مجله دانشگاه علوم پزشکی مازندران
پیاپی 220 (اردیبهشت 1402)

Topical antibiotic medication is an alternative method in treatment of local infections, especially osteomyelitis. Currently several biomaterials are used for this purpose. The present study focused on the fabrication and characterization of chitosan and Vancomycin (VCM)-loaded chitosan (CS)-hydroxyapatite (HA)-gelatin (G) bead in treatment of osteomyelitis.

CS/G/HA/VCM scaffold was prepared by cross-linking using ionotropic gelling. The morphological and mechanical properties, loading efficiency and antibacterial properties were investigated and toxicity assay of fabricated structure was also analyzed.

The lyophilization reduced the area, environment, and sphericity of beads. CS/G/HA/VCM structure showed smaller area (4.5 mm2) and perimeter (180 µm) compared to other structures. Suitable morphology and porosity in fabricated beads were confirmed by SEM images in CS/G/HA and CS/G structures. Reduction of strength was observed after adding VCM into fabricated structure, but this happened less in CS/G/HA/VCM structure. Release on day 14 was 58% for CS/G/HA/VCM structure. AddingVCM into CS/VCM (1.88 Mpa) and CS/G/VCM (10.46 Mpa) structures decreased the mechanical strength while it increased the mechanical strength in CS/G/HA/VCM (83.21 Mpa) structure. No toxic activity of fabricated structures was seen against NIH 3T3 cells. The results of the antimicrobial activity against Staphylococcus aureus showed that chitosan beads containing VCM (CS/VCM, CS/G/VCM, CS/G/HA/VCM) could significantly inhibit the growth of S. aureus compared to the positive control (VCM 5%)(P<0.001).

conclusion: 

According to current study, the CS/G/HA/VCM structure can be introduced as a promising candidate in treatment of osteomyelitis.

Daunorubicin is an effective drug in chemotherapy, but its clinical use is limited due to serious side effects. Royal jelly as a natural compound obtained from bees can be helpful in preventing the damage caused by daunorubicin. The present study aimed to evaluate the effects of royal jelly on the number of apoptotic cells and the expression of genes involved in apoptosis in mice treated with daunorubicin.

In this experimental study, 77 Balb/c mice were randomly divided into seven groups (n= 11 per group): sham, control, royal jelly (50 and 100 mg/kg), daunorubicin (2 mg/kg), and royal jelly (50 and 100 mg/kg) + daunorubicin. The mice received saline (0.09%), IP daunorubicin, and royal jelly orally for eight weeks. To estimate the number of apoptotic cells and the expression of genes related to apoptosis in testis, we used ELISA test and Real-time PCR assay, respectively. Data analysis was done applying One-way Analysis of Variance and Tukey's test in SPSS.

Daunorubicin caused significant increase in the number of apoptotic cells, and expression levels of p53, Bax, caspase 3, caspase 8, and caspase 9 (P<0.01) and a significant decrease in the bcl-2 gene expression (P<0.01).  In treatment groups, these changes were moderated by royal jelly.

Royal jelly administration, by reducing the number of apoptotic cells and affecting the expression of genes involved in apoptosis, improves the damage caused by daunorubicin on the testicular tissue of mice.

It is well established that valproic acid (VPA) is teratogenic associated with oxidative stress in humans and in all animal species tested. In this study, considering the chemical composition of catechins, we investigated its protective effect on the survival of PC12 nerve cells exposed to valproic acid.

The protective effects of epicatechin (EC) at different concentrations (10, 50, 100, 500, 1000 μg/ml) on survival and viability of PC12 neuronal cells exposed to valproic acid were measured by MTT assay and oxidative stress tests (GPx, SOD, ROS, and lipid peroxidation). All data were analyzed in GraphPad Prism 8.0 using one-way ANOVA and Tukey post-test.

According to findings, EC reduced the cytotoxic effects of valproic acid at 500 and 1000 µg/ml (P<0.0001). EC significantly reduced the oxidative stress induced by valproic acid via decreasing reactive oxygen species (ROS) and malondialdehyde (MDA) production (P<0.001 and P<0.0001, respectively).

The present study showed that epicatechin could increase antioxidant potential and exhibits significant cytoprotective effect against valproic acid toxicity in PC12 cells.

