COVID-19 increases extracorporeal coagulation during hemodialysis associated with upregulation of vWF/FBLN5 signaling in patients with severe/critical symptoms.

BACKGROUND: COVID-19 has been shown to increase the risk of extracorporeal coagulation during hemodialysis in patients, but the underlying mechanism remains unclear. This study aimed to investigate the effect and mechanism of COVID-19 on the risk of extracorporeal coagulation in patients with chronic kidney disease undergoing hemodialysis. METHODS: A retrospective analysis of the extracorporeal coagulation status of 339 hemodialysis patients at our center before and after COVID-19 infection was performed, including subgroup analyses. Post-infection blood composition was analyzed by protein spectrometry and ELISA. RESULTS: Compared to the pre-COVID-19 infection period, COVID-19-induced extracorporeal coagulation predominantly occurred in patients with severe/critical symptoms. Further proteomic analysis demonstrated that in patients with severe/critical symptoms, the coagulation cascade reaction, platelet activation, inflammation, and oxidative stress-related pathways were significantly amplified compared to those in patients with no/mild symptoms. Notably, the vWF/FBLN5 pathway, which is associated with inflammation, vascular injury, and coagulation, was significantly upregulated. CONCLUSIONS: Patients with severe/critical COVID-19 symptoms are at a higher risk of extracorporeal coagulation during hemodialysis, which is associated with the upregulation of the vWF/FBLN5 signaling pathway. These findings highlight the importance of early anticoagulant therapy initiation in COVID-19 patients with severe/critical symptoms, particularly those undergoing hemodialysis. Additionally, vWF/FBLN5 upregulation may be a novel mechanism for virus-associated thrombosis/coagulation.

The Level of Fear Experienced by the Individuals and their Applications to Health Institutions during the Covid-19 Pandemic.

AIM: The study aims to investigate the effect of the level of fear experienced by individuals during the COVID-19 pandemic on their application to health institutions. METHOD: This descriptive study was conducted between July and September 2020 with the participants who met the inclusion criteria in Turkey. When the mean COVID-19 Fear Scale score was considered and the standard deviation values ​​were taken as 18.83 ± 6.01, the sample size was determined as 98 individuals, with 95% confidence level, 90% test power, and 0.331 effect size. With the snowball sampling method, the study was carried out with 577 people who filled out the Google form. The Personal Information Form and the COVID-19 Fear Scale were used as data collection tools. The data were analyzed with SPSS 20.0. Descriptive statistics, correlation, Mann-Whitney U (U), and Kruskal-Wallis tests were performed to analyze the data. Ethics committee approval was obtained prior to the study. RESULTS: The mean age of the participants was 32.06 ± 11.25 (min 18-max 71); 77.8% were female; 66% were university graduates, and 54.9% were single. The total mean score of the participants from the COVID-19 Fear Scale was determined as 16.84 ± 5.68 (min 7-max 34), which points to moderate level of fear. The COVID-19 Fear Scale scores of the female participants, the participants with high income, and those living with their families were found to be higher (p < 0.05). The COVID-19 Fear Scale scores were found to be higher in those who sleep less than 7 hours a day, who have a psychological disorder, who applied to health institutions during the coronavirus process, and who postponed their application to health institutions in an emergency due to the fear of infection (p < 0.05). CONCLUSION: It has been determined that during the coronavirus process, 21.5% of individuals attend in person to health institutions and 40.7% of individuals attend in person to health institutions in emergencies. It was found that the level of fear was higher in the participants who applied to health institutions during the pandemic. The participants who postponed their application to health institutions in emergencies due to the fear of infection were found to have higher levels of fear.

[Exudative pericarditis with tamponade after COVID-19. Case report].

A description of a COVID-19 patient with the development of exudative pericarditis complicated by cardiac tamponade is provid. A peculiarity of this case is the presence of an underlying disease in the patient (chronic lymphocytic leukemia), which was in remission for 1.5 years after chemotherapy. Another feature of the patient was the relatively small area of lung damage and the hemorrhagic nature of the pericardial effusion, which persisted for a long time. The insignificant activity of inflammatory markers was noteworthy. Possible mechanisms of development and features of the course of exudative pericarditis in the described patient, issues of diagnosis and treatment of this category of patients are discusse.

[Impact of the SARS-CV-2 virus on the urinary bladder].

