Health-care Professionals' Knowledge and Perception of Adverse Drug Reaction Reporting and Pharmacovigilance in a Tertiary Care Teaching Hospital of Nepal.

Background: Underreporting of adverse drug reactions (ADRs) is common globally, and Nepal is not an exception to this. Health-care professionals (HCPs) play a vital role in reporting ADR during routine practice. Lack of knowledge and awareness about pharmacovigilance and reporting ADRs among HCPs may contribute to underreporting. Objective: The objective of this study was to evaluate the knowledge and perception of HCPs regarding ADR reporting and pharmacovigilance in a tertiary care teaching hospital in, Nepal. Methods: A descriptive cross-sectional study was conducted. A questionnaire was distributed to 215 HCPs (medical doctors, nurses, and pharmacists) between March and September 2018. Knowledge and perception regarding ADR reporting and pharmacovigilance were studied. Data were analyzed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp, Armonk, New York). Results: The HCPs included 75 medical doctors, 126 nurses, and 14 pharmacists. Majority of the participants were female (67%), and the majority of participants were not aware of pharmacovigilance. Among the participants, pharmacists were found to have better knowledge regarding pharmacovigilance. However, other HCPs (doctors and nurses) strongly agreed about the necessity of having adequate knowledge about pharmacovigilance. Out of 215, 57.7% agreed that the important benefit of reporting ADR was to identify safe drugs and improve patient safety. The main reasons for not reporting were - ADR reporting was not widely promoted by relevant authorities (47%), followed by not knowing where and how to report ADR (34.9%). However, other HCPs (doctors and nurses) strongly agreed about the necessity of having adequate knowledge about pharmacovigilance. Conclusions: The knowledge of HCPs on ADR reporting and pharmacovigilance was poor. Despite a low knowledge of ADR reporting and pharmacovigilance among HCPs, there was a positive perception that ADR reporting is necessary and ADR monitoring system should be established in the hospital. This study also highlights a need for future intervention studies focusing on educating HCPs about ADR and pharmacovigilance.

An insight into the pharmaceutical sector in Yemen during conflict: challenges and recommendations.

In our world today, we need to understand, measure, and respond to inequality. The conflict and siege in Yemen have caused serious repercussions and consequences for the pharmaceutical sector and health of the people. Hospital, health centres and facilities, medicines warehouses and pharmaceutical factories have been destroyed. Further, the conflict has aggravated the health situation with shortages of medicines, an increase in chronic illnesses, and multiple epidemics and casualties. This article aims to highlight the challenges faced by the pharmaceutical sector in Yemen. It will address the overall state of health of the Yemeni people, as well as focus on the past, current status and future development of the pharmaceutical sector. Further, it will focus on possible remedial actions to solve some of these problems. These problems can be tackled if the responsible parties have the political will to do so. Acknowledging the different classes of problems is undeniably very important to provide clarity on the future of Yemen's supposedly promising pharmaceutical landscape.

Attitudes and practices of community pharmacists and barriers to their participation in public health activities in Yemen: mind the gap.

BACKGROUND: Patients in Yemen commonly visit community pharmacies to obtain consultation or treatment for common ailments. Community pharmacists have an opportunity to optimize medication use and improve patient outcomes. This study aimed to evaluate the attitudes and practices of community pharmacists regarding their participation in public health activities and barriers to their participation in these activities. METHODS: This cross-sectional study was carried out among community pharmacists working in pharmacies located in urban areas of the Aden governorate of Yemen from March to June 2017 using a self-administered questionnaire. We selected pharmacies from a line list using proportional sampling according to the number of pharmacies in the urban areas of each district. The questionnaire contained four sections: demographic characteristics, attitudes, practices, and barriers encountered. Data were analyzed descriptively, and the Chi-square test was used for analyzing the association of variables (alpha = 0.05). RESULTS: The questionnaire was distributed to 200 community pharmacists working in community pharmacies. Of the 200 respondents, 62% (n = 124) were male. Overall, the mean age (sd) was 30.0 years (8.6) with the number of years of work experience between 2 and 9.9 years (n = 158, 79%). On average, 62.3% of the pharmacists had a positive attitude toward participation in public health activities. Providing education to stop tobacco chewing, smoking, alcohol drinking and improve oral hygiene was an important activity of the community pharmacists. Blood pressure measurements (86%, n = 172) and glucose tests (45%, n = 90) were commonly conducted for clients. Lack of time (71%, n = 142) and lack of teamwork (70%, n = 140) were mentioned as common barriers to participation in public health activities. CONCLUSIONS: Community pharmacists had a positive attitude toward public health activities. Health education and routine health tests were important practices of the community pharmacists. Barriers need to be overcome to enable more active participation by community pharmacists in public health activities by consulting with all stakeholders, assessing the situation, considering alternatives and taking action.