Heart failure influences patients and their family caregivers. This study was conducted to determine the effectiveness of the supportive-educational program based on the Creativity, Optimism, Planning, and Expert Information (COPE) care model on resilience in family caregivers of patients with heart failure.

A clinical trial was conducted in 90 family caregivers of patients with heart failure in Isfahan Dr. Chamran Heart Hospital, 2021-22. The participants were randomly assigned into intervention group (n=45) and control group (n=45). The intervention group was then randomly divided into nine subgroups (n=5 per group). The intervention group received trainings based on COPE model in 6 sessions while the control group received only routine care. Demographic information checklist and Connor-Davidson Resilience Scale (CD-RISC) were completed before, immediately and three months after the intervention. Then, data analysis was performed. 

Gender was found to be significantly different between the intervention group and the control group (P< 0.05), but this confounder showed no significant effect on resilience (P> 0.05). In the intervention group, the mean scores for resilience after the intervention and three months later were 80.71±9.56 and 85.96±6.96, respectively, compared to 64.80±16.09 before the intervention (P< 0.05). In the control group, the mean resilience scores were 70.04±15.29 and 66.29±13.71 after the intervention and three months later, respectively, compared to 71.69±16.95 before the intervention (P<0.05).

According to the positive effects of COPE model on resilience in caregivers, hospital managers and nursing professionals are suggested to consider this model in increasing awareness and knowledge of caregivers about self-care and patient care.

Cancer diagnosis is a threatening and traumatic experience. Confusion caused by distressing thoughts about cancer can lead to additional suffering and, along with avoidance, can be a key factor in maintenance of traumatic reactions. The current research aimed at comparing the effectiveness of Unified Protocol (UP) of transdiagnostic intervention and mindfulness based schema therapy (MBST) on posttraumatic avoidance (PA) and chronic illness-related cognitive fusion (CICF) in patients with breast cancer (BC).

A semi-experimental study with pretest-posttest design and a follow-up period of 45 days was performed. Statistical population included all female patients with BC in Mashhad, Iran 2018-2021. Cognitive Fusion Questionnaire-Chronic Illness (CFQ-CI) and Posttraumatic Avoidance Scale (PAS) were administered. Forty one patients were selected using purposive sampling and were randomly divided into two experimental groups and a control group. UP of transdiagnostic intervention and MBST were applied in intervention groups for 10 weekly sessions. The control group attended two educational sessions. Data analysis was done using multivariate covariance analysis and Bonferroni post hoc test.

The mean scores for CICF and PA were significantly different between the intervention groups and the control group at post-test and follow-up (P<0.001). Findings showed no significant difference between the effectiveness of UP and MBST at post-test and follow-up (P>0.05).

MBST and UP are suggested to be applied in patients with BC to reduce their psychological problems.

The COVID-19 pandemic have led to some psychological disorders and sleep problems that should be taken into account after recovery. After recovering from COVID-19 people are at risk of sleep disorders, depression, and low quality of life and there is paucity of information about this issue. The present study aimed to compare the effectiveness of mindfulness and aerobic exercise on depressive symptoms, perceived stress, and sleep quality in recovered COVID-19 patients.

An intervention field research was performed in 60 male and female patients (mean age: 39.52±5.82) recovered from COVID-19 in Kermanshah, Iran. Participants were randomly divided into four groups (n=15): 1) attending mindfulness-based stress reduction (MBSR) program, 2) aerobic exercise, 3) combination of MBSR and aerobic exercise, and 4) control group. The study was carried out at four stages: pre-test, interventions, post-test, and follow-up test. Dependent variables included depressive symptoms, perceived stress, and sleep quality. Bonferroni Post hoc test in 4*3 mixed ANOVA was used for data analysis.

In this study, depression and perceived stress reduced in all experimental groups compared to the control group (P= 0.001). Also, sleep quality improved in these groups compared to the control group (P= 0.001). Post hoc tests showed the superiority of combination of MBSR and aerobic exercise compared to other interventions.

According to current study, combination of MBSR and physical activity shows to be more helpful than mindfulness training and physical activity alone in improving psychological problems and sleep quality after recovering from COVID-19.

Adherence to the principles of personal protection and commitment to health guidelines and principles of prevention perform important roles in controlling COVID-19 in a community. In this re3search we studied necessary measures to prevent COVID-19 in university dormitories at Mazandaran University of Medical Sciences, 2021.

