tbuckley/cabot-search huggingface dataset:
Interoperability and Information-Blocking Rules
Authors: Shikha Sinha, Raghuveer Puttagunta, Jennifer Vodzak
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
Characterizing the Low-Dose Effects of Methylmercury on the Early Stages of Embryo Development Using Cultured Human Embryonic Stem Cells
Authors: Bai Li, Cunye Qiao, Xiaolei Jin, Hing Man Chan
Journal: Environmental Health Perspectives (2021)

Global concerns of methylmercury (MeHg) exposure have been raised, especially on its effects on pregnant women. Recent epidemiological studies have revealed associations between maternal blood/hair MeHg concentrations, adverse pregnancy outcomes, and developmental deficits. However, the underlying mechanisms remain unclear.In this study, we characterized the effects of MeHg exposure on undifferentiated human embryonic stem cells (hESCs) and extrapolated the effects to human embryonic development.hESCs were exposed to 0, 1, 5, 10, 50, 100 or 200nM MeHg for 24 h or 6 d. Cell adherence and colony formation and expansion were examined under the microscope. Cell attachment, viability/proliferation, apoptosis, stress response, cell cycle, autophagy, and expression of cell lineage marker genes and proteins were measured at the end of exposures.Our results indicated that exposure to nanomolar concentrations of MeHg was associated with a) higher levels of reactive oxygen species (ROS) and hemeoxygenase-1 (HO-1), suggesting increased stress and adaptive responses; b) lower cellular adhesion, viability/proliferation, and colony formation and expansion; c) higher levels of apoptosis, reflected by higher cleaved caspase-3 expression and Annexin V binding; d) higher levels of cytoskeleton protein α-tubulin expression; e) higher rates of G1/S phase cell cycle arrest; and f) autophagy inhibition, as shown by a lower LC3BII/LC3BI ratio and accumulation of SQSTM1 (p62). These outcomes were accompanied by higher expressions of self-renewal genes or proteins or both, including OCT4, SOX2, NANOG, and cytokine receptor IL6ST, as well as pluripotency and the cell fate regulator cyclin D1.These results revealed that under the selection pressure of exposure to low doses of MeHg, some hESCs underwent apoptosis, whereas others adapted and survived with enhanced self-renewal gene expression and specific morphological phenotypes. Findings from the present study provide in vitro evidence that low doses of MeHg adversely affect hESCs when exposed during a period of time that models embryonic pre-, during, and early postimplantation stages. https://doi.org/10.1289/EHP7349.
Completeness of reporting and risks of overstating impact in cluster randomised trials: a systematic review
Authors: Elizabeth L Turner, Alyssa C Platt, John A Gallis, Kaitlin Tetreault, Christina Easter, Joanne E McKenzie, Stephen Nash, Andrew B Forbes, Karla Hemming, Christine Adrion, Naseerah Akooji, Hannah Bensoussane, Aneel Bhangu, Jon Bishop, Bernadeta Bridgwood, Eric Budgell, Agnès Caille, Michael Campbell, Shiwei Cao, Claire Louise Chan, Versha Cheed, Michelle Collinson, Andrew Copas, Stephanie N Dixon, Sandra Eldridge, Alice S Forster, Alicia Gill, Bruno Giraudeau, Alan Girling, James Glasbey, Beatriz Goulao, Kelsey L Grantham, Simon Hackett, Thomas Hamborg, Kelly Handley, Monica Harding, Pollyanna Hardy, Catherine A Hewitt, Richard Hooper, Natalie Ives, Kirsty James, Christopher I Jarvis, Ben Jones, Brennan C Kahan, Mona Kanaan, Jessica Kasza, Lindsay Kendall, Caroline Kristunas, Kristie Kusibab, Hui-Jie Lee, Clémence Leyrat, Stephanie J Macneill, Vichithranie W Madurasinghe, James Martin, Ariane M Mbekwe Yepnang, Kara McCormack, Samir Mehta, Mirjam Moerbeek, Kelly Moran, Lazaro Mwakesi Mwandigha, Lee Aymar Ndouga Diakou, Dmitri Nepogodiev, Omar Omar, Laura A Pankhurst, Alice Parish, Smitaa Patel, Hayley Perry, Ines Rombach, Ryan Simmons, Beth Stuart, Yongzhong Sun, Monica Taljaard, Elsa Tavernier, Jennifer A Thompson, Tracy Truong, Joao Ricardo Vissoci, Adam P Wagner, Tongrong Wang, Xueqi Wang, Jeremy Weber, Nina Wilson, Jonathan Wilson, Rebecca Woolley, Siyun Yang, Zidanyue Yang
Journal: The Lancet Global Health (2021)

