According to epidemiological data, nearly a quarter of the adult population in developed countries suffers from constipation. Due to a significant decrease in quality of life, it represents a serious medical and social problem. Constipation occurs more frequently in the elderly, but both children and adults face this problem. This disease is often caused by the features of modern life: hypodynamia, diet violations, a fiber- and water-depleted diet, frequent stress, etc. Unfortunately, despite the high prevalence of the disease, patients do not seek immediate medical advice. We will discuss this urgent problem and look for new efficient solutions of it with the leading experts: Gastroenterologist Yuri A. Kucheryavy, Cand. of Sci. (Med.), Associate Professor of Department of Propedeutics of Internal Diseases and Gastroenterology, A.I.Yevdokimov Moscow State University of Medicine and Dentistry, Chief Gastroenterologist of Central Healthcare Directorate – Branch of Joint Stock Company “Russian Railways”; Endoscopist Ekaterina V. Ivanova, Dr. of Sci. (Med.), Chief Researcher, Research Laboratory of Surgical Gastroenterology and Endoscopy, Head of Endoscopy Department of Petrovskie Vorota Medical Center, and Coloproctologist Daniil R. Markaryan, Cand. of Sci. (Med.), Senior Researcher, M.V. Lomonosov Moscow State University Clinic.

In recent years, functional disorders of the gastrointestinal tract (GIT) are quite common. The most significant functional disorders are functional dyspepsia (FD), which is widespread in the population. In addition, in the clinical practice of outpatient doctors, the proportion of combined variants or overlap of several types of functional disorders or a combination of functional disorders with organic pathology has increased. So, according to systematic reviews, the combined course of gastroesophageal reflux disease (GERD) and FD occurs in at least one third of patients. At the same time, the combined functional pathology of the gastrointestinal tract changes the clinical picture of GERD, which complicates differential diagnosis, leads to inadequate and multiple prescription of drugs and often low effectiveness of the prescribed therapy. All this negatively affects the quality of life of patients. The tactics of managing patients with the combined course of GERD and FD sometimes presents certain difficulties, since there are no available recommendations for pathogenetic therapy and preventive measures. To date, possible links in the pathogenesis of both GERD and FD have been studied and described, which predetermine certain approaches to the treatment of various variants of these two diseases. Drug therapy for GERD includes the appointment of proton pump inhibitors (PPIs), antireflux drugs. In FD therapy, prokinetics and/or PPIs are effective. A rational approach in the treatment of the intersection of GERD and FD is the appointment of a drug with a dual mechanism of action, which contains both a prokinetic and a PPI. An example of this approach is the appointment of omeprazole and domperidone. The use of this drug is presented in a clinical case.

Irritable bowel syndrome (IBS) – a recurrent functional disorder of the gastrointestinal tract (GIT), the main symptom of which is abdominal pain necessarily associated with a change in intestinal function. IBS is a functional intestinal disorder in which recurrent abdominal pain is associated with a defecation act and a change in the frequency or shape of the stool. The diagnosis of IBS remains exclusively clinical. The difficulty in studying IBS, especially from the perspective of its epidemiology, is that there is still no universal and specific biological marker. Very often patients complain about symptoms typical for several functional disorders, in particular, biliary tract pathology and IBS. The article discusses the multi-component causes and mechanisms of IBS formation, which are also present in other functional gastrointestinal tract diseases. Patients with IBS often have functional disorders of the biliary tract (FDBT) that are not associated with organic pathology. There are no reliable differences in the frequency and nature of FDBT in patients with IBS, depending on its current variant - with constipation or diarrhea prevalence. As a result, the treatment of patients with IBS remains a challenge, and the recurrence of the disease depends on the state of psycho-emotional health, the presence of overlap syndrome in most cases. The article presents the main international criteria for diagnostics of IBS. The main approaches to the treatment of IBS are considered. Good results in the treatment of IBS are observed when using drugs that affect the complex of pathophysiological mechanisms of the disease. This is confirmed in the article by a clinical case study. The prescription of the Sparex drug for pain relief in a patient with IBS and FDBT is justified by the fact that it not only eliminates pain, but also improves the rheological properties of bile, typical for overlap “IBS-FDBT” syndrome.