In this descriptive-analytical study, 114 students in active dormitories during the COVID-19 pandemic participated in an online survey and their views and knowledge about COVID-19 preventive measures in the dormitories were examined. The samples were recruited using census method and data were analyzed in SPSS.

The results of the Chi-square test showed a significant relationship between adherence to preventive measures and educational level (P=0.015). Following personal hygiene was found to be significantly different according to being a local student, having underlying diseases, and the number of students at rooms (P<0.05). Findings showed that physical distancing and screening had no significant relationship with any of the variables studied (P>0.05).

The study showed that among the four areas investigated, personal hygiene practices and following the principles of prevention of COVID-19 were in a good condition, while physical distancing and screening were not satisfying. Therefore, university authorities should make serious changes to improve these issues at dormitories.

Today, development of telemedicine technology has led to wide use of smartphone to connect patients and health care teams to improve patient care. The aim of this study was to determine the effect of a self-care application on pain and mobility rehabilitation in patients following total knee arthroplasty surgery.

A randomized controlled clinical trial was carried out in 100 patients who were candidates for knee arthroplasty surgery at Tehran Baqiyatullah (Aj) Hospital. In this study, the experimental group was provided with a self-care application and the control group received routine hospital care. At days 7 and 14 after the surgery, the two groups were evaluated for pain and mobility rehabilitation using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Von Korff Pain Intensity and Disability Score.

Out of 100 people, 30 were men and 70 were women with an average age of 48.66±15.62. Findings showed significant differences between the two groups, at day 14 after the surgery, in mobility rehabilitation (P= 0.004) and pain (P= 0.001) at 95% confidence interval.

According to this study, the self-care application improved pain and motor recovery after total knee arthroplasty surgery.

Rheumatoid arthritis is one of the most common chronic inflammatory diseases of the joints that has many effects on oral health. The aim of this study was to evaluate the quality of life (QOL) and oral health indicators in patients with rheumatoid arthritis and healthy subjects.

A case-control study was carried out in Sari Tooba Clinic, 2018-2019. Data of all participants (case group, n=24 and control group, n=24), including demographic data, smoke consumption, and wearing removable dentures were recorded and all participants responded to nine questions about oral dryness and other systemic diseases. The Oral Health Impact Profile-14 (OHIP-14) was used and patients were clinically examined. DMFT was calculated and plaque, gingival, and sulcus bleeding indices were determined on Ramfjord teeth. The flow rate of non-stimulated saliva was investigated using a weight estimation method. Quantitative variables were compared between the case group and control group applying independent T-test or its non-parametric equivalent (Mann-Whitney).

There were two men (8.3%) and 22 women (91.7%) in each group. The mean ages in the case and control groups were 45.62 ± 11.29 and 45.58 ± 10.57 years. The age and gender distribution was not significantly different between the two groups. The mean DMFT, plaque, gingival, and sulcus bleeding indices and non-stimulatory saliva flow rate were higher in case group than the control group, but only the plaque index in the case group (5.62±2.63) was significantly different from the control group (4±2.44) (P=0.026). GI, PI and SBI were found to be significantly associated with oral health-related QOL (P<0.05).

Examination, diagnosis, and treatment of oral health indicators is effective in improving the QOL in patients with rheumatoid arthritis.

Enhancing hospitals’ resilience is an essential step towards improving the ability of the system to deal with crisis and minimizing the consequences. Job satisfaction is an important factor in the nurses’ turnover intention that can increase the quality of patient care. In this study, the level of hospital resilience and job satisfaction and the relationship between these two factors were investigated.

The present descriptive cross-sectional study was conducted using a questionnaire to assess crisis management in hospitals based on Resilience Engineering approach and Job satisfaction Scale developed by Brayfield and Rothe. The participants included 184 nurses working at a hospital in Mazandaran province, 2021. Data analysis was done using SPSS V25 applying Pearson correlation and Spearman correlation, Bonferroni test, and simple linear regression.

