Monday, 24 August 2020
Wednesday, 19 August 2020
This morning I read an article from the website of Professor Edzard Ernst. The article title is “The use of Traditional Chinese Medicines to treat SARS-CoV-2 may cause more harm than good”. I totally disagree with this opinion and after some investigation, I would like to change a few words in the title of his paper -- "The use of Traditional Chinese Medicines to treat COVID 19 may cause more good than harm."
Actually Mr Ernst is not the author of this article. This paper was originally published by two Australian doctors two month ago . Their conclusion was mainly based on an article which was published by a group of Japanese doctors in 2017. It was a Meta-Analysis paper. The author using PubMed and Ichushi-Web-the database of the Japan Medical Abstracts Society to identify articles published between 1996 and 2015 describing patients with Japanese herbal medicine induced pneumonia. They found that 73 patients have been diagnosed with pneumonia after taking Japanese herbal medicine . The mean age at pneumonia diagnosis was 63.2 15.5 years. The herbal formulas they used were sho-saiko-to () 26%, sairei-to 16%, seishin-renshi-in (8%and bofu-tsusyo-san () 8%.These formulas all are traditional Chinese medicine formulas which were widely used for hundreds or thousands of years in China, but not for early stage common cold or flu complaints. Chinese medicine diagnosis for early stage common cold or flu is Taiyang syndrome and the treatment principle should be expelling wind cold or wind heat. The indication of sho-saiko-to is Shaoyang syndrome and of course it is not suitable for Taiyang syndrome. The other 3 formulas are all not suitable for this stage of Taiyang syndrome. If the treatment missed the target of diagnosis, it will not work at all.
In addition to the diagnosis problem, I noticed that the mean age at pneumonia diagnosis was over 60. Elderly people are easier to develop into pneumonia when they catch cold, that is common sense. The conclusion of Mr Enomoto’s article was against the basic principle of statistics -- age group differentiation.
Mr.Gray the author of that article believes that the Chinese herb Scutellariae Radix (Huangqin) is the cause of ARDS. Many of the Chinese medicine formulas which are used in Covid 19 treatment contain Huangqin. That is why he gets his opinion of more harm than good. His evidence for this also came from a Japanese report . In this report only 5 patients have got ARDS after receiving the herbal treatment. He uses this very small sample report to against the report from Dr Ren which includes 701 cases of Covid 19 with a positive result. From Mr Gray’s article I cannot find any evidence based on a large sample RCT research or laboratory research.
Mr Edzard Ernst is a very famous retired professor and critic of Chinese medicine. We all benefit greatly from constructive logically based criticism but this becomes wasteful and distracting if the criticism is not based on the principles of medical statistics, and is selective in it’s use of research results to support a personal agenda. I would like to be able to say that this paper made a useful addition to the discussion on the efficacy of Traditional Chinese Medicines in the modern world, but unfortunately I cannot.
Just a few days ago, we received some positive news from the US National Centre for Biotechnology Information (NCBI) who stated that “overall,” treatment with the Chinese herbal medicine Lianhua Qingwen for 14 days resulted in a “significantly higher rate of, and a shorter time to, symptom recovery.” Their conclusion is "Traditional Chinese medicine can help COVID 19 patients recover faster” 
I hope that every reader can have a second thought about this topic. Always follow the science.
- Paul E. Gray. The use of Traditional Chinese Medicines to treat SARS-CoV-2 may cause more harm than good. Pharmacol Res. 2020 Jun; 156: 104776.
- Enomoto Y. Japanese herbal medicine-induced pneumonitis: a review of 73 patients. Respir. Investig. 2017; 55:138–144.
- Osamu Sakamoto. Clinical and CT characteristics of Chinese medicine‐induced acute respiratory distress syndrome. Respirology 2003; 8(3):344-50. doi: 10.1046.
- Ren J.L. Traditional Chinese medicine for COVID-19 treatment. Pharmacol. Res. 2020:104743.