Overstating the impact of interventions through incomplete or inaccurate reporting can lead to inappropriate scale-up of interventions with low impact. Accurate reporting of the impact of interventions is of great importance in global health research to protect scarce resources. In global health, the cluster randomised trial design is commonly used to evaluate complex, multicomponent interventions, and outcomes are often binary. Complete reporting of impact for binary outcomes means reporting both relative and absolute measures. We did a systematic review to assess reporting practices and potential to overstate impact in contemporary cluster randomised trials with binary primary outcome. We included all reports registered in the Cochrane Central Register of Controlled Trials of two-arm parallel cluster randomised trials with at least one binary primary outcome that were published in 2017. Of 73 cluster randomised trials, most (60 [82%]) showed incomplete reporting. Of 64 cluster randomised trials for which it was possible to evaluate, most (40 [63%]) reported results in such a way that impact could be overstated. Care is needed to report complete evidence of impact for the many interventions evaluated using the cluster randomised trial design worldwide.
Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth
Authors: Fangrui Wu, Shenyou Nie, Yuan Yao, Tong Huo, Xin Li, Xiaowei Wu, Jidong Zhao, Yi-Lun Lin, Yinjie Zhang, Qianxing Mo, Yongcheng Song
Journal: Theranostics (2021)

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis.MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%).The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L.Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia.Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological activities against MLL-rearranged leukemia and other cancer cells.Results: Compound-1 was identified to be a novel small-molecule inhibitor of the AF9/ENL-DOT1L/ AF4/AFF4 interaction with IC50s of 0.9-3.5 µM.Pharmacological inhibition of the PPIs significantly reduced SEC and DOT1L-mediated H3K79 methylation in the leukemia cells.Gene profiling shows compound-1 significantly suppressed the gene signatures related to onco-MLL, DOT1L, HoxA9 and Myc.It selectively inhibited proliferation of onco-MLL-or Myc-driven cancer cells and induced cell differentiation and apoptosis.Compound-1 exhibited strong antitumor activity in a mouse model of MLL-rearranged leukemia.Conclusions: The AF9/ENL-DOT1L/AF4/AFF4 interactions are validated to be an anticancer target and compound-1 is a useful in vivo probe for biological studies as well as a pharmacological lead for further drug development.
EAACI Biologicals Guidelines—Omalizumab for the treatment of chronic spontaneous urticaria in adults and in the paediatric population 12–17 years old
Authors: Ioana Agache, Cezmi A. Akdis, Mubeccel Akdis, Knut Brockow, Tomas Chivato, Stefano del Giacco, Thomas Eiwegger, Kilian Eyerich, Ana Giménez‐Arnau, Jan Gutermuth, Emma Guttman‐Yassky, Marcus Maurer, Graham Ogg, Peck Y. Ong, Liam O’Mahony, Jürgen Schwarze, Amena Warner, Thomas Werfel, Oscar Palomares, Marek Jutel
Journal: Allergy (2021)