The Unmet Need for Pharmacists as Important Members of the Emergency Department Team in Resource-Limited Settings: A Case of Nepal.

Background: The role of pharmacists in many developed countries has evolved from the traditional practice of dispensing medicines to contributing directly or indirectly to improve patient health outcomes. They are providing hospital services and patient care including services in the emergency department (ED). However, there is limited evidence for pharmacist involvement in the ED from resource-limited countries such as Nepal. Objective: The aim of this study is to discuss the role of pharmacists and highlight the unmet need of pharmacists in ED in Nepal. Methods: A narrative review of existing literature was conducted. Results: The status of ED services in Nepalese hospitals is not yet at a desirable level, and there is limited information about the role of pharmacists in EDs. Evidence obtained from developed nations on the role of pharmacists in EDs suggests that they help in improving patient outcomes by minimizing medication errors, adverse drug reactions, and enhance patient care. Conclusion: The study highlights the need for pharmacists in EDs in resource-limited settings. There is limited evidence of pharmacists' role in EDs from Nepal. Therefore, this study suggests a need for further studies on the possible contribution of pharmacists to ED services in Nepal.

Effect of the 2015 earthquake on pediatric inpatient pattern at a tertiary care hospital in Nepal.

BACKGROUND: Earthquakes impact child health in many ways. Diseases occurring immediately following an earthquake have been studied in field based hospitals but studies on the inpatient disease pattern among children without trauma in a permanent hospital setup is lacking. METHODS: We examined the diagnoses of all children without trauma, admitted to Kanti Children's Hospital, Kathmandu for fifteen-week duration (from 4th week to end of the 18th week) following the 7.8 magnitude Nepal earthquake on 25th April 2015. The admitted children were grouped based on direct effect of earthquake on their family (house damaged or family member injured or dead) and on whether their place of residence was located in an earthquake affected district. Most common diagnoses were identified and their distribution between the aforementioned groups analyzed to examine differences, if any, in disease occurrence or presentation. The fifteen weeks study duration was divided into three parts of five weeks each, to study trends in illness presentation. Variables were compared among various groups using appropriate statistical tests (p < 0.05). RESULTS: A total of 1057 patients were admitted. The proportion of patients requiring admission for pneumonia, acute gastroenteritis and acute or poststreptococcal glomerulonephritis (AGN/PSGN) was significantly higher among children belonging to earthquake affected districts. Proportion of patients with any infective condition was also significantly higher in this group. Acute gastroenteritis and any infective condition were significantly higher among children from substantially affected families. The proportion of AGN/PSGN among admitted patients increased in successive time categories among patients from affected districts and from substantially affected families. Urinary Tract Infection, bronchiolitis, tuberculosis, pleural effusion, protein energy malnutrition/failure to thrive, nephrotic syndrome, meningitis/meningoencephalitis, epilepsy or seizure disorders, leukemia/malignancies, enteric fever, infective hepatitis and congenital heart disease were not significantly different among children from affected and not affected districts or between substantially affected and not affected families. Patients from substantially affected families were admitted to semi-intensive care ward or ICU in significantly higher proportions (12.6% vs 7.8%, p = 0.014). CONCLUSION: Children seeking care for certain diseases were more likely to be from earthquake affected families and districts. Those from affected families required critical care more often.

Knowledge and Practice on Injection Safety among Primary Health Care Workers in Kaski District, Western Nepal.