INTRODUCTION: There are publications about the impact of a new coronavirus infection (COVID) on the lower urinary tract, including the development of overactive bladder (OAB) or COVID-associated cystitis. The cause of dysuria in patients with COVID is not fully understood. MATERIAL AND METHODS: A total of 14 consecutive patients after COVID with complaints of frequent urination with urgency were included in the study. The main inclusion criterion was the development or worsening of OAB symptoms after resolution of COVID, confirmed by the eradication of SARS-CoV-2 by a polymerase chain reaction. The severity of OAB was assessed using the International Scale of Symptoms (Overactive Bladder Symptom Score, OABSS). RESULTS: Three (21.4%) out of fourteen patients had OAB symptoms prior to COVID, while in 11 (78.6%) patients OAB symptoms developed in post-COVID period. In 4 patients (28.6% of the entire cohort and 36.4% of patients in de novo group) urge urinary incontinence and urgency developed. The average score on the OABSS scale in patients with baseline OAB was 6.7+/-0.8, which corresponded to the moderate severity. In this group, one patient developed urge urinary incontinence and urgency, which were not present prior to COVID. In a retrospective evaluation of symptoms before the COVID, their average score on the OABSS scale was 5.2 +/- 0.7, i.e., past COVID led to an increase in OAB symptoms by 1.5 points. In patients with OAB de novo, the symptoms were less pronounced, with a score of 5.1+/-0.6 points, that is between mild and moderate OAB. At the same time, urinalysis in 9 patients did not have signs of inflammation: in 5 cases, 5-7 white blood cells per field of view was seen only once. A follow-up urine test was normal, suggesting contamination. None of the cases revealed bacteriuria over 102 CFU/ml. All patients were prescribed trospium chloride at a dose of 30 mg per day. The choice of the drug was due to the absence of a negative effect on the central nervous system, which is very important both during COVID and in post-COVID period, since the neurotoxicity of SARS-CoV-2 has been proven. CONCLUSION: A past history of COVID led to an increase in OAB symptoms by 1.5 points in patients who had OAB prior to infection. In 11 patients, after the treatment of COVID, the moderate symptoms of OAB developed de novo. Our small study showed the importance of focusing the attention of internists and infectious disease doctors on urination disorders in patients with COVID and timely referral to a urologist. For the treatment of post-COVID OAB, trospium chloride is the drug of choice, as it does not aggravate the potential neurotoxicity of SARS-CoV-2.

[Venous gangrene of small intestine following coronavirus infection (SARS-COVID-19)]. / Venoznaya gangrena tonkoi kishki na fone koronavirusnoi infektsii (SARS-COVID-19).

The pandemic of a new coronavirus infection has made certain adjustments to modern emergency medicine. Systemic endothelial dysfunction following COVID-19 largely determines hemostatic disorders. Numerous studies revealed that intense platelet adhesion followed by platelet aggregates in COVID-19 patients and functional disorders of fibrinolysis system are combined with activation and severe endothelial dysfunction. The last one inevitably leads to thrombosis and adverse vascular events. There are a lot of studies devoted to deep vein thrombosis and fatal massive pulmonary embolism under COVID-19 infection. However, there are no descriptions of mesenteric thrombosis followed by intestinal wall necrosis. Our experience is based on the treatment and follow-up of 14 patients with venous gangrene of small intestine under COVID-19-induced severe endothelial dysfunction. We present a 40-year-old man with coronavirus infection complicated by ileum gangrene and subsequent favorable outcome.

[Features of surgical patients of COVID-19 patients]. / Osobennosti khirurgicheskogo lecheniya bol'nykh COVID-19.

The novel coronavirus pandemic has significantly increased the workload of surgical service worldwide. Restrictive measures led to postponement of elective surgical and diagnostic interventions and reduced the number of emergency manipulations around the world. Large-scale studies identified optimal period for postponing surgical procedures and advisability of this postponement. The authors present opinions of surgeons and their views on treatment strategy for various elective and emergency surgical interventions in abdominal surgery, traumatology-orthopedics and oncology. The main factors reducing perioperative mortality in patients with a new coronavirus infection are observance of anti-epidemic measures by patients and medical personnel, competent use of personal protective equipment, as well as adherence to protocols and algorithms for the treatment of these patients.