There were 83% female participants and the average age was 36.36±6.66 years with 8.5±5.91 years of work experience. The average resilience score of the hospital was 2.685, indicating moderate levels of resilience. The highest to the lowest scores for the dimensions of resilience were associated with flexibility, management commitment, learning, and awareness. The resilience score showed a downward trend; ICU> operating room and internal ward> emergency unit. Also, the average score for job satisfaction was 59.066 which indicates a moderate level of job satisfaction. The correlation between organizational resilience and job satisfaction of employees was 0.312.

The moderate level of organizational resilience and job satisfaction and the moderate correlation between these two variables require measurements to improve resilience and job satisfaction in order to effectively deal with crises and increase the quality of services.

Nurses in emergency departments are under high levels of work pressure that reduces the quality of care and patient safety. This study aimed to investigate the nurses’ workload using the WANE tool and determine the relationship between that and patient safety culture in selected hospitals affiliated with Mazandaran University of Medical Sciences.

This cross-sectional study was performed in 106 nurses working at emergency departments in 2021 selected via convenience sampling. Data were collected using the Persian forms of Workload Assessment of Nurses on Emergency (WANE) and Hospital Survey on Patient Safety Culture (HSOPS). Data analysis was carried out in SPSS V25.

The mean values for burden of direct care and indirect care were 13.38±6.5% and 19.53±5.7% of the total 24-hour care time. Direct care burdon was higher in the morning at Heart Hospital and in the afternoon at Sari Imam Khomeini Hospital and Zare Hospital. Indirect care in the afternoon was found to create the highest burdon at all hospitals. The total score for patient safety culture in all nurses studied was 136.04±15.6. The most direct and indirect care times in 24 hours was related to nurses with moderate level score for patient safety culture (138 to169), (210.44±103.8 and 303.11±95.68, respectively). Findings showed a direct relationship between patient safety culture and direct care and indirect care (r=0.211, P≥0.030 and r=0.309, P≥0.001).

Using the WANE tool is recommended for measuring the accuracy of direct and indirect nursing care time. The workload of emergency nurses can be reduced as much as possible by modifying the physical environment, accurate performance assesment, and assigning the computerized tasks to non-nursing personnel.

Chronic kidney disease-associated pruritus (CKD-aP) is a common symptom in patients with end-stage renal disease. So far, no clear explanation has been found about the pathogenesis of CKD-aP. Therefore, the present study aimed at investigating the relationship between pruritus in hemodialysis patients and serum iron, ferritin, total iron binding capacity, and transferrin saturation.

In this cross-sectional descriptive correlational study, 112 patients in hemodialysis clinics at Ghaemshahr Razi Hospital and Sari Shahrvand Clinic were investigated. The presence of pruritus and its severity were measured by a questionnaire and Visual Analogue Scale (VAS), respectively. Demographic information including age, gender, underlying diseases, dialysis information, and laboratory data, including urea, creatinine, potassium, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, hemoglobin, albumin, serum iron, ferritin, total iron binding capacity, and transferrin saturation were recorded.

Out of 112 patients, 38 (33.9%) had CKD-aP and 74 patients (66.1%) did not report pruritus during the last six months. Findings showed no significant relationships between pruritus and its severity and demographic variables, information related to dialysis, and laboratory results (P> 0.05).

We found no significant relationship between the presence and intensity of pruritus and demographic and paraclinical variables in hemodialysis patients, through which the hypothesis of the role of iron deficiency and anemia in causing pruritus in hemodialysis patients was rejected.

Breast cancer is one of the most common cancers and the first cause of cancer-related deaths in women. Evidence suggests that allergies may be associated with cancer progression. Immunoglobulin E as part of the allergic immune response plays a role in the occurrence of type 1 hypersensitivity responses and allergic diseases such as asthma, allergies, allergic rhinitis, and probably cancers.

We carried out a cross-sectional study in breast cancer patients as a case group and people without cancer as a control group. Total IgE level in the groups was measured by ELISA method using the monoset kit by Calbiotech (USA). Data, including total IgE level and eosinophil percentage of the patients along with participans’ age were recorded in excel. Data analysis was done in SPSS V19 using T-test, Mann-Whitney and partial correlation.

In this study, 160 patients were examined. The mean ages of patients in the case group and control group were 48.18±10.49 years and 41.68±7.95 years, respectively. There was a significant difference between the two groups in mean age (P<0.001). IgE level was not found to be significantly different between the two groups (P=0.92). Findings revealed no significant difference in eosinophil percentage between breast cancer patients and healthy patients (P=0.82). We observed no significant correlation between age and IgE levels (r=-0.043, P=0.594) and eosinophil percentage (r=0.145, P=0.068) after control for groups.

