- Email: [email protected]
Safeguards for gene therapy
238
amounted to a breach of their statutory duty. However, BT’s failure to warn of the risk that keyboard work might cause RSI to new recruits or to encourage workers to report any aches and pains at onset did not amount to a breach of
statutory duty. Diana Brahams
Conference AIDS in Africa 1 in 40 African adults is now infected with HIV. These 6 million women and men, and the three-quarters of a million infected children, are unevenly distributed over the continent. In East Africa the real burden of disease and death is only just beginning to be felt, but already AIDS cases make up to 80% of the case-load in some adult hospital wards. Practically everywhere the number of people with asymptomatic HIV infections is multiplying rapidly. 1 in 8 adults in Abidjan now carry HIV 1 or HIV 2. The burden of associated diseases is overwhelming: 40% of patients dying from AIDS have cerebral lesions, most commonly toxoplasmosis and tuberculosis. Already there are 50 000 AIDS orphans in just one region (Kagera) in Tanzania, and agricultural production in the same area has fallen by 3-20%. Yet only a small fraction of those infected with HIV in any part of Africa have died. From the point of view of cost to the community and health services the epidemic is
only just beginning. The Sixth International Conference
on
graciously opened by the President of Senegal, Monsieur Aboon Diouf, and even President Bush sent a message. Finally, such conferences disseminate information to the rest of the world. For example, studies in Nairobi suggest that the use of oral contraceptives and intrauterine devices is associated with any increased or reduced risk of seroconversion, and data from Cameroon give some preliminary evidence of a protective effect of spermicide use on the acquisition of HIV. More evidence is accumulating about the long incubation period of HIV-2. But despite much of interest, many of the outcomes of the meeting might have been achieved more cost-effectively. Perhaps the several, much smaller, satellite meetings by WHO/GPA, Family Health International, and Bristol Myers Squibb held in Dakar are a more appropriate model for the future. Certainly another world conference in Amsterdam in the middle of 1992 and a Seventh AIDS in Africa conference in Yaounde at the end of next year seems a bit like conference overload. One participant, who has known AIDS for longer and more closely than most, saw the Dakar meeting "as a rerun of the first AIDS in Africa conference in Brussels in 1985 but with the decimal point moved". In other words, HIV prevalences continue to rise and even experts do not always learn quickly enough.
not
International First Floor,
Family Health,
Margaret Pyke Centre, 15 Bateman’s Buildings, London W1V 5TW
Malcolm Potts
AIDS in Africa
(Dec 16-18, 1991) brought 1800 participants from 79 countries to Dakar, Senegal. Many conference presentations measured the spread of HIV or threw light on the
knowledge and attitudes of vulnerable groups such as prostitutes and their clients. Less than 10% of commercial sex workers in one Cameroon sample used condoms regularly and 60% of long-distance lorry drivers in Zimbabwe have sex with a prostitute at least once a month. Somewhat fewer papers dealt with preventive measures such as education, distribution of condoms, or treatment of other sexually transmitted diseases (STD). The poverty of the Sahel, political unrest in Zaire, debt burdens in Nigeria, and the legacy of previous bad government in Uganda are all factors mitigating against disease control. So is the low status of women. In many parts of Africa women handle much of the subsistence farming and petty commerce but receive the least reward. Even so, there have been successes in HIV prevention: prostitutes in Ghana have changed their behaviour, the social marketing of condoms in Zaire has been most successful, and the comprehensive control of STDs through government services has been initiated in Tanzania. The challenge is to develop the will and mobilise the resources (national and international) to turn pilot projects into epidemiologically significant programmes. At present, however, it is difficult to escape the conclusion that HIV is out of control. Among other things, it must also be asked whether large, expensive conferences are themselves an appropriate response? Conferences help forge needed partnerships between developing and developed countries and are certainly essential for recharging the skills and motivation for those fighting in the trenches in the battle against AIDS. Scientists from Belgium, France, and the USA played an important part in the Dakar meeting. Conferences also allow national leaders to express support: the sixth conference was
Noticeboard Safeguards for gene therapy Somatic gene
therapy
will be allowed in the UK if the
recommendations of the Committee on the Ethics of Gene Therapy are accepted by the Government. But the Department of Health will be seeking the views of many professional and lay organisations before the Government reaches its decision. The consultation period will end on May 18. Any proposed gene therapy must be ethically acceptable and shown to be safe, says the committee’s report, published last week.’ The committee, a non-statutory body set up by UK health ministers in 1989 under the chairmanship of Sir Cecil Clothier, QC, says that gene therapy raises no new ethical issues, but because the treatment is new it recommends that gene therapy should be subject to the ethical codes that apply to research involving patients. Familiar ethical considerations that are likely to assume greater prominence when gene therapy is being considered include safety (because of the possibility of unpredicted consequences of gene insertion), the need for long-term surveillance, consent (especially regarding uncertainties about outcome), the probability that children will be among the first candidates for gene therapy, and
confidentiality. Gene therapy, the committee recommends, should be restricted to the alleviation of disease in individual patients and should not be used to change normal human traits. The first candidates for gene therapy should be patients with a lifethreatening or seriously disabling genetic disease. Severe genetic disorders that show their effects in early childhood, or even before birth, should be treated correspondingly early. Germline gene therapy should not be attempted at present, says the report, because "there is insufficient knowledge to evaluate the risk to future generations". At a meeting of the Human Genome Organisation in London last August Dame Mary Warnock, chairman of the 1984 committee that approved in-vitro fertilisation and limited research on human embryos, said that unpredictable outcome was a more valid reason for rejecting germline therapy than was
fear of doctors’ powers.