[The determinants of vaccination against the new coronavirus infection (COVID-19) of residents of the circumpolar region of Russia].

The maintenance of health of residents of the Northern Regions of Russia, including those living in the Arctic zone of the cbountry, is a condition of its advance development in XXI century. The percentage of Russian citizen vaccinated against the new coronavirus infection (COVID-19) does not exceed 50% after beginning of implementation of vaccination program. It can be conditioned by lower level of both of credence of citizen to health care system and health literacy.Purpose of the study is to establish determinants of vaccination of population against COVID-19 in circumpolar region of Russia as exemplified by the Arkhangelsk Oblast.The sociological survey was carried out using the interview technique of patients of medical organizations (n=433) and conditionally healthy residents of the Arkhangelsk Oblast (n=139). To evaluate the level of general health literacy the Russian version of questionnaire HLS19 - Q22-RU was applied. The most of conditionally healthy respondents and consumers of medical services looked for information about methods of prevention and treatment (80.4% and 58.2% correspondingly), had an experience of vaccination against COVID-19 (79% and 56.3% correspondingly). The relative chances of conditionally healthy respondents, women, and respondents having no children and no credence to national health care system to independently look for information related to COVID-19 is higher at 2.94, 2.08, 1.55 and 1.48-1.57 times correspondingly. The relative chances of conditionally healthy respondents having no children in family and assessing one's economic status as "higher than average" to be vaccinated against COVID-19 is higher at 4.02, 1.52, 1.53 times correspondingly. Availability of experience of vaccination against COVID-19 is conditioned by higher level of general health literacy.In the Arkhangelsk Oblast and other circumpolar regions of Russia the programs of increasing loyalty of citizen to measures of population prevention, including vaccine prevention, is to be implemented with consideration of established determinants of of vaccinations against COVID-19.

The global transmission of new coronavirus variants.

Coronavirus Disease 2019 (COVID-19) has caused tremendous losses to the world. This study addresses the impact and diffusion of the five major new coronavirus variants namely Alpha, Beta, Gamma, Eta, and Delta lineage. The results of this study indicate that Africa and Europe will be affected by new coronavirus variants the most compared with other continents. The comparative analysis indicates that vaccination can contain the spread of the virus in most of the continent, and non-pharmaceutical interventions (NPIs), such as restriction on gatherings and close public transport, will effectively curb the pandemic, especially in densely populated continents. According to our Global Prediction System of COVID-19 Pandemic, the diffusion of delta lineage in the US shows seasonal oscillation characteristics, and the first wave will occur in October 2021, with the record of 323,360, and followed by a small resurgence in April 2022, with the record of 184,196, while the second wave will reach to 232,622 cases in October 2022. Our study will raise the awareness of new coronavirus variants among the public, and will help the governments make appropriate directives to cope with the new coronavirus variants.

Power system load forecasting using mobility optimization and multi-task learning in COVID-19.

Affected by the new coronavirus (COVID-19) pandemic, global energy production and consumption have changed a lot. It is unknown whether conventional short-term load forecasting methods based on single-task, single-region, and conventional indicators can accurately capture the load pattern during the COVID-19 and should be carefully studied. In this paper, we make the following contributions: 1) A mobility-optimized load forecasting method based on multi-task learning and long short-term memory network is innovatively proposed to alleviate the impact of the COVID-19 on short-term load forecasting. The incorporation of mobility data and data sharing layers potentially reduces the difficulty of capturing the load patterns and improves the generalization of the load forecasting models. 2) The real public data collected from multiple agencies and companies in the United States and European countries are used to conduct horizontal and vertical tests. These tests prove the failure of the conventional models and methods in the COVID-19 and demonstrate the high accuracy (error mostly less than 1%) and robustness of the proposed model. 3) The Shapley additive explanations technology based on game theory is innovatively introduced to improve the objectivity of the models. It visualizes that mobility indicators are of great help to the accurate load forecasting. Besides, the non-synchronous relationships between the indicators' correlations and contributions to the load have been proved.

[A new approach in the diagnosis of lung lesions in patients with COVID-19: lung ultrasound protocol versus CT scan].