A review of current data suggests that the attention to the problem of dyspepsia is huge. The definition of functional dyspepsia was given in the Rome IV criteria, according to which two of its main options are distinguished – epigastric pain syndrome and postprandial distress syndrome. The term “uninvestigated dyspepsia” is important, which means the presence of dyspepsia symptoms in patients who have not performed diagnostic procedures to identify the organic causes of the pathology. The prevalence of uninvestigated dyspepsia in the world is about 21%. The prevalence of functional dyspepsia is significantly lower than the prevalence of uninvestigated dyspepsia and fluctuates around 10%. The risk factors for dyspepsia are usually tobacco smoking, non-steroidal anti-inflammatory drugs and/or aspirin, and Helicobacter pylori infection. The concept of the pathogenesis of functional dyspepsia undergoes significant changes. By analogy with the pathophysiology of irritable bowel syndrome, lesions of the relationship between the modulation of the cerebral cortex and the signal system of the gastroduodenal zone, the association of sluggish immune inflammation in the duodenum with motility and sensory activity of the stomach are most actively studied. The treatment of functional dyspepsia is a complex problem and changes after new ideas about its pathogenesis. Modern meta-analyzes have made it possible to expand the indications for the proton pump inhibitors administration, which can be actively used not only for the treatment of epigastric pain syndrome, but also for postprandial distress syndrome. Along with the required Helicobacter pylori eradication, there are reasons for the use of probiotics and antibiotics for the dyspepsia treatment.

Main groups of antisecretory drugs used in the treatment of acid-dependent diseases, including gastroesophageal reflux disease (GERD), are described in a review. Mechanisms of activation, degradation and inactive metabolites formation of proton pump inhibitors (PPIs) – final elements of acid production blockage – are considered in detail. Special attention is paid to the presence of PPIs’ derivatives with different functional activity: inactive derivatives, active and inactive metabolites. Topographic description of these derivatives, their significance in terms of an effect on bioavailability, clinical effectiveness and a potential of PPIs interactions with other administered drugs. The combined decision-making algorithm in the presence of gastroesophageal reflux disease symptoms is presented, compiled on the basis of the most authoritative current recommendations. This algorithm provides for the use of PPIs in standard doses once a day for 4–8 weeks with a possible dose escalation in a case of ineffectiveness. If treatment with high doses of PPIs is ineffective, a set of measures is needed to identify the causes of this inefficiency and to choose additional medical strategy. Depending on the clinical situation, after erosions epithelization the treatment can be stopped, used on demand, prolonged in the intermittent or supportive forms. Particular attention is paid to the Panum® drug, which has proven its effectiveness in patients with different degrees of reflux esophagitis. The availability of dosage forms for prescription and over-the-counter leave allows ensuring its comfortable and unhindered purchase by patients and eliminating excessive burden on the healthcare system.

Introduction. Statistical data indicate a frequent combination of functional biliary disorders with non-alcoholic fatty liver disease.

Aim. To study the efficacy and safety of Phosphogliv® URSO in patients with functional disorders of the gall-bladder, biliary sludge in combination with fatty hepatosis in comparison with the group receiving monotherapy ursodeoxycholic acid (UDCA).

Materials and methods. The study included 30 patients with a diagnosis of functional gall-bladder disorder, biliary sludge in combination with non-alcoholic fatty liver disease. Patients of the main group received monotherapy with Phosphogliv® URSO. The comparison group received monotherapy UDCA. After three-month therapy, the dynamics of clinical symptoms, laboratory parameters, and ultrasound parameters were assessed.

Results. Positive dynamics of clinical manifestations of functional disorders of the gallbladder, as well as parameters of cholestatic syndrome and bilirubin level was observed in both groups. In patients taking Phosphogliv® URSO, a significant decrease in cytolysis syndrome indicators was recorded, a significant difference was revealed in relation to an increase in HDL levels and a decrease in the atherogenic coefficient in the main group. When assessing the ultrasound parameters of the gall-bladder in patients of group 1, a significant decrease in the thickness of its wall, reverse development of biliary sludge, an improvement in the contractile function of the gall-bladder in comparison with the UDCA monotherapy group were revealed.

Conclusion. The use of a combined medicine containing glycyrrhizic acid and UDCA (Phosphogliv® URSO) can be recommended for patients with functional disorders of the gallbladder, biliary sludge and non-alcoholic fatty liver disease, given its more pronounced anticytolytic effect, restoration of functional disorders of the gallbladder and resolution of biliary sludge in comparison with monotherapy UDCA.