Chronic spontaneous urticaria (CSU) imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity and insufficient efficacy of classical drugs such as H1 R-antihistamines. Better understanding of the mechanisms has enabled a stratified approach to the management of CSU, supporting the use of targeted treatment with omalizumab. However, many practical issues including selection of responders, the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its cost-effectiveness still require further clarification. The EAACI Guidelines on the use of omalizumab in CSU follow the GRADE approach in formulating recommendations for each outcome. In addition, future therapeutic approaches and perspectives as well as research priorities are discussed.
Medical Debt as a Social Determinant of Health
Authors: Carlos F. Mendes de Leon, Jennifer J. Griggs
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
P27-8 Genetic panel testing by liquid biopsy in our hospital
Authors: Masahiro Matsumoto, Kohei Takaki, Tsuyoshi Kaihara, Kazuki Ogawa, Genki Sato, Momoka Nakatani, Sora Watanabe, Seiya Kinjo, Shinya Kajiura, Ryuji Hayashi, Toshiro Miwa
Journal: Annals of Oncology (2021)
HBV Genotype: A Significant Risk Factor in Determining Which Patients With Chronic HBV Infection Should Undergo Surveillance for HCC: The Hepatitis B Alaska Study
Authors: Brian J. McMahon, Leisha D. Nolen, Mary Snowball, Chriss Homan, Susan Negus, Elena Roik, Philip R. Spradling, Dana Bruden
Journal: Hepatology (2021)

Background and Aims Information is limited regarding HBV genotype and the outcome of chronic HBV (CHB) infection. We examined the effect of HBV genotype on HCC occurrence in Alaska Native (AN) persons with CHB, where five HBV genotypes are found: A2, B6, C2, D, and F1. Approach and Results We calculated HCC incidence per 1,000 person-years of follow-up to determine which groups by age, sex, and genotype met current American Association for the Study of Liver Diseases (AASLD) HCC surveillance criteria. We used Poisson regression to compare HCC risk by genotype, age, sex, and Alaska region. Incidence of HCC was calculated using the sex-specific AASLD cutoff recommended for the Asian population of 50 years for women and 40 years for men. HCC screening was conducted semiannually using alpha-fetoprotein levels and abdominal ultrasound. Among 1,185 AN persons, median follow-up was 35.1 years; 667 (63%) were male. The HBV genotype distribution was 49% D, 18% F, 13% A, 6% C, 3% B, 0.1% H, and 12% undetermined. Sixty-three cases of HCC occurred. HCC incidence for genotype F was 5.73 per 1,000 person-years of follow-up, followed by 4.77 for C, 1.28 for A, 0.47 for D, and 0.00 for B. The HCC risk was higher for genotypes F (relative rate [RR], 12.7; 95% CI, 6.1-26.4), C (RR, 10.6; 95% CI, 4.3-26.0), and A (RR, 2.9; 95% CI, 1.0-8.0) compared to genotypes B and D. Among men < 40 years of age and women < 50 years of age, genotype F had the highest incidence (4.79/1,000 person-years). Conclusions HBV genotype was strongly associated with HCC. HBV genotype should be considered in risk factor stratification.
Abstract 78: 30:2 vs 15:2 Compression-Ventilation Ratio by Emergency Medical Services Responders in Patients with Out-of-Hospital Nonshockable Cardiac Arrest
Authors: Ken Nagao, Eizo Tachibana, Kei Nishikawa, Tsukasa Yagi, Naohiro Yonemoto, Morimasa Takayama, Hiroshi Nonogi, Shinichi Shirai, Takeshi Kimura
Journal: Circulation (2011)