Thursday, 30 July 2020
The peak of the Covid 19 pandemic has passed in the UK and most Europe countries. Many Covid 19 patients showed some sequel symptoms after their body temperature returned to normal: the cough disappeared, virus turned negative and they were discharged from hospital. Some people called these symptoms Covid 19 sequelae. The formal name of this condition should be called “Post Viral Syndrome after COVID 19.” At this stage, patients showed different symptoms to different degrees. Western medicine usually gives a basic symptomatic treatment. The effects are usually not satisfactory. Traditional Chinese medicine (TCM) already shows a particularly good effect in the acute phase of Covid 19. Additionally, in the post virus era it can also play an important role on the Post-Viral syndrome of Covid 19. My opinion about this syndrome and personal clinical experienceis as follows.
The incidences of post-viral syndrome are various.Not every Covid-19 patient will develop squeal symptoms. Most young patients or basically healthy individuals can fully recover after the virus disappear - no squeal symptoms remain. As Huangdi Neijing said: "The healthy qi strong person will not get the illness, only qi deficiency person will become sick." However, for elderly and weak patients, the incidence of squeal symptoms is quite high and in some cases the symptoms may be severe and even life-threatening. The incidence of different squeal symptoms varies. Common squeal symptoms mainly include:
Fatigue is the most common and mildest sequel symptom of Covid-19. More than half of Covid-19 patients have varying degrees of fatigue. TCM theory believes that the main causes of fatigue are qi and blood deficiency. Covid 19 patients have experienced high fever for up to 2-3 weeks. They have taking a variety of western medicines, and a large number of bitter and coldness herbs which might injury healthy qi. Huangdi Neijing said: “Normal body temperature produce healthy qi, but high fever will consume healthy qi”. The healthy qi of patient is exhausted by the “pathogenic heat” caused by coronavirus. This is the reason for fatigue. Modern medicine calls it "Post-Viral fatigue syndrome". Some patients may develop to a chronic fatigue syndrome (CFS).
After few months of lockdown, almost everyone has a certain degree of negative psychological impact. For patients with Covid 19, they have gone through several weeks of isolated treatment and some severe cases have experienced it in ICU. They have experienced the life and death test. The horrible memory about the ventilator and the witnessing the death of other patients became a negative psychological stimulation to patients. After being discharged from hospital some patients showed many psychological or physical symptoms such as depression, panic attack, restlessness, insomnia and worry about virus recurrence. These symptoms are called "Post-traumatic Stress Disorder" (PTSD) in western medicine. Although some people who are not infected by Covid 19 also experienced depression due to the scare about the pandemic and the changes in their life and work, this kind of post-viral depression is common.
3. Pulmonary Fibrosis:
According to the report 21.5% of SARA patients had showed the imaging of pulmonary fibrosis during the recovery period.  The main symptoms were dry cough and progressive dyspnea. Imaging of the lungs showed characteristic changes in pulmonary fibrosis. The proportion of pulmonary fibrosis in Covid 19 should be very familiar with SARA. It has been reported that the average survival time after diagnosis of pulmonary fibrosis is only 2.-3 years, and the mortality rate is higher than most of cancer. Pulmonary fibrosis is called "chronic cancer." Western medicine treats pulmonary fibrosis using two newly developed drugs, pirfenidone and nintedanib, but both have strong gastrointestinal side effects. Research on the treatment of pulmonary fibrosis with Chinese herbal medicine has showed satisfactory results.
Some patients experienced body ache after Covid 19, and the pain is wandering. The position is mainly in the muscles and bones of the limbs and back. The pain is usually combined with fatigue and depression. Western medicine diagnoses it as "fibromyalgia" (FM). The etiology of this disease is not clear, but it is believed to be related to traumatic stress, immune disorders, Epstein-Barr virus infection and other factors. The cytokine storm caused by Covid 19 virus is very likely to be a new cause of fibromyalgia.
5. Heart failure:
Heart and lungs all located in the chest (upper Jiao). According to the Zang-fu theory of TCM, heart is the "officer of the monarch", it dominates blood circulation; Lung is the "officer of prime minister", it dominates the qi. The heart and lungs are extremely closely related in their physiological functions, and they also influence each other in pathology. When lungs get ill heart must be affected. Western medical research shows that Covid 19 first invaded the human body through the angiotensin-converting enzyme 2 (ACE2) receptor located on the cell surface. Many patients develop viral myocarditis and pericarditis after Covid 19, which leads to heart failure. For some elderly people who have history of coronary heart disease, after the Covid 19, the patients can still be aggravated by heart failure or arrhythmia. This became the main reason of death for elderly Covid 19 patients.