Introduction. Alcoholic liver disease (ALD) is the most common liver disease, the terminal stage of which is alcoholic liver cirrhosis (ALC), which ranks first in terms of prevalence and frequency of lethal outcomes in hospital patients. The pathogenesis of alcoholic liver disease is based on direct damage to the hepatocyte membrane, oxidative stress, hepatic parenchyma inflammation with hyperproduction of inflammatory mediators, immune mechanisms, hepatic parenchyma fibrosis. S-adenosyl-L-methionine (ademetionine) is able to affect the different parts of the pathogenesis of ALD. One of the new ademetionine drugs is Samelix (manufacturer – Canonfarma Production JSC, Russia).

Aim of the study. Evaluation of Samelix efficacy and safety in patients with chronic alcoholic liver disease with cholestasis syndrome at the inpatient stage of treatment.

Materials and methods. 23 patients (men – 11, women – 12) were admitted to the study. The average age was 51.8 ± 3.4 years. Duration of the disease in the remaining patients averaged 3.5 ± 1.9 years (from 0.5 to 8 years). All patients received detoxification therapy, vitamin therapy, and Verospiron was used in patients with liver cirrhosis. Within 10-12 days the therapy with Samelix was carried out: 800 mg/day intravenous drip. The dynamics of biochemical indices (ALT, AST, GGT, bilirubin, ALP); clinical manifestations; life quality according to the SF-36 questionnaire; side effects were assessed.

Conclusions. There was a significant reduction in the number of patients with skin itching, increased fatigue and depressed mood, positive dynamics of biochemical indicators in the form of a decrease in AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin. Thus, the therapy allows to effectively reduce symptoms in patients with alcoholic liver disease, resulting in an improvement on all scales and summary indicators – psychological and physical component of health.

The new American Association for the Study of Liver Diseases and Infectious Diseases Society of America recommendations for the management of hepatitis C patients are analyzed. To screen for viral hepatitis C, it is recommended that antibodies to the hepatitis C virus and RNA be detected in individuals with increased risk of infection. Patients with an increased risk of infection include people who inject narcotic drugs; patients with prolonged hemodialysis; health workers after contact with the blood or mucous membranes of a patient with viral hepatitis C; persons who received blood transfusions or blood components before 1987. In most patients, non-invasive tests can be used to diagnose liver fibrosis, which include physical examination, determination of serum fibrosis markers, including the FIB-4 index, ultrasound or computed tomography of the liver and liver elastography. The introduction of direct antiviral drug regimens significantly facilitated the treatment of viral hepatitis C and significantly increased the frequency of response to antiviral treatment. The development of combined pathogenetic regimens with a relatively short duration of treatment has become an important step in the management of patients with viral hepatitis C. New American recommendations suggest the use of pangenotypic regimens in patients with viral hepatitis C without fibrosis or with compensated liver cirrhosis: glecaprevir (300 mg)/pibrentasvir (120 mg) 3 pills per day within 8 weeks or the combination of sofosbuvir (400 mg)/velpatasvir (100 mg) 1 pill per day for 12 weeks with the expected response to therapy in 95–100% of patients. Review authors note a number of rational aspects of the new American recommendations, but consider that experienced and qualified specialists should treat patients with chronic viral hepatitis C in Russia.

Introduction. The increase in serum transaminases (ALT and AST) and the persistence of their high values is associated with morbidity and mortality from liver diseases. Bicyclol has anti-inflammatory and antioxidant effects, which formed the basis for this study.

Materials and methods. The study enrolled 51 patients (MELD < 19); hepatitis stage – 84.4%, cirrhosis – 15.6%. Treatment: Bicyclol 75 mg/day for 12 weeks. Criteria of efficacy: dynamics of ALT, AST, CRP; general well-being (D-FIS scale).