BACKGROUND The 2010 AHA guidelines for CPR recommended that emergency medical services (EMS) responders should use minimal interruptions in chest compressions using a 30:2 compression-ventilation ratio in adult victims. However, it is unclear whether this CPR by EMS responders can improve survival for adults with non-shockable cardiac arrest (CA) including pulseless electrical arrest (PEA) and asystole. METHODS We compared the effects of a 30:2 compression-ventilation ratio CPR by EMS responders recommended in the 2005 CPR guidelines with those of a 15:2 compression-ventilation ratio CPR recommended in the 2000 CPR guidelines from the data of the All-Japan Utstein Registry, a prospective, nationwide, observational registry. The study endpoints were return of spontaneous circulation (ROSC) on hospital arrival and 30-day favorable neurological outcome after CA. RESULTS Of the 58,448 adult patients with bystander-witnessed out-of-hospital CA due to presumed cardiac etiology in the year 2005, 2008 and 2009, 24,250 with non-shockable cardiac arrest who did not receive bystander CPR were included; 16,091 received a 30:2 CPR by EMS responders, and 8,159 received a 15:2 CPR by EMS responders. The 30:2 group had significantly higher rates of ROSC and favorable neurological outcome than the 15:2 group in the whole cohort (ROSC; 6.6% vs. 4.2%, p&lt;0.001, favorable neurological outcome; 1.3% vs. 0.8%, p&lt;0.001), and in the subgroups of patients with PEA (ROSC; 9.8% vs. 5.8%, p&lt;0.001, favorable neurological outcome; 2.4% vs. 1.6%, p=0.002). Although the 30:2 group had a significantly higher ROSC rate than the 15:2 group (4.3% vs. 3.3%, p=0.002), favorable neurological outcome did not differ between the 30:2 group and the 15:2 group (0.5% vs. 0.3%, p=0.28) in the subgroups of patients with asystole. The adjusted odds ratios after a 30:2 CPR was 1.62 (95% CI, 1.43-1.84) for ROSC and 1.56 (95% CI, 1.18-2.05) for favorable neurological outcome, and other independent predictor of each study endpoint was PEA. CONCLUSION A 30:2 compression-ventilation ratio CPR by EMS responders improved ROSC and favorable neurological outcome in adult patients with bystander-witnessed out-of-hospital PEA CA, but this CPR had not neurological benefits for adult patients with asystole CA.
Paranoia and belief updating during the COVID-19 crisis
Authors: Praveen Suthaharan, Erin J. Reed, Pantelis Leptourgos, Joshua G. Kenney, Stefan Uddenberg, Christoph D. Mathys, Leib Litman, Jonathan Robinson, Aaron J. Moss, Jane R. Taylor, Stephanie M. Groman, Philip R. Corlett
Journal: Nature Human Behaviour (2021)

The COVID-19 pandemic has made the world seem less predictable. Such crises can lead people to feel that others are a threat. Here, we show that the initial phase of the pandemic in 2020 increased individuals' paranoia and made their belief updating more erratic. A proactive lockdown made people's belief updating less capricious. However, state-mandated mask-wearing increased paranoia and induced more erratic behaviour. This was most evident in states where adherence to mask-wearing rules was poor but where rule following is typically more common. Computational analyses of participant behaviour suggested that people with higher paranoia expected the task to be more unstable. People who were more paranoid endorsed conspiracies about mask-wearing and potential vaccines and the QAnon conspiracy theories. These beliefs were associated with erratic task behaviour and changed priors. Taken together, we found that real-world uncertainty increases paranoia and influences laboratory task behaviour. Suthaharan et al. show that levels of paranoia increased in the general population during the early stages of the COVID-19 pandemic, in association with more erratic belief updating. Government policies also played a role.
Endoscopic submucosal dissection of intramucosal adenocarcinoma on Barrett's esophagus
Authors: Sergio Rubel Cohen, Damián Orellano, Daniel Castellón García, César Acevedo Sylvester
Journal: Endoscopy (2021)

A 63-year-old man was investigated because of long-standing pathological gastroesophageal reflux. Diagnostic endoscopy showed long-segment Barrett’s esophagus associated with a flat lesion compatible with a granular laterally spreading tumor (LST-G), and endoscopic submucosal dissection was decided upon [1].
Focal Nodular Hyperplasia and Hepatic Adenoma
Authors: 윤병철
Journal: Clinical and Molecular Hepatology (2012)