AIM: To develop a protocol for ultrasound diagnostics of COVID-19 pneumonia and to assess the diagnostic capabilities of the method in comparison with computer tomography (CT). MATERIALS AND METHODS: The study included 59 patients with a new coronavirus infection. In order to identify changes in the lung tissue characteristic of a new coronavirus infection, we used a special protocol for ultrasound of the lungs, which was developed by us in such a way that the data obtained were compared by segment with the results of CT of the lungs. RESULTS: When comparing the results of lung ultrasound with the data of CT diagnostics, according to the new protocol, the percentage of lung tissue damage during ultrasound of the lungs averaged 70.8% in the group [62.5; 87.5], and according to the results of CT 70.0% [60.0; 72.5] (p=0.427). Thus, the ultrasound of the lung lesions was almost completely consistent with the changes revealed by CT. In order to assess the diagnostic value of lung ultrasound in identifying severe lung tissue lesions corresponding to CT 34, ROC analysis was performed, which showed the high diagnostic value of lung ultrasound in identifying severe lung tissue lesions. CONCLUSION: A new protocol was developed for assessing the severity of lung tissue damage according to ultrasound data, which showed a high diagnostic value in detecting COVID-19 pneumonia in comparison with CT. The results obtained give reason to recommend this protocol of ultrasound of the lungs as a highly sensitive method in diagnosing the severity of COVID-19 pneumonia. Its application is very important for dynamic examination of patients, especially in conditions of low availability of CT.

[Diagnostic and treatment difficulties in kidney damage in the patient with generalized sarcoidosis during COVID-19. Case report].

The presented clinical observation reflects the difficulties of differential diagnosis of progressive kidney damage in a patient with sarcoidosis who has undergone a new coronavirus infection. The differential circle included interstitial nephritis as an exacerbation of the underlying disease, acute drug-induced kidney injury, acute glomerulonephritis. Nephrobiopsy confirmed the diagnosis of acute sarcoid tubulointerstitial nephritis with acute tubular necrosis. Timely administration of corticosteroids led to the control of the sarcoidosis process, restoration of kidney function.

[Informativeness estimation for the main clinical and laboratory parameters in patients with severe COVID-19].

AIM: To conduct a retrospective assessment of the clinical and laboratory data of patients with severe forms of COVID-19 hospitalized in the intensive care and intensive care unit, in order to assess the contribution of various indicators to the likelihood of death. MATERIALS AND METHODS: A retrospective assessment of data on 224 patients with severe COVID-19 admitted to the intensive care unit was carried out. The analysis included the data of biochemical, clinical blood tests, coagulograms, indicators of the inflammatory response. When transferring to the intensive care units (ICU), the indicators of the formalized SOFA and APACHE scales were recorded. Anthropometric and demographic data were downloaded separately. RESULTS: Analysis of obtained data, showed that only one demographic feature (age) and a fairly large number of laboratory parameters can serve as possible markers of an unfavorable prognosis. We identified 12 laboratory features the best in terms of prediction: procalcitonin, lymphocytes (absolute value), sodium (ABS), creatinine, lactate (ABS), D-dimer, oxygenation index, direct bilirubin, urea, hemoglobin, C-reactive protein, age, LDH. The combination of these features allows to provide the quality of the forecast at the level of AUC=0.85, while the known scales provided less efficiency (APACHE: AUC=0.78, SOFA: AUC=0.74). CONCLUSION: Forecasting the outcome of the course of COVID-19 in patients in ICU is relevant not only from the position of adequate distribution of treatment measures, but also from the point of view of understanding the pathogenetic mechanisms of the development of the disease.

[New opportunities for preventive anti-inflammatory therapy in the management of patients with moderate and severe COVID-19].

The specific feature of new coronavirus infection (COVID-19) is high risk of hyperinflammatory response or cytokine storm development, which underly the pathogenesis of several life-threatening conditions and determine the disease outcomes. Pathophysiological features of COVID-19 justify the search of effective drugs capable to control the hyperinflammatory response. AIM: To evaluate the efficacy and safety of Aterixen (1-[2-(1-Мethylimidazol-4-yl)-ethyl]perhydroazin-2,6-dion) for achieving clinical improvement in adult patients hospitalized with moderate and severe COVID-19. MATERIALS AND METHODS: Multicenter, adaptive, randomized, double-blind, placebo-controlled, phase III study to evaluate the efficacy and safety of Aterixen , tablets, 100 mg, in patients with COVID-19. The study analysis included 116 patients who, by randomization, were divided into 2 groups: 57 patients were included in the Aterixen drug group and 59 patients were in the placebo group. RESULTS AND CONCLUSION: Obtained results have shown high efficacy and statistically significant superiority of Aterixen over placebo. Thus, it allows us to consider it as viable medication for COVID-19 pathogenetic therapy.