Results. After 4 weeks of treatment the share of patients with ALT normalization was 50,9% (p < 0,001); with AST normalization – 62.7% (p < 0.001); after 12 weeks - 79,5% and 89,7% respectively (p < 0,001). CRP decreased statistically significantly after 2 and 4 weeks from the beginning of treatment. The D-FIS questionnaire was filled in by 36 patients at the beginning of the study, in 4 weeks - by 35 patients, in 12 weeks – by 32 patients. Median D-FIS decreased from 12 (8.2; 32.2) to 8 (5; 29) points (p < 0,001) after 4 weeks of treatment, after 12 weeks – to 6.5 (3; 28.5) points (p < 0.001). The CRP was positively correlated with the D-FIS value. Fibrosis (“Fibromax”, “Fibroscan”) was studied in 10 additional patients, the dose of Bicyclol was 150/75 mg/day during 6 months, the result was statistically significant (p < 0.001).

Conclusion. Application of Bicyclol leads to reduction of fatigue, local and systemic inflammation, fibrosis in chronic diffuse liver diseases regardless of etiology.

The persistent post-cholecystectomy (CE) symptoms can be divided into four groups: 1) surgical errors; 2) recurrence of cholelithiasis; 3) functional disorders due to removal of the gallbladder (transient or persistent); 4) pathology not associated with CE. Biliary pain persists in 20–40% of patients after CE, in most cases caused by sphincter of Oddi dysfunction (SOD). SOD is subdivided into biliary, pancreatic, two-duct types, as well as pancreatobiliary reflux. The SOD is rooted in the increased pressure in the sphincter, which leads to the increased intraductal pressure and, as a result, to the occurrence of biliary or pancreatic pain. In addition, the direct contractile effects of cholecystokinin on smooth muscles of the biliary tract change due to mechanical disturbance of innervation. Hypertension of the pancreatic part of the sphincter of Oddi can cause not only the occurrence of functional pain of the pancreatic type, but also the development of recurrent pancreatitis. SOD is characterized by typical anamnestic data that are common to the functional pathology of the digestive system, such as duration of symptoms, absence of organic pathology, multiple complaints, a non-progressive course, the provoking role of psychoemotional factors. From a practical standpoint, the clinical criteria for SOD can be: 1) an attack of biliary or pancreatic pain; 2) a transient increase in the activity of hepatic or pancreatic enzymes; 3) transient expansion of the common bile or major pancreatic duct. If it is difficult to differentiate diagnosis, endoscopic ultrasonography is advisable. Antispasmodics and ursodeoxycholic acid form the basis of the treatment, especially when biliary sludge and microlithiasis are detected. There must be strong arguments for the surgical treatment.

Alcohol abuse with resultant alcoholic liver disease (ALD) are a leading cause of morbidity and mortality worldwide. Due to absence of clinical symptoms of the disease in the early stages, it is diagnosed in the later stages with higher complications and mortality rates. Diagnosis of ALD requires a better determination of life history and prognostic factors, as well as the search for reliable non-invasive techniques. Early detection of alcoholic steatohepatitis in primary care settings and subsequent interventions will facilitate the satisfaction of this requirement. Despite some important advances in understanding the pathogenesis and clinical features of ALD, the past 40 years have not seen significant advances in the therapy. The long-term alcohol abstinence is the main therapy for ALB patients, regardless of the disease stage. It is associated with improved clinical outcomes across the ALD spectrum: from asymptomatic early cases to complicated severe cases. Clinical ultimate outcomes depend on the ALD stage. The ultimate outcomes are associated with normalisation of abnormal laboratory test results and reduction in liver fibrosis in compensated patients. These ultimate outcomes can be monitored using non-invasive tools, but current medical interventions are largely limited and ineffective. Supportive therapy forms the basis of the treatment, it is worth paying special attention to combined herbal medicines as less toxic ones with single contraindications and consistent with the desire of many patients to use natural preparations.

Introduction. Functional gastrointestinal disorders (FGID) occupy one of the leading positions among intestinal pathologies. At present, scientific data indicate the lack of efficiency of existing methods of FGID treatment and the need for further research. This study is devoted to the assessment of the impact of STIM Lax and STIM treatment on clinical manifestations in patients with FC and FD.

Aim of the study. Evaluation of the effectiveness of biologically active additives (BAA) STIM and STIM Laks in 39 patients with functional gastrointestinal disorders. Objectives of the study: to evaluate the effect of the drug on clinical symptoms according to an individual diary and using specialized questionnaires with a score of symptoms before and after treatment.