FNH와 HA는 혈관종 다음으로 흔한 양성 간종양이다. 최근 의학의 발달로 인한 유전자 검사 등으로 이 종양들의 병태생리에 대한 이해가 더 향상되었으나 아직 발생 원인과 역학 등이 명확하게 밝혀지지 않았다. 이 종양들은 특징적으로 여자에서 호발하며 발생에 여성호르몬 등이 관여하는 등 많은 부분에서 유사점을 가지고 있으나 종양에 대한 치료는 같지 않다. 영상 또는 조직학적 특징적인 소견으로 적절하게 감별하여 환자에게 적절한 치료를 시행해야 하겠다.
O-14 Exploratory biomarker analysis of trastuzumab deruxtecan in DESTINY-Gastric01, a randomized, phase 2, multicenter, open-label study in patients with HER2-positive or -low advanced gastric or gastroesophageal junction adenocarcinoma
Authors: K. Shitara, Y. Bang, S. Iwasa, N. Sugimoto, M. Ryu, D. Sakai, H. Chung, Y. Omuro, H. Kawakami, H. Yabusaki, Y. Sakamoto, T. Nishina, K. Inaki, Y. Kuwahara, F. Suto, M. Sugihara, K. Saito, A. Kojima, K. Yamaguchi
Journal: Annals of Oncology (2021)
Outcomes of Myelodysplastic Syndromes (MDS) Patients with Chromosome 17 Abnormalities: A Report on Behalf of the MDS Clinical Research Consortium (MDSCRC)
Authors: Rami S. Komrokji, Najla Al Ali, John Barnard, David P. Steensma, Amy E. DeZern, Gail J. Roboz, David A Sallman, Eric Padron, Aziz Nazha, Alan F List, Guillermo Garcia-Manero, Mikkael A. Sekeres
Journal: Blood (2017)
Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial
Authors: Christopher C Butler, Ly-Mee Yu, Jienchi Dorward, Oghenekome Gbinigie, Gail Hayward, Benjamin R Saville, Oliver Van Hecke, Nicholas Berry, Michelle A Detry, Christina Saunders, Mark Fitzgerald, Victoria Harris, Ratko Djukanovic, Stephan Gadola, John Kirkpatrick, Simon de Lusignan, Emma Ogburn, Philip H Evans, Nicholas P B Thomas, Mahendra G Patel, F D Richard Hobbs
Journal: The Lancet Respiratory Medicine (2021)
<i>NEDD4L </i>Polymorphism and Acute Appendicitis and the Need for a Deeper Dive
Authors: Maryam K. Mohammed, Brian S. Zuckerbraun
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
Prevention of Post-Transplantation Diabetes: Small Steps, Big Opportunities
Authors: Adnan Sharif
Journal: Journal of the American Society of Nephrology (2021)

Post-transplantation diabetes mellitus (PTDM) is common, affecting up to a third of kidney allograft recipients due to generic and transplant-specific risk factors, and is also associated with increased risk for cardiovascular disease, all-cause mortality, and overall graft failure.[1][1] In
Autophagy induction regulates aquaporin 3‐mediated skin fibroblast ageing*
Authors: H. Xie, L. Zhou, F. Liu, J. Long, S. Yan, Y. Xie, X. Hu, J. Li
Journal: British Journal of Dermatology (2021)

Background Long- and short-term ultraviolet (UV) exposure have distinct biological effects on human fibroblasts. Objectives To elucidate the underlying mechanisms of the biological effects of UV exposure on human skin fibroblasts. Methods We subjected human skin fibroblast cells with or without aquaporin 3 (AQP3), death effector domain-containing protein (DEDD) or Beclin1 manipulation to UVA treatment and evaluated autophagy and senescence in them. Results Short-term UVA irradiation induced autophagy and upregulated AQP3 but not senescence, whereas long-term UVA irradiation inhibited autophagy, AQP3 and trigger senescence in vitro and in vivo. Silencing AQP3 abolished short-term UVA irradiation-induced autophagy and led to cellular senescence, whereas AQP3 overexpression partially rescued the senescence and autophagy inhibition induced by long-term UVA exposure in vitro. Mechanistically, the transcription factor Jun was found to bind to the AQP3 promoter to activate its transcription following short-term UVA exposure. Subsequently, AQP3 interacted with DEDD to induce its ubiquitination-mediated degradation and promote autophagy, and bound to Beclin1 to directly activate autophagy. Finally, autophagy induced by AQP3 overexpression robustly prevented UVA-induced senescence in vitro and in vivo. Conclusions Our study indicates that AQP3 controls skin fibroblast photoageing by regulating autophagy and represents a potential target for future interventions against skin ageing.