6. Lost the sensation of smell and taste:
The Huangdi Neijing states that “The lung qi flows through the nose, the smell function depend on the normal function of lungs.” In Covid 19 patients, their lung qi was injured by the virus. Patients lost smell sensation. In some cases patient also loss of taste. This condition is very common, and it has even become one of the characteristic symptoms for the diagnosis of covid 19. After the virus, the recovery of smell and taste is often an extremely slow process, and it is still uncertain whether it can be completely recovered.
7. Impaired reproductive function:
Studies have shown that Covid19 destroys lung cells and/or ACE2 protective pathways. The expression of .ACE2 in the ovaries and testis indicates that this enzyme affects germ cells and fertility function. Therefore, theoretically, Covid 19 may cause male or female infertility. The impact of the virus on the fertility function will be gradually revealedin the future.
The above seven points are the main manifestations of the post-viral syndrome of Covid 19. In addition, there are other diseases such as acute and chronic kidney damage, proteinuria, and stroke which are induced by Covid 19.
Chinese medicine treatment:
TCM has shown an excellent effect in the treatment and prevention of Covid 19. The three formulas and three remedies recommended by China's National Health Commission are widely used in China during the pandemic. For treatment of chronic diseases TCM may show more advantages. I treated some patients with post-viral syndrome in the past few months. I would like to share my personal experience on the treatment of this syndrome.
1) Post-viral fatigue syndrome: The main pathogenesis of this syndrome is deficiency of qi and blood. TCM theory believes “If there is deficiency, supplement it”. TCM usually use Sijunzi decoction for replenishing qi and Siwu decoction for nourishing blood. For the patient with more digestive system disorders, we should benefit lung by tonifying spleen. Guipi Wan, or ChenXia Liujunzi Decoction can be selected. Spleen and stomach are the source of qi and blood. If spleen is strong, the qi and blood are sufficient, and the fatigue will be improved. The food therapy can be applied. Add some Huangqi, Dangshen, Danggui, Longyan, Gouqizi while cooking soups. Wuzhualong is the most favourite herb of my tutor, Professor Deng Tietao. It can not only invigorate qi, but also has the effect of reducing phlegm and relieving cough. It is a very good choice for the Post-viral fatigue after Covid 19.
2) Post-viral depression and PTSD: The depression after Covid 19 is mostly due to liver-qi stagnation, and Xiaoyaosan and Chaihu Shugan San can be used to relieve liver depression; PTSD symptoms are mostly due to heart shen disturbed. Chinese medicine Baizi Yangxin Wan, Tianwang Buxin Wan and Ganmai Dazao decoction can be selected. I recommend adding Baihe, Meiguihua, Suxinhua, Yujin etc. to release the depression. Appropriate psychological treatment can help, but it is not recommended to use antidepressantsif not very necessary. Chinese herbal medicine is a natural way of anti-depression.
3) Post-coronary pulmonary fibrosis: For the treatment of pulmonary fibrosis, Chinese medicine adopts the treatment principles of clearing dryness and moisturizing the lungs, lowering qi and relieving asthma, promoting blood circulation and removing blood stasis. The prescriptions are mostly Qingzao Jiufei Decoction, Suzi Jiangqi Decoction, Sanzi Yangqin Decoction, plus Danshen, Chishaoyao, Sanqi and other herbs for promoting blood circulation and removing blood stasis. There are many research reports showing that single or compound Chinese medicine can significantly improve pulmonary fibrosis in rats caused by bleomycin. Among them, the classic ancient prescription Yupingfeng San has shown good effect in anti-pulmonary fibrosis. I also have an English article devoted to discussing the mechanism of Yupingfeng on the prevention and treatment of Covid 19.
4) Fibromyalgia caused by the virus: Acupuncture has a very good effect on the treatment of fibromyalgia. Acupuncture should be the first choice for muscle and joint pain after Covid 19.There are many research reports on the mechanism of acupuncture analgesia. Not only relieving pain, acupuncture is also a comprehensive treatment measure, which can also alleviate related symptoms such as, depression, and sleep disorders.