Materials of the research. 39 patients divided into two groups were admitted to the research. Of these, 20 patients were with FC (4 men and 16 women; mean age – 40.3 ± 8.9 years). Monotherapy with STIM Laks was conducted (1 tablet 3 times a day for 30 days), and 19 FD patients (10 men and 9 women; mean age – 36.9 ± 14.1 years). Before and after the course of treatment a carbolene sample was conducted, stool form and frequency, intensity of flatulence, purring, transfusion, abdominal pain were clinically evaluated.

Results. Therapy of FС and FD with STIM and STIM Laks effectively reduces the frequency and intensity of clinical symptoms, normalizes the transit time of the carbolene sample, the frequency of stool. Increase of flatulence was observed in 7 (17.9%) patients, its resolution within 1–3 days led to a decrease in the dose of the drug, without affecting the end result.

Conclusions. This study indicates a high efficacy and good tolerability of treatment with STIM Laks and STIM in patients with FGID.

Introduction. Constipation is a derangement of the motor, secretory and/or evacuation function of the colon. The same symptoms are recorded in at least 20% of the population in the developed countries – as those occurring sporadically or for a long period.

Basic content. The secretory function of the colon significantly affects stool consistency and its free movement. The secretion increases by 8–10 times in the presence of local mechanical irritation.  Intestinal mucus is produced by colonic goblet cells. The frequency, time of defecation and stool consistency is in large part determined by the motor function of the colon. The relation of various types of contraction varies depending on the main function – propulsion or mixing. Rhythmic phasic contractions in the colon generate a pendular movement with slow propulsion of the contents and absorption of water. The tonic contractions enhance the mixing effect of weak rhythmic contractions. The propulsive contractions are specifically attributed to the lower gastrointestinal tract and occur spontaneously. They occur quite regularly, from 2 to 10 times a day, and ensure the propulsion of intestinal contents over great distances in the colon. When reaching the sphincter area, such wave causes its relaxation by mechanisms of descending inhibition. The dietary regime and adequate intake of carbohydrates with various chain lengths, including dietary fiber, as well as flavonoids and other components that modify peristaltic activity and secretion, play an important role in the regulation of intestinal secretion and peristalsis. The drugs enhancing intestinal secretion and peristalsis, such as bisacodyl and sodium picosulfate, are also used to treat constipation. These substances hydrolyse into bis-(p-hydroxyphenyl)-pyridyl-2-methane in the intestine, which, upon contact with the receptors in colonic mucosa, stimulates propulsive activity and increases intestinal secretion. The selective action of sodium picosulfate is confined to the colon.

Conclusion. Pharmacological and non-pharmacological treatments for constipation are aimed at maintaining and enhancing the natural propulsive contractions of the colon and intestinal secretion.

Ulcerative colitis and Crohn’s disease are severe immune-mediated diseases. Extraintestinal manifestations of inflammatory bowel disease (IBD) significantly increase the burden to the patient. The most common extraintestinal manifestations include erythema nodosum, ankylosing spondylitis, and primary sclerosing cholangitis. Some of the extraintestinal manifestations depend on the activity of the inflammatory process in the intestine and can be reversed during treatment of IBD, while the others require specific therapy, since it does not depend on the degree of inflammation in the intestine. Patients with IBD are at increased risk of developing complications caused by other organ systems, such as osteoporosis, venous thromboembolism, and cardiovascular diseases. Immunemediated diseases such as multiple sclerosis and psoriasis have been associated with inflammatory bowel disease, but these conditions can also be complications of IBD therapy. In this regard, patients and healthcare providers should exercise vigilance in identifying extraintestinal manifestations and complications of IBD, and the therapy should be aimed both at treating the underlying disease and reversing extraintestinal manifestations as much as possible. Interleukin-12/23 is an important cytokine in the inflammatory process development in the immune-mediated diseases. Ustekinumab is effective in treating not only IBD, but also psoriasis by blocking interleukin 12/23. The drug shows a higher survival index of the therapy as compared to tumour necrosis factor-α inhibitors. The article describes the experience of using ustekinumab in severe concomitant pathology – Crohn’s disease in the form of ileocolitis and psoriasis vulgaris with initial manifestations of psoriatic arthritis against ineffectiveness of tumour necrosis factor-α inhibitors.