239
In
drawing
up its
guidelines the Clothier Committee took
account of the public’s concerns about "a procedure which could be
used to change human characteristics" and irrational fears "which derive from misunderstandings of biology ... and popular creations of fiction, such as Frankenstein’s monster". The committee proposes that a non-statutory expert advisory board be set up to work in conjunction with local research ethics committees to assess proposals for gene therapy, including its supervision. Until substantive arrangements for assessment are in place proposals for gene therapy should be submitted to the local research ethics committee and to the Clothier Committee. 1.
Report of the Committee on the Ethics of Gene Therapy. Cm Stationery Office. 1992. £6. Pp 90 ISBN 0-101178824.
Trial
1788. London: HM
by myth
US criminal courts perpetuate stereotypes of patients with AIDS and frequently contradict current knowledge on the risk factors of HIV infection. So says the second report of the US AIDS Litigation Project, an ongoing investigation funded jointly by the National AIDSProgram Office and the US Public Health Serviced The aim of this scheme is to promote wider knowledge among the legal profession and public about laws concerning the rights of AIDS patients. The latest report discusses 817 cases, most of which focus on alleged discrimination and criminal law litigation. Not only is HIV disease a major scientific and public health issue in both the developing and the developed world, but it is also, to quote Dr Jim Allen, Director of the National AIDS Program Office, "the most litigated disease in history". Prosecutions have been made against HIV-positive people on the basis of attempted murder and assault with a deadly weapon. Courts have shown little understanding of the relative risks of behaviours that might be associated with the transmission of HIV. Judges seem to have difficulty in deciding whether and, if so, how the outcome of an act (which may be inconsequential), the act itself (such as a bite), or the intention behind the act should be punished. Health insurance is a particular cause for concern. A company has already tried to bring an action to annul retrospectively a policy after the deceased was found to be HIV positive, even though that individual was unaware of his antibody status. The failure of the judiciary to defend the human rights of those with HIV infection is, the report notes, a reflection of the poor AIDS education policy of the current Bush administration. Combined with the recent debacle over entry of HIV-positive delegates to the US for an AIDS conference, the US Government and its instruments of state continue to give negative signals to a population in desperate need of an aggressive but fair public health education programme about HIV disease. 1 Gostin L, Porter L. The AIDS Litigation Project II: a national review of court and Human Rights Commission decisions. Washington DC: US Public Health Service, 1992. Pp 372 Copies available from National AIDS Program Office, Humphrey Building, 200 Independence Avenue SW, Washington DC, 20201,
USA.