BACKGROUND: Unsafe injection practice can transmit various blood borne infections. The aim of this study was to assess the knowledge and practice of injection safety among injection providers, to obtain information about disposal of injectable devices, and to compare the knowledge and practices of urban and rural injection providers. METHODS: The study was conducted with injection providers working at primary health care facilities within Kaski district, Nepal. Ninety-six health care workers from 69 primary health care facilities were studied and 132 injection events observed. A semi-structured checklist was used for observing injection practice and a questionnaire for the survey. Respondents were interviewed to complete the questionnaire and obtain possible explanations for certain observed behaviors. RESULTS: All injection providers knew of at least one pathogen transmitted through use/re-use of unsterile syringes. Proportion of injection providers naming hepatitis/jaundice as one of the diseases transmitted by unsafe injection practice was significantly higher in urban (75.6%) than in rural (39.2%) area. However, compared to urban respondents (13.3%), a significantly higher proportion of rural respondents (37.3%) named Hepatitis B specifically as one of the diseases transmitted. Median (inter-quartile range) number of therapeutic injection and injectable vaccine administered per day by the injection providers were 2 (1) and 1 (1), respectively. Two handed recapping by injection providers was significantly higher in urban area (33.3%) than in rural areas (21.6%). Most providers were not aware of the post exposure prophylaxis guideline. CONCLUSION: The knowledge of the injection providers about safe injection practice was acceptable. The use of safe injection practice by providers in urban and rural health care facilities was almost similar. The deficiencies noted in the practice must be addressed.

Knowledge, attitude and practice towards medicines among school teachers in Lalitpur district, Nepal before and after an educational intervention.

BACKGROUND: Few studies regarding Knowledge, Attitude and Practice (KAP) towards medicines among school teachers have been carried out in Nepal. Obtaining baseline KAP is important to note deficiencies and plan appropriate interventions. School teachers have to know about medicines as they can be an important source of information about rational and safe use of medicines. The department of Clinical Pharmacology, KIST Medical College, Lalitpur, conducted a study regarding KAP of school teachers about medicines before and after an educational intervention from April 2011 to December 2011. METHODS: The study was done in selected schools of Lalitpur district. Teachers were selected on a voluntary basis after obtaining written informed consent. Gender, ethnic or caste group, native place, age, educational qualifications, subject taught were noted. An educational intervention using a combination of methods like presentations, brainstorming sessions, interactive discussions using posters and distribution of information leaflets about the use of medicines was conducted. The KAP and overall scores among subgroups according to gender, age, level of education, subject, ethnicity, type of school (primary vs. secondary and government vs. private school) were studied. KAP and overall scores before and after the intervention was compared using Wilcoxon signed ranks test as the scores were not normally distributed. RESULTS: A total of 393 teachers participated before and after the intervention. The median (interquartile range) knowledge, attitude and practice scores before the intervention were 63 (10), 23 (5) and 270 (48) respectively while the overall score was 356. The median knowledge, attitude and practice scores after the intervention were 71 (10), 28 (5) and 270 (48) respectively while the overall score increased to 369. Maximum possible score of knowledge, attitude and practice were 100, 40 and 320 respectively. Scores improved significantly for knowledge (p<0.001), attitude (p<0.001) and total scores (p<0.001) but not for practice (p=0.528). CONCLUSION: The intervention was effective in improving knowledge and attitude of the teachers. More studies among school teachers about their knowledge, attitude and practice about medicines are required in Nepal.

Study of status of safe injection practice and knowledge regarding injection safety among primary health care workers in Baglung district, western Nepal.

BACKGROUND: Unsafe injection practices and injection overuse are widespread in developing countries harming the patient and inviting risks to the health care workers. In Nepal, there is a dearth of documented information about injection practices so the present study was carried out: a) to determine whether the selected government health facilities satisfy the conditions for safe injections in terms of staff training, availability of sterile injectable equipment and their proper disposal after use and b) to assess knowledge and attitudes of healthcare workers in these health care facilities with regard to injection safety. METHODOLOGY: A descriptive cross-sectional mixed type (qualitative and quantitative) survey was carried out from 18th May to 16th June 2012. In-depth interviews with the in-charges were conducted using a semi-structured questionnaire. Observation of the health facilities using a structured observation tool was done. The data were analysed manually by summarizing, tabulating and presenting in various formats. RESULTS: The in-charges (eight males, two females) who participated in the study ranged in age from 30 to 50 years with a mean age of 37.8 years. Severe infection followed by pain was the most important cause for injection use with injection Gentamicin being most commonly prescribed. New single use (disposable) injections and auto-disable syringes were used to inject curative drugs and vaccines respectively. Sufficient safety boxes were also supplied to dispose the used syringe. All health care workers had received full course of Hepatitis B vaccine and were knowledgeable about at least one pathogen transmitted through unsafe injection practices. Injection safety management policy and waste disposal guideline was not available for viewing in any of the facilities. The office staff who disposed the bio-medical wastes did so without taking any safety measures. Moreover, none of these staff had received any formal training in waste management. CONCLUSIONS: Certain safe injection practices were noticed in the studied health care facilities but there remain a number of grey areas where unsafe practices still persists placing patient and health workers at risk of associated hazards. Training concentrating on injection safety, guidelines to dispose biomedical waste and monitoring of the activity is needed.