Introduction. Despite improvements in earlier diagnosis and the development of conservative therapy for Crohn’s disease (CD), approximately 70%–80% of patients undergo surgical treatment for complications. Surgical treatment is not a cure for this disease. The question of choosing therapy as a prevention of postoperative relapse of CD is still open. AIM. To compare the effectiveness of immunosuppressive and biological therapy as a postoperative preventive therapy.

Materials and methods. The retrospective study included 125 patients with CD who underwent surgery in terms from 2010 to 2017. After the operation, patients were divided into 3 groups. Patients from the first group received azathioprine, from the second - adalimumab, and patients from the third group were prescribed combined therapy with azathioprine and adalimumab. Clinical, endoscopic, and laboratory data for analysis of disease activity was collected 3, 6, and 12 months after surgery.

Results. During the year of therapy in all three groups relapses occurred in only 22 patients (22/125 17.6%). There were no statistically significant differences between the groups at any of the assessment stages. There was also no statistically significant correlation between the presence of risk factors and relapses.

Conclusion. Our research has shown that the choice of anti-relapse therapy depending on risk factors is controversial. However, active endoscopic monitoring is important regardless of the treatment strategy. Also, our data allow us to conclude that the frequency of relapses of CD during the postoperative preventive therapy does not depend on the specific drug chosen, as well as on demographic and anamnestic parameters.

Today, there is an explosion of discoveries related to a growing understanding of the role of microbial communities, key species of bacteria, products or metabolites derived from commensals, and in particular the relationship between some of these components and painful conditions in humans. Microbiota plays a fundamental role in the induction, training and functioning of the host’s immune system. In turn, the immune system has evolved significantly as a means of maintaining the host’s symbiotic relations with these very diverse and developing microbes. At optimal performance, this alliance of the immune system and microbiota allows to induce protective reactions to pathogens and maintain regulatory pathways involved in maintaining tolerance to harmless antigens. In this review, we outline the role of the intestinal microbiota in the immune system, starting with initial information supporting further insights into the effects of intestinal microbiota dysbacteriosis on the host’s susceptibility to infection. Probiotics are considered a good form of therapy to control harmful intestinal microorganisms, improve digestion and the absorption of nutrients. The beneficial effects of probiotics have been demonstrated in many diseases. One of the main mechanisms of probiotics is the regulation of the immune response of the host. The article reviews and discusses the regulatory role of probiotics in the “intestine-lungs” system and the immune system of mucous membranes for potential antiviral mechanisms. The unique role of probiotics in modulation of intestinal microbes and establishment of intestinal homeostasis and production of interferon as antiviral mechanism is described. In addition, the regulatory role of probiotics in the system «intestine-lungs» and the immune system of the mucous membranes for potential antiviral mechanisms, including in COVID-19 is considered and discussed. Symbiotic products Bac-Set® Forte and Bac-Set® Cold/Flu are described.

Introduction. The article examines disorders of the digestive function, diet regimes, appetite in conditions of prolonged self-isolation and quarantine during a coronavirus pandemic. The article analyzes the clinical efficacy and safety of the use of specialized dietary therapeutic and dietary preventive food products in conditions of self-isolation and quarantine.

Methods. A survey was conducted of 620 individuals of various ages who were in self-isolation and quarantine from 1 to 1.5 months. All participants were questioned, examined by a gastroenterologist and therapist, biochemical and clinical blood tests, endoscopic examination of the stomach and duodenum, ultrasound of the abdominal organs.

Results. A survey of 620 individuals showed that self-isolation / quarantine can lead to changes in diets, dietary patterns, changes in eating habits, the development of a number of symptoms from the gastrointestinal tract and other organs, changes in body weight, and chronicity. a number of previously existing diseases. The use of dietary food leads to an improvement in the antitoxic function of the liver, anti-inflammatory effects, and an improvement in the symptoms of gastrointestinal diseases.

Discussion. Clinical and laboratory data make it possible to state the need for the use of specialized dietary products of domestic production in the diet prophylactically in people from risk groups, as well as in patients with various diseases of the gastrointestinal tract both during illness and for the purpose of rehabilitation.

Conclusion. Data on the efficacy and safety of dietary food products give reason to recommend them for inclusion in the diets of patients infected with SARS-CoV-2, both during illness, in order to prevent complications and improve the effectiveness of treatment and subsequent rehabilitation of patients, as well as for the rehabilitation of individuals, who were in self-isolation and quarantine for a long time.