5) Heart failure: Heart failure is more common in severe case of Covid 19. In some mild cases tachycardia and arrhythmia can be found after the virus. TCM usually chooses Xuefu Zhuyu Decoction and Shengmai San to treat the heart failure. Studies have confirmed that these prescriptions can improve myocardial blood supply, reduce myocardial oxygen consumption, improve microcirculation and many other effects, thereby gradually improving heart failure.
6) Loss of smell and taste after the Covid 19: Acupuncture at Yingxiang (LI 20) and Bitong points beside the nose, and certain specific areas of the scalp acupuncture, to help restore the sense of smell; Acupuncture on the face, cheeks, and neck acupoints such as Dichang (ST4), Jiache (ST6) and Lianquan (RN23) and combined with strengthening spleen herbs, can help restore the sense of taste.
7) Infertility after Covid 19: Wuzi Yanzong Wan can improve sperm quantity and quality, improve sperm motility, improve semen liquefaction time, and increase reproductive ability. It is used for the treatment of male infertility. For female infertility Nuangong Yunzi Wan, Zishen Yutai Wan, or Fuke Bazhen Wan can be selected according to the syndrome differentiation.
After the peak of the pandemic passed, it can be predicted that the peak of post-viral syndrome will follow. Ray suggests that prevalence of fatigue-related symptoms after Covid 19 infection should be studied first, and pragmatic, relatively low-cost techniques should be explored to treat post-viral fatigue. Relieve symptoms and improve the quality of life of people affected by the long-term sequelae of Covid 19. I think Chinese medicine should be the best option. Patients and doctors must be aware of the post-viral syndrome, and apply suitable treatment,ensuring a complete recovery and to prevent it from recurring.
If the patient's virus test has turned negative, it is better co
1. Ray Perrin. Into the looking glass: Post-viral syndrome post COVID-19. Med Hypotheses. 2020 Nov; 144: Published online 2020 Jun 27.
2. Xie L Dynamic changes of serum SARS-coronavirus IgG, pulmonary function and radiography in patients recovering from SARS after hospital discharge[J]. Respir Res, 2005,6:5. DOI: 10.1186/1465-9921-6-5.
3. Peter M. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. The Lancet Respiratory Medicine. May 15, 2020
4. Yunping Bai. A Chinese Herbal Formula Ameliorates Pulmonary Fibrosis by Inhibiting Oxidative Stress via Upregulating Nrf2. Front Pharmacol. 2018; 9: 628.
5. Jiepeng Wang. Danggui Buxue Tang ameliorates bleomycin-induced pulmonary fibrosis in rats through inhibiting transforming growth factor-β1/Smad3/ plasminogen activator inhibitor-1 signaling pathway. J Tradit Chin Med. 2020 Apr;40(2):236-244.
6. Dixin Zou. Analysis of pharmacological mechanisms and targets mining of Wuzi-Yanzong-Wan for treating non-obstructive oligoasthenospermia. Biomed Pharmacother. 2019 Jul; 115:108898.
Saturday, 18 July 2020
Saturday, 23 May 2020
Thursday, 21 May 2020
Saturday, 18 April 2020
Thursday, 5 March 2020
Yupingfeng San (YPF) is the most commonly used formula for prevent disease in the history of traditional Chinese medicine. It consists of three ingredients. They are Huangqi (Astmgali Radix), Baizhu ( Largehead Atractylodes Rh) and Fangfeng (Divaricate Saposhniovia Root.). It has been widely used in China since the Yuan dynasty (1217 AD). According to traditional Chinese medicine philosophy, this formula can build up healthy Qi and to prevent invasion of external evils. In Chinese “Yupingfeng” mean jade screen and “San” mean powder. Is it possible to use YPF to prevent and treat Covid 19? Is there any scientific research evidence to support the clinical application of this classical formula? This paper aimed to answer these questions by systematic review.
Database includes PubMed, MEDLINE, CNKI, CSCD. Use Yupingfeng as key word.
Search time limit is from 2000-2020. All the Included articles were published in English.
1. Immunoregulatory and anti-inflammatory function
Inflammatory cytokine storm is very important pathological change of Covid 19.
To observe the Immunoregulatory and anti-inflammatory effects of YPF, Song J. applied YPF to treat a rat chronic bronchitis model. The results showed that the inflammation in the pulmonary tissue and the bronchus of rats was significantly reduced in the treatment groups. In serum samples collected at different times from rats after administration of YPF, the result showed increased proliferation of splenic lymphocytes area. They use serum samples of YPF group to treat alveolar macrophages. The result found interleukin-8 (IL-8) in the cell culture media has been inhibited .