Reassurance on safety of pertussis vaccines A report commissioned by the US Government provides that the risks of severe permanent adverse effects after pertussis vaccination are very low. The report was a review by the Institute of Medicine (IOM) at the National Academy of Sciences, Washington DC, of information on possible adverse consequences of pertussis and rubella vaccines. It was released in August, 1991, and has been summarised in the Jan 15 issue of the Journal of the American Medical Association.1 The IOM review examined 18 adverse effects in relation to DTP vaccine and 4 in relation to the currently used vaccine strain RA 27/B. Evidence for a causal relation with pertussis vaccine was found for four adverse effects, and that with rubella vaccine for two. For DTP, evidence "consistent with a causal relation" was found for acute encephalopathy (range of excess risks 00 to 10-5 per million immunisations). The IOM concludes that this degree of risk reassurance
reported by the UK National Childhood Encephalopathy Studythe only large case-control study of vaccine-related encephalopathy so far. The NCES had concluded that the data suggested but did not prove that DTP causes serious acute neurological disorders in the first 7 days after 1 in 310 000 is consistent with that
vaccinations. The IOM also found evidence consistent with a causal relation and for shock and unusual shock-like state (data insufficient for calculation of excess risk but incidence rates 3-5 to 291 per 100 000 immunisations). Stronger evidence of a possible causal relation (ie, evidence that "indicates a causal relation") was found between DTP and anaphylaxis (incidence rates 2 cases per 100 000 injections DTP and 6 per 100 000 children given three doses of DTP) and between the pertussis component of DTP and protracted inconsolable crying (incidence rates 0’ 1 to 6% recipients of a DTP injection). There was insufficient evidence to indicate a causal relation with chronic neurological damage, learning disabilities, and attention deficit disorder. The IOM team was not asked to examine febrile seizures, afebrile seizures, or epilepsy, but did so because these are considered by some to be components of encephalopathy. The conclusion was that the evidence indicates a causal relation between DTP vaccine and febrile seizures but not between DTP vaccine and afebrile seizures. The evidence was insufficient for conclusions to be drawn about epilepsy. CP, Fineberg HV Adverse events following pertussis and rubella vaccine. Summary of a report of the Institute of Medicine. JAMA 1992; 267: 392-96. 2. Alderslade R, Bellman MH, Rawson NSB, Ross EM, Miller DL. The National Childhood Encephalopathy Study. In: Whooping cough: Reports from the Committee on Safety of Medicine and Joint Committee of Vaccination and Immunisation. London: HM Stationery Office. 1981: 79-169. 1. Howson
Infections in intensive
care
Patients in intensive care, already severely ill, are at greatly increased risk ofnosocomial infections, the prevalence in intensivecare units (ICUs) ranging from 13 to 42% compared with 5-10% for hospital-acquired infections in general.1 The first step towards reducing this alarmingly high rate of infection is to improve knowledge of the patterns of infections. The European Prevalence of Infection in Intensive Care (EPIC) study, funded by Roussel Uclaf, has been set up to gather information on the prevalence of infections in ICUs, demographic profiles of infected patients, risk factors (eg, the use of immunosuppressive drugs and invasive procedures), pathogens, and antibiotics prescribed. EPIC is hoping to recruit at least 20% of ICUs in 17 European countries to take part in a one-day point prevalence study, on April 29. Many infections could probably be prevented with simple measures, such as the enforcement of basic handwashing techniques, but even more fundamental is the need to ensure that all members of the ICU team are aware of the extent of infection and have the necessary information to develop priorities for infection control. A report of three separate outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) infection in a Dutch university hospitaP shows the extreme measures sometimes needed to eradicate a resistant organism. The Scutari strategy of isolating infected patients did not work, and SALT (Staph aureus limitation technique) was regarded as unacceptable because it applies less rigorous controls to colonised patients than infected ones. Vandenbroucke-Grauls et al chose instead a more vigorous "search and destroy" approach, which involved isolation of infected patients, search for symptom-free carriers, keeping track of known carriers through hospital records, and isolation and screening of patients coming from other hospitals with MRSA. Further information on the EPIC study is available from Medical Action Communications, Action International House, Crabtree Office Village, Eversley Way, Thorpe, Egham, Surrey TW20 8RY, UK (telephone 0784 434353, fax 0784 431323).
1. Daschner F Nosocomial infections
in intensive care units. Intensive Care Med 1985; 11: 284-87. 2. Vandenbroucke-Grauls CM, Frenay HME, van Klingeren B, Savelkoul TF. Control of epidemic methicillin-resistant Staphylococcus aureus in a Dutch university hospital. Eur J Clin Microbiol Infect Dis 1990; 10: 6-11.