Clinicopathological Profile of Dengue Infection in a Tertiary Care Centre in Nepal.

BACKGROUND: Dengue is a mosquito-borne viral disease with a wide spectrum of presentations ranging from subclinical disease to severe dengue. Dengue is endemic to the Terai of Nepal. Interestingly, an increasing incidence has been reported from hilly areas like Kathmandu valley. This study explored the clinicopathological profile of dengue infection. METHODS: A total of 84 serologically confirmed dengue cases from September to November 2019 at KIST Medical College were recruited in a cross-sectional study after obtaining ethical approval. Dengue was categorized as dengue without warning signs, dengue with warning signs, and severe dengue. Clinicopathological information was recorded in the proforma by reviewing patients' records. A descriptive statistical tool and chi-square test were carried out. RESULTS: Out of 84 patients, 76% (64) were dengue without warning signs, 21.4% (18) were dengue with warning signs and 2.4% (2) were severe dengue. About 97.6% (82) presented with fever. During the course of illness, anemia was identified in 38.1% (32), thrombocytopenia in 65.5% (55), hemoconcentration in 6% (5), and leucopenia in 82.1% (69). Similarly, elevated aspartate transaminase and alanine transaminase (ALT) was observed in 67.7% (42) and 53.2% (33) respectively. The severity of dengue on presentation to hospital was significantly associated with thrombocytopenia, leucopenia, and elevated ALT. Similarly, the severity during course of illness in hospital was significantly associated with hemoconcentration, thrombocytopenia, leucopenia, and elevated ALT. CONCLUSIONS: Most common presentation of dengue infection was fever. The most common laboratory abnormalities were leucopenia, thrombocytopenia, hemoconcentration, anemia, and elevated liver enzymes. Awareness of these clinical and laboratory parameters is important for the prompt diagnosis, severity estimation, and overall management of dengue infection.

Student perception about working in rural Nepal after graduation: a study among first- and second-year medical students.

BACKGROUND: The Federal Democratic Republic of Nepal is a developing country in South Asia with a population of 29.8 million. In September 2011, there were 18 medical schools with 14 being in the private sector. KIST Medical College is a private school in Lalitpur district. The present study was conducted to obtain information on student perceptions about working in rural Nepal after graduation. METHODS: The study was conducted among first- and second-year undergraduate medical students using a semi-structured questionnaire developed by the authors using inputs from the literature and their experiences of teaching medical students. Year of study, gender, method of financing of medical education, place of family residence and occupation of parents were noted. Participant responses were analysed, grouped together and the number of respondents stating a particular response was noted. RESULTS: Of the 200 students, 185 (92.5%) participated with 95 being from the first year and 90 from the second. Most students were self-financing and from urban areas. Regarding the question of working in rural Nepal after graduation, 134 (72.4%) said they will work after their undergraduate course. Students preferred to work in the government or nongovernmental sector. Student felt doctors are reluctant to serve in rural Nepal due to inadequate facilities, low salary, less security, problems with their professional development, less equipment in health centres, decreased contact with family and difficulties in communicating with an illiterate, rural population. About 43% of respondents felt medical education does not adequately prepare them for rural service. Repeated rural exposure, postings in rural hospitals and health centres, and training students to diagnose and treat illness with less technology were suggested. The median monthly salary expected was 60 000 Nepalese rupees (US$ 820) and was significantly higher among first-year students. CONCLUSIONS: The majority of respondents were in favour of working in rural Nepal after graduation. They wanted facilities in rural areas and health centres to be improved. Changes in the education system were suggested. Providing relatively better facilities for rural doctors compared with urban doctors and reorienting medical education for producing doctors for rural Nepal can be considered. Further studies are required in other private medical schools.