[Coronavirus infection and risk of postoperative venous thromboembolic events]. / Koronavirusnaya infektsiya i risk posleoperatsionnykh venoznykh tromboembolicheskikh sobytii u khirurgicheskikh bol'nykh.

OBJECTIVE: To determine whether patients with perioperative or previous coronavirus infection (CVI) have a greater risk of venous thromboembolic events (VTE). MATERIAL AND METHODS: A multiple-center regional prospective retrospective cohort study included elective and emergency patients who underwent surgery in November 2020. The primary endpoint was VTE (PE/DVT) within 30 days after surgery. CVI was stratified as perioperative (7 days before surgery - 30 days after surgery), recent (1-6 weeks before surgery) and remote (≥7 weeks before surgery) infection. There was no information about prevention or preoperative anticoagulation at baseline data collection. RESULTS: Incidence of postoperative VTE was 1.5% (10/650) in patients without CVI, 33.3% (3/9) in patients with perioperative CVI, 18.1% (2/11) in patients with recent CVI and 8.3% (1/12) in patients with remote CVI. After adjusting the confounders, patients with perioperative and recent CVI remained at a higher risk of VTE. In general, VTEs were independently associated with 30-day mortality. In patients with CVI, mortality rate among ones without VTE was 21.7% (5/23), with VTE - 44.4% (4/9). CONCLUSION: Patients with perioperative CVI have a higher risk of postoperative VTE compared to those without CVI and patients with previous CVI and no residual symptoms. Mortality in this group is also higher than in other cohorts.

[Emergency surgery under Covid-19 pandemic and its influence on postoperative outcomes]. / Ekstrennaya khirurgiya v usloviyakh pandemii Covid-19 i ee vliyanie na iskhody khirurgicheskogo lecheniya.

OBJECTIVE: To analyze the effectiveness of emergency surgical care under COVID-19 pandemic and its impact on postoperative outcomes. MATERIAL AND METHODS: We analyzed the results of treatment of 1.749 patients who were treated from May 01 to September 30 in 2018-2020. The study group consisted of 48 COVID-19 patients with urgent surgical diseases. The control group consisted of patients with emergency surgical diseases and no coronavirus infection. RESULTS: The new coronavirus infection significantly increases in-hospital mortality by 8 times and postoperative mortality by 6.5 times compared to pre-pandemic period. CONCLUSION: Emergency surgical care to COVID-19 patients is accompanied by increase of in-hospital mortality up to 31.3% and postoperative mortality up to 33.3%.

[Hybrid revascularization in a patient with Covid-19 and chronic limb ischemia stage IV]. / Gibridnaya revaskulyarizatsiya u patsienta s COVID-19, khronicheskoi ishemiei nizhnei konechnosti IV stepeni.

The authors report hybrid treatment of a patient with angina pectoris class II, multiple previous reconstructive interventions on the aortofemoral segment and chronic ischemia of the left lower limb stage IV and concomitant COVID-19. Coronary angiography was performed after regression of infectious disease under antiviral therapy. Occlusion of the left anterior descending artery was observed that required LAD stenting. On the next day, hybrid revascularization of the lower extremities was implemented: thrombectomy and endarterectomy from the branch of the aorto-femoral bypass graft and deep femoral artery at the first stage, stenting of the orifice of proximal branch of aorto-femoral bypass graft at the second stage, endarterectomy from superficial femoral artery, recanalization and stenting of superficial femoral artery and popliteal artery at the third stage and prosthetic- femoral bypass with autologous vein at the fourth stage. Postoperative angiography revealed patent stents and no residual stenoses. The choice in favor of these procedures and step-by-step approach has been substantiated. The authors emphasized effectiveness and safety of this treatment strategy.

[Influence of therapeutic exercises and hardware massage in electrostatic field on lung damage in patients with novel coronavirus pneumonia]. / Otsenka vliyaniya lechebnoi gimnastiki i apparatnogo massazha v elektrostaticheskom pole na stepen' porazheniya legkikh u patsientov s pnevmoniei pri novoi koronavirusnoi infektsii.