amounted to a breach of their statutory duty. However, BT’s failure to warn of the risk that keyboard work might cause RSI to new recruits or to encourage workers to report any aches and pains at onset did not amount to a breach of
statutory duty. Diana Brahams
Conference AIDS in Africa 1 in 40 African adults is now infected with HIV. These 6 million women and men, and the three-quarters of a million infected children, are unevenly distributed over the continent. In East Africa the real burden of disease and death is only just beginning to be felt, but already AIDS cases make up to 80% of the case-load in some adult hospital wards. Practically everywhere the number of people with asymptomatic HIV infections is multiplying rapidly. 1 in 8 adults in Abidjan now carry HIV 1 or HIV 2. The burden of associated diseases is overwhelming: 40% of patients dying from AIDS have cerebral lesions, most commonly toxoplasmosis and tuberculosis. Already there are 50 000 AIDS orphans in just one region (Kagera) in Tanzania, and agricultural production in the same area has fallen by 3-20%. Yet only a small fraction of those infected with HIV in any part of Africa have died. From the point of view of cost to the community and health services the epidemic is
only just beginning. The Sixth International Conference
on
graciously opened by the President of Senegal, Monsieur Aboon Diouf, and even President Bush sent a message. Finally, such conferences disseminate information to the rest of the world. For example, studies in Nairobi suggest that the use of oral contraceptives and intrauterine devices is associated with any increased or reduced risk of seroconversion, and data from Cameroon give some preliminary evidence of a protective effect of spermicide use on the acquisition of HIV. More evidence is accumulating about the long incubation period of HIV-2. But despite much of interest, many of the outcomes of the meeting might have been achieved more cost-effectively. Perhaps the several, much smaller, satellite meetings by WHO/GPA, Family Health International, and Bristol Myers Squibb held in Dakar are a more appropriate model for the future. Certainly another world conference in Amsterdam in the middle of 1992 and a Seventh AIDS in Africa conference in Yaounde at the end of next year seems a bit like conference overload. One participant, who has known AIDS for longer and more closely than most, saw the Dakar meeting "as a rerun of the first AIDS in Africa conference in Brussels in 1985 but with the decimal point moved". In other words, HIV prevalences continue to rise and even experts do not always learn quickly enough.
not
International First Floor,
Family Health,
Margaret Pyke Centre, 15 Bateman’s Buildings, London W1V 5TW
Malcolm Potts
AIDS in Africa
(Dec 16-18, 1991) brought 1800 participants from 79 countries to Dakar, Senegal. Many conference presentations measured the spread of HIV or threw light on the
knowledge and attitudes of vulnerable groups such as prostitutes and their clients. Less than 10% of commercial sex workers in one Cameroon sample used condoms regularly and 60% of long-distance lorry drivers in Zimbabwe have sex with a prostitute at least once a month. Somewhat fewer papers dealt with preventive measures such as education, distribution of condoms, or treatment of other sexually transmitted diseases (STD). The poverty of the Sahel, political unrest in Zaire, debt burdens in Nigeria, and the legacy of previous bad government in Uganda are all factors mitigating against disease control. So is the low status of women. In many parts of Africa women handle much of the subsistence farming and petty commerce but receive the least reward. Even so, there have been successes in HIV prevention: prostitutes in Ghana have changed their behaviour, the social marketing of condoms in Zaire has been most successful, and the comprehensive control of STDs through government services has been initiated in Tanzania. The challenge is to develop the will and mobilise the resources (national and international) to turn pilot projects into epidemiologically significant programmes. At present, however, it is difficult to escape the conclusion that HIV is out of control. Among other things, it must also be asked whether large, expensive conferences are themselves an appropriate response? Conferences help forge needed partnerships between developing and developed countries and are certainly essential for recharging the skills and motivation for those fighting in the trenches in the battle against AIDS. Scientists from Belgium, France, and the USA played an important part in the Dakar meeting. Conferences also allow national leaders to express support: the sixth conference was
Noticeboard Safeguards for gene therapy Somatic gene
therapy
will be allowed in the UK if the
recommendations of the Committee on the Ethics of Gene Therapy are accepted by the Government. But the Department of Health will be seeking the views of many professional and lay organisations before the Government reaches its decision. The consultation period will end on May 18. Any proposed gene therapy must be ethically acceptable and shown to be safe, says the committee’s report, published last week.’ The committee, a non-statutory body set up by UK health ministers in 1989 under the chairmanship of Sir Cecil Clothier, QC, says that gene therapy raises no new ethical issues, but because the treatment is new it recommends that gene therapy should be subject to the ethical codes that apply to research involving patients. Familiar ethical considerations that are likely to assume greater prominence when gene therapy is being considered include safety (because of the possibility of unpredicted consequences of gene insertion), the need for long-term surveillance, consent (especially regarding uncertainties about outcome), the probability that children will be among the first candidates for gene therapy, and
confidentiality. Gene therapy, the committee recommends, should be restricted to the alleviation of disease in individual patients and should not be used to change normal human traits. The first candidates for gene therapy should be patients with a lifethreatening or seriously disabling genetic disease. Severe genetic disorders that show their effects in early childhood, or even before birth, should be treated correspondingly early. Germline gene therapy should not be attempted at present, says the report, because "there is insufficient knowledge to evaluate the risk to future generations". At a meeting of the Human Genome Organisation in London last August Dame Mary Warnock, chairman of the 1984 committee that approved in-vitro fertilisation and limited research on human embryos, said that unpredictable outcome was a more valid reason for rejecting germline therapy than was
fear of doctors’ powers.