This study showed that the levels of IgE and the percentage of eosinophils in the peripheral blood cannot be not considered as a predictive factor in the diagnosis of breast cancer.

Behavioral and personality traits of family members, especially the parents can affect a child's behavior. According to high prevalence of mental disorders in Iran, this study was conducted to determine the relationship between personality disorders in parents and psychiatric disorders in children and adolescents.

A cross-sectional-analytical survey was performed in children and adolescents aged 6-18 years in Ilam and its suburbs, west of Iran, 2018-2019. A total of 1022 children and adolescents were selected using multi-stage cluster sampling. Semi-structured interviews were carried out and data were collected using Kiddie-SADS-Present and Lifetime Version (K-SADS-PL) and Millon Clinical Multiaxial Inventory. Data analysis was done applying descriptive statistics and calculation of odds ratio with 95% confidence interval.

The prevalence of psychiatric disorders was 10.80% in boys and 8.15% in girls. The most prevalent disorders in boys were depression (0.81%), enuresis (3.67 %), hyperactivity (1.84 %), and specific fear (1.22 %) and in girls separation anxiety (4.17%) was more common. Findings showed significant direct relationships between depressive personality disorder in mothers and depression in children (OR= 1.07, 95% CI: 1-1.14, P=0.02) and between depressive personality disorder in fathers and nocturnal enuresis in children (OR= 1.07, 95% CI: 1.01-1.14, P=0.02), and also between avoidant personality disorder in fathers and specific fear disorder in children (OR=1.09, 95% CI: 1-1.20, P=0.04).

In this study, we observed high prevalence of psychiatric disorders in children and adolescents that are significantly linked to the personality traits of parents and should be taken into account in making diagnosis and designing interventions.

Responsive medical education considers the priority of society's health issues in all its operational areas, and its goal is to train doctors who want and can serve their society. Based on this, the aim of this research was to design and validate an ideal model for social responsiveness in general medical education.

In this study, grounded theory as a qualitative approach was used. The participants included 21 key informants of medical education (managers, supervisors, doctors of academic staff, and educational-therapeutic centers leadership) in Mazandaran province who were selected by snowball purposive sampling. Data were collected using semi-structured interviews. Data analysis was done at three stages of open, axial, and selective coding, and based on that, the qualitative research model was designed. Also, acceptability index was used for accreditation.

The research showed 104 concepts shaped by 29 main categories which define a paradigmatic model of social accountability in general medical education at six inclusive layers (causal conditions, contextual conditions, intervening conditions, central phenomenon, strategies, and consequences) to be deep and rich.

The present study, by applying grounded theory, proposes a holistic-systematic perspective and model on social accountability in education that can be used by the Ministry of Health, Treatment and Medical Education and policy makers and planners.

In clinical treatment of cancer, improving the efficacy of drugs and targeted drug delivery have always been a fundamental problem requiring more focused solutions. The purpose of this study was to investigate the protective effects of copper nanoparticles in prostate normal and cancer cell lines.

In this experimental study, different concentrations of copper nanoparticles (0, 25, 50, 100, 150, 200, 250, 300, and 600 μg) were prepared. Cell growth and oxidative stress in reactive oxygen species (ROS) and reduced glutathione (GSH) were studied in prostate normal and cancer cell lines using MTT assay. 

Copper nanoparticles created toxicity in prostate normal cells due to release of ROS and reduction of glutathione reserves. Also, this mechanism inhibited the growth of cancer cells.

According to this study, copper nanoparticles induced toxicity in normal cells through oxidative stress pathway and inducing ROS and decreased the growth of normal cells. Also, copper nanoparticles inhibited the growth of cancer cells by the oxidative stress pathway. So, copper nanoparticles cannot be an effective drug in treatment of prostate cancer as they cause high toxicity in normal cells.

Pain management is one of the important issues in dental treatments. Fear of pain can make the process of anesthesia injection before dental treatment difficult for both the dentist and the patient. The aim of this study was to compare the effect of Najo-Caine P® with topical Benzocaine in reducing the pain of needle insertion in palatal anesthesia in 9-12 year old children.