Procedural Safety and Long-Term Clinical Outcomes in Patients Receiving Ultra-Long Everolimus-Eluting Stent: A Single-Center Real-World Experience.

Background: Diffuse long coronary lesions are difficult to treat percutaneously. The aim of the present study was to assess the procedural safety and long-term efficacy of the ultra-long (48-mm) drug-eluting stent Xience Xpedition. Methods: This was an investigator-initiated, observational, all-comers study. A total of 92 patients with 93 lesions were enrolled in the study from October 2016 to October 2020. The primary outcome of the study was major adverse cardiac events (MACEs). Secondary outcomes were individual components of the primary outcome and procedural success. Results: The mean (standard deviation (SD)) age of the participants was 58.8 (10.8) years. More than half of the patients had ST-segment elevation myocardial infarction (STEMI) at presentation (55.4%). Ten patients were in cardiogenic shock (CGS; 10.8%). Most of the lesions were located in the left anterior descending artery (48.3%). American College of Cardiology/American Heart Association (ACC/AHA) type C was the most common lesion type amongst the intervened vessels (46.74%), with a mean syntax score (SD) of 16.99 (8.89). The mean stent diameter used was 2.77 mm (0.25). MACE was observed in 7.6% of patients studied at a median follow-up of 24 months. MACE was significantly lower in the population without CGS, occurring in only 2.4% of the patients; a significant difference in MACE was observed in patients with and without CGS (P < 0.001). Procedural success was obtained in 89.2% of total population; however, 96.3% of patients without CGS had procedural success. Conclusions: The deployment of the ultra-long 48-mm Xience Xpedition stent is feasible, safe, and effective; and it was associated with a good intermediate-term clinical outcome.

Student feedback on the use of paintings in Sparshanam, the Medical Humanities module at KIST Medical College, Nepal.

BACKGROUND: Paintings have been used in Medical Humanities modules in Nepal at Manipal College of Medical Sciences and KIST Medical College. Detailed participant feedback about the paintings used, the activities carried out, problems with using paintings and the role of paintings in future modules has not been previously done. Hence the present study was carried out. METHODS: The present module for first year medical students was conducted from February to August 2010 at KIST Medical College, Nepal. Paintings used were by Western artists and obtained from the Literature, Arts and Medicine database. The activities undertaken by the students include answering the questions 'What do you see' and 'What do you feel' about the painting, creating a story of 100 words about the scene depicted, and interpreting the painting using role plays and poems/songs. Feedback was not obtained about the last two activities. In August 2010 we obtained detailed feedback about the paintings used. RESULTS: Seventy-eight of the 100 students (78%) participated. Thirty-four students (43.6%) were male. The most common overall comments about the use of paintings were "they helped me feel what I saw" (12 respondents), "enjoyed the sessions" (12 respondents), "some paintings were hard to interpret" (10 respondents) and "were in tune with module objectives" (10 respondents). Forty-eight (61.5%) felt the use of western paintings was appropriate. Suggestions to make annotations about paintings more useful were to make them shorter and more precise, simplify the language and properly introduce the artist. Forty-one students (52.6%) had difficulty with the exercise 'what do you feel'. Seventy-four students (94.9%) wanted paintings from Nepal to be included. CONCLUSIONS: Participant response was positive and they were satisfied with use of paintings in the module. Use of more paintings from Nepal and South Asia can be considered. Further studies may be required to understand whether use of paintings succeeded in fulfilling module objectives.

Non-Pharmacological Infection Prevention and Control Interventions in COVID-19: What Does the Current Evidence Say?

