Pioneering Women in Medicine
Authors: N. Lynn Eckhert
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
Changes in food purchases after the Chilean policies on food labelling, marketing, and sales in schools: a before and after study
Authors: Lindsey Smith Taillie, Maxime Bercholz, Barry Popkin, Marcela Reyes, M Arantxa Colchero, Camila Corvalán
Journal: The Lancet Planetary Health (2021)

BackgroundIn 2016, Chile implemented a unique law mandating front-of-package warning labels, restricting marketing, and banning school sales for products high in calories, sodium, sugar, or saturated fat. We aimed to examine changes in the calorie, sugar, sodium, and saturated fat content of food and beverage purchases after the first phase of implementation of this law.MethodsThis before and after study used longitudinal data on food and beverage purchases from 2381 Chilean households from Jan 1, 2015, to Dec 31, 2017. Nutrition facts panel data from food and beverage packages were linked to household purchases at the product level using barcode, brand name, and product description. Nutritionists reviewed each product for nutritional accuracy and categorised it as high-in if it contained added sugar, sodium, or saturated fat and exceeded phase 1 nutrient or calorie thresholds, and thus was subject to the labelling, marketing, and school regulations. Using fixed-effects models, we examined the mean nutrient content (overall calories, sugar, saturated fat, and sodium) of purchases in the post-policy period compared to a counterfactual scenario based on pre-policy trends.FindingsCompared with the counterfactual scenario, overall calories purchased declined by 16·4 kcal/capita/day (95% CI –27·3 to –5·6; p=0·0031) or 3·5%. Overall sugar declined by 11·5 kcal/capita/day (–14·6 to –8·4; p<0·0001) or 10·2%, and saturated fat declined by 2·2 kcal/capita/day (–3·8 to –0·5; p=0·0097) or 3·9%. The sodium content of overall purchases declined by 27·7 mg/capita/day (–46·3 to –9·1; p=0·0035) or 4·7%. Declines from high-in purchases drove these results with some offset by increases in not-high-in purchases. Among high-in purchases, relative to the counterfactual scenario, there were notable declines of 23·8% in calories purchased (–49·4 kcal/capita/day, 95% CI –55·1 to –43·7; p<0·0001), 36·7% in sodium purchased (–96·6 mg/capita/day,–105·3 to –87·8; p<0·0001), and 26·7% in sugar purchased (–20·7 kcal/capita/day, –23·4 to –18·1; p<0·0001).InterpretationThe Chilean phase 1 law of food labelling and advertising policies were associated with reduced high-in purchases, leading to declines in purchased nutrients of concern. Greater changes might reasonably be anticipated after the implementation of phases 2 and 3.FundingBloomberg Philanthropies, International Development Research Center, and Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.
Endoscopic ultrasound-guided fine-needle biopsy: size really does matter!
Authors: Bradley D. Confer
Journal: Endoscopy (2021)

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become the gold standard for the diagnosis of pancreatic and peripancreatic masses, often achieving a sensitivity of 90 %, with a specificity of 100 % [1]. It is not clear whether the size of needle used matters, with a recent meta-analysis demonstrating similar sensitivity, specificity, and safety profiles for 22 G and 25 G FNA needles [2]. However, FNA needles are limited by: a high reliance on rapid on-site evaluation (ROSE); their lower yield in a highly desmoplastic stroma, often seen in pancreatic cancers; their inability to achieve histologic architecture; and often the obtaining of an insufficient quantity of tissue to allow genome profile analysis for targeted therapies to be performed [3]. Many of these limitations have been overcome with the development of newer “core needles” that obtain histologic and not just cytologic samples [4].
Percutaneous Coronary Intervention(PCI)中にSirolimus Eluting Stent(SES)が脱落した1例
Authors: 古川卓, 成瀬代士久, 若林康, 長坂士朗, 竹内泰代, 佐野誠, 笠原和之, 牧野紀和
Journal: Circulation (2008)
TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis
Authors: Tianhe Sun, Zhiyu Huang, Wei-Ching Liang, Jianping Yin, Wei Yu Lin, Jia Wu, Jean-Michel Vernes, Jeff Lutman, Patrick Caplazi, Surinder Jeet, Tiffany Wong, Manda Wong, Daryle J. DePianto, Katrina B. Morshead, Kai-Hui Sun, Zora Modrusan, Jason A. Vander Heiden, Alexander R. Abbas, Hua Zhang, Min Xu, Elsa-Noah N’Diaye, Meron Roose-Girma, Paul J. Wolters, Rajbharan Yadav, Siddharth Sukumaran, Nico Ghilardi, Racquel Corpuz, Claire Emson, Y. Gloria Meng, Thirumalai R. Ramalingam, Patrick Lupardus, Hans D. Brightbill, Dhaya Seshasayee, Yan Wu, Joseph R. Arron
Journal: Science Translational Medicine (2021)

Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2-anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade.
臨床不安定狭心症の非責任プラーク進行に対する入院時のトロポニンTレベル上昇の影響:容積測定、血管内超音波分析
Authors: Yano H, Hibi K, Kimura K, Nozawa N, Ozaki H, Kusama I, Kosuge M, Ebina T, Nakachi T, Iwahashi N, Okuda J, Tsukahara K, Kanna M, Umemura S
Journal: Journal of the American College of Cardiology (2006)
25031 Greater disease burden associated with palmoplantar pustulosis versus plaque psoriasis: Real-world evidence from the North American–based Corrona Psoriasis Registry
Authors: Mark Lebwohl, Nirali Kotowsky, Rose A. Medeiros, Nicole Foster, Judson Janak, Wendell C. Valdecantos, Mary Flack, Amanda K. Golembesky, Bruce Strober
Journal: Journal of the American Academy of Dermatology (2021)
Imatinib plus hydroxyurea versus hydroxyurea monotherapy in progressive glioblastoma (GBM) - An international open label randomised phase III study (ambrosia-study)
Authors: Gregor Dresemann, Mark Rosenthal, Klaus Hoeffken, Wolfgang Wagner, E Engel, B Heinrich, E Kettner, H Doehner, A Karup-Hansen, Anna Nowak, M Mehdorn, Eberhard Schleyer, Zariana Nikolova, Christian Hosius, Kea Franz, D Krex, S Green, S Selgav-Nayagam, R Parker, Michael Weller
Journal: Neuro-Oncology (2007)
Infection with SARS-CoV-2 is not the same as covid-19
Authors: Andrew N Bamji
Journal: BMJ (2021)

Both professionals and the Department of Health and Social Care are still failing to distinguish between infection with SARS-CoV-2 and covid-19, and positive tests continue to be reported as cases of covid-19.1 Covid-19 is a severe immunological consequence of SARS-CoV-2 infection but is not universal. It requires the development of hypoxia and biochemical and immunological indicators. In some laboratories, the cycle threshold in the PCR test (the …
Decline of influenza and respiratory syncytial virus detection in facility-based surveillance during the COVID-19 pandemic, South Africa, January to October 2020 separator commenting unavailable
Authors: S. Tempia, S. Walaza, J. N. Bhiman, M. L. McMorrow, J. Moyes, T. Mkhencele, S. Meiring, V. Quan, K. Bishop, J. M. McAnerney, A. von Gottberg, N. Wolter, M. Du Plessis, F. K. Treurnicht, O. Hellferscee, H. Dawood, F. Naby, E. Variava, C. Siwele, N. Baute, J. Nel, G. Reubenson, H. J. Zar, C. Cohen
Journal: Eurosurveillance (2021)

Background In South Africa, COVID-19 control measures to prevent SARS-CoV-2 spread were initiated on 16 March 2020. Such measures may also impact the spread of other pathogens, including influenza virus and respiratory syncytial virus (RSV) with implications for future annual epidemics and expectations for the subsequent northern hemisphere winter. Methods We assessed the detection of influenza and RSV through facility-based syndromic surveillance of adults and children with mild or severe respiratory illness in South Africa from January to October 2020, and compared this with surveillance data from 2013 to 2019. Results Facility-based surveillance revealed a decline in influenza virus detection during the regular season compared with previous years. This was observed throughout the implementation of COVID-19 control measures. RSV detection decreased soon after the most stringent COVID-19 control measures commenced;however, an increase in RSV detection was observed after the typical season, following the reopening of schools and the easing of measures. Conclusion COVID-19 non-pharmaceutical interventions led to reduced circulation of influenza and RSV in South Africa. This has limited the country's ability to provide influenza virus strains for the selection of the annual influenza vaccine. Delayed increases in RSV case numbers may reflect the easing of COVID-19 control measures. An increase in influenza virus detection was not observed, suggesting that the measures may have impacted the two pathogens differently. The impact that lowered and/or delayed influenza and RSV circulation in 2020 will have on the intensity and severity of subsequent annual epidemics is unknown and warrants close monitoring.
Covid-19: China pressured WHO team to dismiss lab leak theory, claims chief investigator
Authors: Owen Dyer
Journal: BMJ (2021)

A World Health Organisation mission to study the covid pandemic's origins in China, which announced in February that the possibility that the virus had escaped from a laboratory needed no further investigation, 1 was put under pressure by Chinese scientists who made up half the team to reach that conclusion, the scientist who led the mission has said.
Genetic Ontogeny Defines Distinct Prognostic Subgroups in AML Patients Age 60 and Older Following Hematopoietic Stem Cell Transplantation
Authors: Christopher J. Gibson, Vincent T Ho, Priti Kumari, Corey Cutler, John Koreth, Sarah Nikiforow, Philippe Armand, Joseph H. Antin, Jerome Ritz, Robert J. Soiffer, Steven M. Devine, Edwin Alyea, R. Coleman Lindsley
Journal: Blood (2017)
Application of Lyon Consensus criteria for GORD diagnosis: evaluation of conventional and new impedance-pH parameters
Authors: Leonardo Frazzoni, Marzio Frazzoni, Nicola De Bortoli, Mentore Ribolsi, Salvatore Tolone, Salvatore Russo, Rita Luisa Conigliaro, Roberto Penagini, Lorenzo Fuccio, Rocco Maurizio Zagari, Edoardo Savarino
Journal: Gut (2021)