In a double-blind clinical trial, 23 children aged 9-12 years were selected via convenience sampling, who needed palatal anesthesia injection on both sides of the jaw, at the Dental Clinic affiliated with Mazandaran University of Medical Sciences, in 2022. The desired areas were air-dried for 5 seconds. Benzocaine was applied with a cotton swab on one side of the jaw, and in the next session with the same preparation on the other side of the jaw, Najo-Caine P® anesthesia (2.5% lidocaine cream and 2.5% prilocaine similar to EMLA) was applied by the injector for 2 minutes.

The Visual Analogue Scale (VAS) scores for Benzocaine and Najo-Caine P® were compared. The VAS score for Najo-Caine P® (3.52) was lower than that of Benzocaine (3.78), but, the difference was not statistically significant (P= 0.488).

Current study suggests that Najo-Caine P®, as a form of EMLA cream, can be used as an alternative to Benzocaine before palatal infiltrate injection to reduce palatal pain in children.

Acute hepatitis is an acute inflammation of liver cells that can occur due to viral, bacterial, fungal, and medicinal causes. This study investigated the final diagnosis of inpatients with the initial diagnosis of acute hepatitis in Qaemshahr Razi Hospital.

In this descriptive cross-sectional study, the medical records of all patients (n=120) admitted with the initial diagnosis of acute hepatitis in 2014-2019 were studied. Data, including demographic information, clinical signs, and laboratory test results were obtained and analyzed in SPSS V21.

The patients were 120 and there were significant differences between place of residence, family history, previous history of hepatitis, blood transfusion, smoking and drugs, alcohol, high-risk sexual relationships, and having HIV (P<0.05). The most common causes of acute hepatitis were hepatitis B and A.

Due to the high prevalence of hepatitis B and drug-induced hepatitis, it is possible to reduce the incidence of acute hepatitis by reviewing and paying more attention to hepatitis B vaccination as well as following up of patients receiving hepatotoxic drugs.

Malignant neoplasms that affect the lymphatic system are called lymphoma and include a wide range of diseases that originate from B cells. Lymphoma is the second common neoplasm of the head and neck and includes Hodgkin's lymphoma and non-Hodgkin's lymphoma. This article reports the case of a primary non-Hodgkin's lymphoma in the oral cavity. He attended Sari Maxillofacial Surgery Clinic because of a gradual growth of a mass in the posterior region of the maxilla. The patient was primarily diagnosed with periodontal abscess but misdiagnosis led to treatment failure and disease progression. After attending our clinic, immunohistochemical examination was performed which revealed a diffuse large B-cell lymphoma. The patient underwent surgery and treatment with CHOP regimen (cyclophosphamide, daunorubicin, vincristine, and prednisolone). The development of lymphoma in the oral cavity is very rare and its symptoms such as pain, swollen gums, and loose teeth are similar to other dental problems and may lead to diagnostic problems. The present report draws attention to non-Hodgkin's lymphoma in differential diagnosis of soft and hard tissues of the oral lesions that can lead to appropriate treatment and better prognosis.

Viral hepatitis accounts for about 1.4 million deaths in the world every year. Surveillance systems and effective interventions play important roles in the management of these diseases. This study aimed to review the programs and measures done in Iran to eliminate viral hepatitis B and C.

Using qualitative content analysis, the programs for hepatitis B and C care system in Iran were reviewed. Fifteen semi-structured expert interviews were conducted, and 31 documents were reviewed. The activities, plans and programs associated with the viral hepatitis surveillance system were extracted based on the interview results and the documents.

The activities of the hepatitis surveillance system in Iran were categorized into six categories, including the viral hepatitis surveillance system goals, target groups, current structure of hepatitis B and C surveillance system, upstream policies and documents, current programs, and infrastructures. The most prominent interventions were the following: hepatitis B vaccination in target groups, screening, hepatitis surveys, needle and syringe distribution, safe injection, safe blood transfusion, and hepatitis treatments.

This study showed that the main weakness of the hepatitis surveillance system is detecting active disease cases, which can be improved by integrating the hepatitis program into the network system and active participation of private and public sectors as well as non-governmental organizations. Vaccination campaigns and treatment of hepatitis B and C can also help in eliminating hepatitis C and controlling hepatitis B by 2030.