OBJECTIVE: To analyze the efficacy and safety of therapeutic exercises and chest hardware massage in electrostatic field in patients with COVID-associated viral pneumonia. MATERIAL AND METHODS: We retrospectively analyzed 1551 patients admitted to the Clinical Hospital No. 1 (MEDSI Group JSC) with COVID-associated pneumonia between April 01, 2020 and June 15, 2021 (ICD-10 U07.1 and U07.2). Considering inclusion and exclusion criteria, we enrolled 153 patients. All patients were divided into comparable groups and subgroups depending on the methods of rehabilitation treatment and CT stage of viral pneumonia. Lung damage was assessed semi-automatically using Philips Portal v11 COPD software. Rehabilitation measures included therapeutic exercises and chest hardware massage in electrostatic field. therapeutic exercises. RESULTS: Therapeutic exercises significantly reduced severity of lung damage in patients with viral pneumonia CT-2 and no oxygen support (from 28.05% [28; 29.5] at admission to 15.3% [14.2; 19.3] at discharge). It was not observed in patients without rehabilitation treatment and in patients undergoing therapeutic exercises and massage in electrostatic field. CONCLUSION: Therapeutic exercises in patients with COVID-19 and baseline lung damage > 25% and < 50% (CT-2 stage) significantly reduce severity of lung damage at discharge compared to the control group.

The critical role of mesenchymal stromal/stem cell therapy in COVID-19 patients: An updated review.

New coronavirus disease 2019 (COVID-19), as a pandemic disaster, has drawn the attention of researchers in various fields to discover suitable therapeutic approaches for the management of COVID-19 patients. Currently, there are many worries about the rapid spread of COVID-19; there is no approved treatment for this infectious disease, despite many efforts to develop therapeutic procedures for COVID-19. Emerging evidence shows that mesenchymal stromal/stem cell (MSC) therapy can be a suitable option for the management of COVID-19. These cells have many biological features (including the potential of differentiation, high safety and effectiveness, secretion of trophic factors and immunoregulatory features) that make them suitable for the treatment of various diseases. However, some studies have questioned the positive role of MSC therapy in the treatment of COVID-19. Accordingly, in this paper, we will focus on the therapeutic impacts of MSCs and their critical role in cytokine storm of COVID-19 patients.

[Pulmonary arterial hypertension: achievements and realities of modern treatment, a look into the future].

The paper summarizes the most important aspects of modern treatment of patients with pulmonary arterial hypertension (PAH): the goals of therapy are indicated, the issues of risk stratification of PAH progression/mortality, the place of combination specific therapy and switching strategies are considered, as well as new promising approaches to therapy; features of the course of the new coronavirus infection COVID-19 in this category of patients are discussed.

[Assessment of the influence of different factors on the risk of the development of a new coronavirus infection in patients with contrast induced acute kidney injury].

AIM: The main aim of our study was to assess the role of risk factors in patients with previous contrast induced acute kidney injury (CI-AKI) on a probability of a development of the new coronavirus infection. MATERIALS AND METHODS: Our study includes 65 patients with the history of CI-AKI after coronary angiography from 2013 to 2017 years; 10 of them had a new coronavirus infection, which had developed before November 2020. CI-AKI was defined as an increase of 25% or more, or an absolute increase of 0.5 mg/dl or more in serum creatinine from baseline value, assessed at 48 hours following the administration of the contrast. The primary endpoint was the development of a new coronavirus infection. RESULTS: We found statistically significant difference in the prevalence of the allergic reaction to iodine (р=0.0178) between non-COVID and COVID-patients group. Also, there were statistically significant differences in the secondary endpoints: renal replacement therapy (р=0.0178) and repeated percutaneous coronary intervention in the last year (р=0.0112) were more common among patients with coronavirus. The difference in the prevalence of arterial hypertension was near to statistical significance (р=0.0882). CONCLUSION: COVID-patients with CI-AKI had more allergic reactions to iodine than non-COVID patients. The trend of more common arterial hypertension between COVID-patients was found in our research. There were not any statistical significant differences in other risk factors. There were statistically significant difference in the secondary endpoints such as repeated percutaneous coronary intervention and renal replacement therapy. Other endpoints didnt show a statistically significant difference.