IL-8 plays an important role in the pathogenesis of bronchitis and cystic fibrosis. It also is a very important pathological factor in the cytokine storm of Covid 19 . To investigate the immunomodulating mechanism of YPF, Sun H applied YPF polysaccharides to treat mice lymphocytes and macrophages. The results showed YPF polysaccharides effectively enhanced the proliferation of lymphocytes and promoted mRNA expression of inducible nitric oxide synthase (iNOS), IL-6, TNF-α, INF-γ, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and TLR-4 in lymphocytes and macrophages. Moreover, it can effectively normalized cell proliferation and down regulated mRNA expression levels of pro-inflammatory cytokines, NF-κB, TLR-4, and iNOs in chronic inflammation cells . These cytokine factors all play important role in the chain reaction of Covid 19 cytokine storm .
2. Anti-virus effect function
Coronavirus is the pathogen of Covid 19. The anti-virus effect of YPF was approved by some laboratory researches. To investigate the antivirus effect of YPF, Liu Q. applied real-time RT-PCR and western blotting technique to detect influenza virus (IFV) and the human respiratory syncytial virus (HRSV). The result showed YPF extract inhibited both IFV and HRSV in a dose-dependent manner when given before, during and after a viral infection. YPF was effective in blocking the entry of the virus. Furthermore, pre-treatment with YPF reduced the susceptibility of cells to the invasion of HRSV by inhibiting the expression of ICAM-1. YPF extract increased the survival rate of lethal influenza-infected mice, prolonged the survival time and alleviated the virus-induced lung lesions, which is comparable with the effects of ribavirin treatment . To enhance the anti coronavirus function of YPF, I added Lizhihe (Litchi core) in my modified YPF formula, because of it can significantly inhibit protease activity of SARS coronavirus 3CL .
3. Anti-asthma function
Difficulty breathing is one of the common symptoms of Covid 19. Previous studies showed YPF has a good function of anti-asthma. Wang Z. reported that YPF could alleviate the inflammation in the lung tissue of mice, decrease the proportion of Th17 cells, and increase the proportion of Treg cells in bronchoalveolar lavage fluid, it could decrease IL-4 and TNF-α level and increase TGF-β level in blood . Liu X applied network pharmacology to explore potential mechanism of YPF on asthma. In vitro experiments showed that YPF significantly decreased the production of TNF-α and IL-6, as well as both mRNA and protein levels of IL-1β, NLRP3, Caspase-1 and ASC. In vivo experiment showed YPF treatment not only reduce the clinical symptoms, but also reduced inflammatory cell infiltration, mucus secretion in lung of asthmatic mice. Moreover, YPF treatment remarkably decreased the mRNA and protein levels of IL-1β, NLRP3, Caspase-1 and ASC in lung of asthmatic mice .
4. Anti pulmonary fibrosis
Pulmonary fibrosis is a major pathological change in Covid 19 patients. YPF showed an anti pulmonary fibrosis function in the previous studies. Li L applied total extract of YPF to treat bleomycin-induced pulmonary fibrosis in rats. The result showed YPF treatment can reduce the alveolitis and fibrosis, reduced the loss of body weight and increase of lung coefficient. YPF also significantly decreased the levels of hydroxyproline and type I collagen, and reduced the over-expression of high-mobility group box 1 (HMGB1), transforming growth factor-beta 1 (TGF-β1), Col-I and α-smooth muscle actin (α-SMA) .It can improve lung fibrosis by alleviating HMGB1 activity and TGF-β1 activation .
Cui W applied the total glycoside of Yupingfeng (YPF-G) to treat pulmonary fibrosis, the result found that both dose of YPF-G significantly reduced bleomycin-induced alveolitis and pulmonary fibrosis in rats. The levels of HMGB1, laminin, hyaluronic acid, and hydroxyproline were effectively reduced. The increased protein expression of HMGB1 was dramatically inhibited after YPF-G treatment .