To validate Lyon Consensus criteria for diagnosing gastro-oesophageal reflux disease (GORD) by reflux monitoring.Manual review of impedance-pH tracings from patients with proton pump inhibitor (PPI)-dependent heartburn, evaluated off PPI. Acid exposure time (AET) thresholds defined by the Lyon Consensus and impedance parameters were investigated, namely, total refluxes (TRs), postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI).The study included 488 patients, 178 (36%) with normal (<4%) AET, 89 (18%) with inconclusive (4%-6%) AET and 221 (45%) with abnormal (>6%) AET, alongside with 70 healthy controls. At receiver operating characteristic analysis, area under curve was 0.89, 0.95 and 0.89 for TRs, PSPW index and MNBI, respectively, and threshold values were 40, 50% and 2000 Ω; the 4% physiological AET threshold defined by the Lyon Consensus showed 100% specificity but 63% sensitivity. The thresholds defined for impedance parameters were validated against AET by means of ordered logistic regression, being in concordance with the 4% AET threshold (OR 2.5 for TRs, 18.9 for PSPW index and 5.7 for MNBI). TRs positivity and concordant PSPW index/MNBI positivity were found in 80%-90% of patients in the abnormal AET group, in 73%-74% of cases in the inconclusive AET group and in 28%-40% of cases in the group with normal AET.Our results show the overall validity of the Lyon Consensus approach to GORD diagnosis. Adding evaluation of impedance parameters, namely, TRs, PSPW index and MNBI to AET appraisal, substantially improves the diagnostic yield of reflux monitoring.
Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells
Authors: Anna Sole, Sandrine Grossetête, Maxime Heintzé, Loelia Babin, Sakina Zaïdi, Patrick Revy, Benjamin Renouf, Anne De Cian, Carine Giovannangeli, Cécile Pierre-Eugène, Isabelle Janoueix-Lerosey, Lucile Couronné, Sophie Kaltenbach, Mark Tomishima, Maria Jasin, Thomas G.P. Grünewald, Olivier Delattre, Didier Surdez, Erika Brunet
Journal: Cancer Research (2021)

Abstract Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow–derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. Significance: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow–derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.
Abstract 9910: Chronic Inflammatory Responses to Polymer Can Evoke Both Late Restenosis and Very Late Stent Thrombosis After Sirolimus-Eluting Stent Implantation in Human Coronary Arteries
Authors: Katsumi Inoue, Masao Imai, Takeshi Kimura, Masakiyo Nobuyoshi
Journal: Circulation (2011)

Background: Sirolimus-eluting stents (SES) can reduce the rate of restenosis by marked inhibition of neointimal hyperplasia. However, late adverse events occurring more than 1 year (Y) after SES implantation, in-stent late luminal loss (LLL) and very late stent thrombosis (VLST), have been reported. The detailed mechanisms of these events are poorly understood at present. Methods and Results: Postmortem histopathological investigation of late vascular responses of coronary arteries was performed in 32 consecutive patients (pts) more than 1 Y after SES implantation. Although most simple lesions with a single SES showed gradual endothelial coverage (80 to 90%) after 1 Y, there was considerable inflammatory reaction involving T lymphocytes (T cells), macrophages (MΦ) and multinucleated giant cells adjacent to the struts. Furthermore, 14 cases showed necrotic core formation with numerous circumferential cholesterol clefts and pronounced infiltration by lipid-laden MΦ that were immunoreactive for collagen-degrading matrix metalloproteinases around the struts. In 3 of these arteries, the luminal surface was focally ruptured and massive thrombi composed of platelets and fibrin were observed. Furthermore, in 2 pts who died of VLST more than 2 Y after SES implantation, the arterial wall of SES segments was aneurysmally dilated with an extensive inflammatory infiltrate involving the intima, media and adventitia consisting predominantly of T cells and eosinophils, and occasional giant cells. Furthermore, 2 other pts developing coronary aneurysms in the stented segments demonstrated diffuse restenosis. Granulomatous inflammatory reaction with mild to moderate inflammatory cell infiltration but remarkable smooth muscle cell proliferation was clearly observed in the restenotic regions in these pts. Conclusions: These findings suggest that the polymer of SES can evoke significant chronic destructive and/or proliferative inflammatory responses followed by severe adverse clinical events such as LLL or VLST, depending on the intensity of inflammation. Although relatively milder inflammatory changes induce intimal hyperplasia, vessel wall destruction by severe inflammation can lead to aneurysm formation in extreme cases.