Coronavirus disease-19 (COVID-19), a major global public health emergency has significantly impacted human health and livelihoods. The pandemic continues to spread and treatments and vaccines are at different stages of development. Mass vaccination has been rolled out worldwide. This review article provides a narrative summary of the evidence on various non-pharmacological interventions (NPIs) for COVID-19 containment. The authors reviewed the evidence published by the Norwegian Institute of Public Health map of COVID-19 evidence. Additional literature was identified from PubMed and Google Scholar, preprint sites, and news media. The search terms included "Social distancing measures" and "COVID 19", "Non-pharmacological interventions'' and "COVID 19", "COVID-19", "non-pharmacological interventions", "face mask", etc. The strength of the evidence for most studies on NPIs was 'weak to moderate' for restrictive NPIs. Ascertaining the impact of each NPI as a standalone intervention is difficult since NPIs are implemented simultaneously with other measures. Varying testing and reporting strategies across the countries and classification of deaths directly caused by COVID-19 create challenges in assessing the impact of restrictive NPIs on the case numbers and deaths. Evidence on hygiene measures such as face mask is more robust in design providing credible evidence on prevention of COVID-19 infection. Evidence from modeling studies, natural before-after studies, and anecdotal evidence from the strategies adopted by 'role model' countries suggests that continued use of NPIs is the only containment strategy until 'herd immunity' is achieved to reduce the severe disease and mortality.

Medical humanities in Nepal--snakes and ladders.

In the last decade there has been a quantitative growth in medical schools in Nepal, a developing country in South Asia. Medical Humanities (MH) uses disciplines traditionally termed as the humanities in the pursuit of medical educational goals. The subject is slowly developing in Nepal. Sessions have been conducted at Manipal College of Medical Sciences, Pokhara and KIST Medical College, Lalitpur. In this article the authors examine inhibitory factors (snakes) and facilitating factors (ladders) for the development of the subject in Nepal.

Overview, Challenges and Future Prospects of Drug Information Services in Nepal: A Reflective Commentary.

Drug information center (DIC) or Medicine information services provides impartial, well-referenced, critically evaluated, updated information on various aspects of medications to healthcare professionals and consumers. Medicine information services also contribute to the minimization of medication errors by promoting medication education and supporting pharmaceutical services. The main objective of this reflective commentary is to highlight the recent scenario of medicine information services in Nepal, challenges for DIC, how DICs can be strengthened and future perspectives of DIC. The availability of medicine information in various online drug information sites and numerous applications (apps) have made it easier to assess the information in the country such as Nepal. However, the reliability and validity of such information should be considered before dissemination. DIC plays a crucial role in improving drug safety by aiding clinicians in safer use of medications and promoting adverse drug reaction (ADR) reporting in Nepal. Financial support for operating the DIC efficiently is scarce in Nepal resulting in operational problems. The performance of the medicine information services in the country should be evaluated periodically to ensure the good quality of the service. Steps should be taken by the government, private hospitals and regulatory bodies to sustain the already established DIC and to establish additional DICs in the future to provide quality health care service to the community.

A voluntary medical humanities module in a medical college in Western Nepal: participant feedback.

BACKGROUND: A pioneering, voluntary Medical Humanities (MH) module was conducted at the Manipal College of Medical Sciences, Pokhara, Nepal using small-group interactive sessions, literature and art excerpts, case scenarios, role-plays, and debates. DESCRIPTION: Participant feedback was obtained using focus-group discussions and reflective writing assignments. Medicine and the Arts, Ethics and Medicine, and Social Issues in Medicine were the three main units. Students from the third, fifth, and sixth semester and "interested" faculty members participated. EVALUATION: Learning the humanities had a number of advantages. Role-plays were an enjoyable and effective learning methodology. The module would be of help in individualizing treatment to specific patients. Other topics can be considered. Faculty and students learning together was an enjoyable experience. CONCLUSIONS: The participants enjoyed being a part of the module. More literature and art excerpts from Nepal and South Asia should be used. MH can help to orient practice in a Nepalese/South Asian sociocultural context.

Establishing and strengthening a medicine and therapeutics committee in a medical college in Nepal: initial experiences.

Drug and Therapeutics Committees (DTCs) serve as a forum to bring together various stakeholders to improve drug use. DTCs are a key intervention to promote rational use of medicines. DTCs are however, functioning in only a limited number of hospitals in Nepal. A Medicine and Therapeutics Committee (MTC) was started at KIST Medical College, a new medical school in Lalitpur district, Nepal to promote the rational use of medicines in February 2008. The MTC has members from various departments and the full support of the administration. The MTC has been involved in preparing the hospital medicine list and limiting the number of brands available in the pharmacy. Measures to regulate pharmaceutical promotion have been undertaken. Pharmacovigilance and medication counseling activities have been started. Educational programs for various levels of staff are regularly carried out and drug use in the hospital is periodically monitored. Initial experiences regarding MTC functioning is positive.