5. Clinical randomized controlled trials
Except laboratory research YPF also showed some good effects on clinical trials of some related diseases include SARS. A meta-analysis aimed to evaluate the immunomodulating function of YPF in children with recurrent respiratory tract infections. Twelve trials with 1236 patients were identified. YPF significantly increased serum levels of IgA, IgG, IgM and CD3 (+) T-lymphocytes. It also reduced the frequency of recurrent respiratory tract infections and increased total effective rates of symptom improvement . A randomized, double-blind, parallel, placebo-controlled study analysed 240 patients from eight centres in China. Participants were eligible if they had mild to severe chronic obstructive pulmonary disease. They were randomly assigned to receive YPF or placebo. The result showed YPF group had a significantly lower exacerbation rate than placebo group and a significantly reduced risk of second exacerbation. The mean change in the COPD assessment test score in the YPF group were signifacantly lower than placebo group .
During the epidemic period of SARS in Hong Kong there were 2,601 medical staff administered with Kandu Bufei Decoction which is a modified YPF ．It was confirmed that 1,063 people had taken it for a successive two weeks. They were regarded as the treatment group．The control group consisted of 15,374 subjects who didn’t take Chinese herbal medicine．The result showed: No one in the herbal treatment group contracted the SARS infection while in the control group, 64(0.4%) were infected .
The pandemic of Covid 19 is gradually getting under control in China. Chinese herbal medicine played a very important role in this battle against Covid 19 in China. More than 85% of patients received herbal medicine treatment. Because the involvement of Chinese herbal medicine the cure rate was significantly increased and mortality rate significantly decreased.
YPF is a natural immune enhancer. Its immunoregulatory function can prevent viral infection. The anti-inflammatory and antivirus function can block the cytokine storm reaction of Covid 19. The anti-asthma effect can release the shortness of breath. The anti pulmonary fibrosis effect can reduce the pulmonary fibrosis in the severe stages and recover stages.
Based on above research evidence we have reason to conclude YPF probably has the effects on prevention and treatment of Covid 19.
- Song J. Anti-inflammatory and immunoregulatory effects of Yupingfeng powder on chronic bronchitis rats. Chin J Integr Med. 2013; 19(5):353-9.
- Xuetao Cao. COVID-19: immunopathology and its implications for therapy. Nature Reviews Immunology . 2020; 20, 269-270.
- Sun H. Bidirectional immunomodulating activity of fermented polysaccharides from Yupingfeng. Res Vet Sci. 2017; 110:22-28.
- Liu Q. Jiawei-Yupingfeng-Tang, a Chinese herbal formula, inhibits respiratory viral infections in vitro and in vivo. J Ethnopharmacol. 2013; 150 (2):521-8.
- Shouji Gong. A study on anti-SARS. CoV 3CL protein of flavonoids from litchichinem sonn core. Chinese Pharmacological Bulletin 2008；24 (5): 699～700.
- Wang Z. Yupingfeng Pulvis Regulates the Balance of T Cell Subsets in Asthma Mice. Evid Based Complement Alternat Med. 2016; 6916353.
- Liu X. Yupingfeng San Inhibits NLRP3 Inflammasome to Attenuate the Inflammatory Response in Asthma Mice. Front Pharmacol. 2017; 8, 1-12.
- Li L. Total extract of Yupingfeng attenuates bleomycin-induced pulmonary fibrosis in rats.Phytomedicine. 2015; 22 (1):111-9.
- Cui W. Total glycosides of Yupingfeng protects against bleomycin-induced pulmonary fibrosis in rats associated with reduced high mobility group box 1 activation and epithelial-mesenchymal transition.Inflamm Res. 2015; 64(12):953-61.
- Song T. Adjuvant Treatment with Yupingfeng Formula for Recurrent Respiratory Tract Infections in Children: A Meta-analysis of Randomized Controlled Trials.Phytother Res. 2016; 30 (7):1095-103.
- Ma J. Effects of YuPingFeng granules on acute exacerbations of COPD: a randomized, placebo-controlled study.Int J Chron Obstruct Pulmon Dis. 2018; 13, 3107-3114.
- Liu Dehui. Clinical Observation on the Preventive Effect of KangduBufei Decoction on AcuteSevere Respiratory Syndrome. Chinese Journal of Integrated Traditional and Western Medicine. 2004; 24(8): 685-688.
Tuesday, 4 February 2020
Thursday, 23 January 2020
Am J Chin Med. 2013;41(4):743-64.