239
In
drawing
up its
guidelines the Clothier Committee took
account of the public’s concerns about "a procedure which could be
used to change human characteristics" and irrational fears "which derive from misunderstandings of biology ... and popular creations of fiction, such as Frankenstein’s monster". The committee proposes that a non-statutory expert advisory board be set up to work in conjunction with local research ethics committees to assess proposals for gene therapy, including its supervision. Until substantive arrangements for assessment are in place proposals for gene therapy should be submitted to the local research ethics committee and to the Clothier Committee. 1.
Report of the Committee on the Ethics of Gene Therapy. Cm Stationery Office. 1992. £6. Pp 90 ISBN 0-101178824.
Trial
1788. London: HM
by myth
US criminal courts perpetuate stereotypes of patients with AIDS and frequently contradict current knowledge on the risk factors of HIV infection. So says the second report of the US AIDS Litigation Project, an ongoing investigation funded jointly by the National AIDSProgram Office and the US Public Health Serviced The aim of this scheme is to promote wider knowledge among the legal profession and public about laws concerning the rights of AIDS patients. The latest report discusses 817 cases, most of which focus on alleged discrimination and criminal law litigation. Not only is HIV disease a major scientific and public health issue in both the developing and the developed world, but it is also, to quote Dr Jim Allen, Director of the National AIDS Program Office, "the most litigated disease in history". Prosecutions have been made against HIV-positive people on the basis of attempted murder and assault with a deadly weapon. Courts have shown little understanding of the relative risks of behaviours that might be associated with the transmission of HIV. Judges seem to have difficulty in deciding whether and, if so, how the outcome of an act (which may be inconsequential), the act itself (such as a bite), or the intention behind the act should be punished. Health insurance is a particular cause for concern. A company has already tried to bring an action to annul retrospectively a policy after the deceased was found to be HIV positive, even though that individual was unaware of his antibody status. The failure of the judiciary to defend the human rights of those with HIV infection is, the report notes, a reflection of the poor AIDS education policy of the current Bush administration. Combined with the recent debacle over entry of HIV-positive delegates to the US for an AIDS conference, the US Government and its instruments of state continue to give negative signals to a population in desperate need of an aggressive but fair public health education programme about HIV disease. 1 Gostin L, Porter L. The AIDS Litigation Project II: a national review of court and Human Rights Commission decisions. Washington DC: US Public Health Service, 1992. Pp 372 Copies available from National AIDS Program Office, Humphrey Building, 200 Independence Avenue SW, Washington DC, 20201,
USA.
Reassurance on safety of pertussis vaccines A report commissioned by the US Government provides that the risks of severe permanent adverse effects after pertussis vaccination are very low. The report was a review by the Institute of Medicine (IOM) at the National Academy of Sciences, Washington DC, of information on possible adverse consequences of pertussis and rubella vaccines. It was released in August, 1991, and has been summarised in the Jan 15 issue of the Journal of the American Medical Association.1 The IOM review examined 18 adverse effects in relation to DTP vaccine and 4 in relation to the currently used vaccine strain RA 27/B. Evidence for a causal relation with pertussis vaccine was found for four adverse effects, and that with rubella vaccine for two. For DTP, evidence "consistent with a causal relation" was found for acute encephalopathy (range of excess risks 00 to 10-5 per million immunisations). The IOM concludes that this degree of risk reassurance
reported by the UK National Childhood Encephalopathy Studythe only large case-control study of vaccine-related encephalopathy so far. The NCES had concluded that the data suggested but did not prove that DTP causes serious acute neurological disorders in the first 7 days after 1 in 310 000 is consistent with that
vaccinations. The IOM also found evidence consistent with a causal relation and for shock and unusual shock-like state (data insufficient for calculation of excess risk but incidence rates 3-5 to 291 per 100 000 immunisations). Stronger evidence of a possible causal relation (ie, evidence that "indicates a causal relation") was found between DTP and anaphylaxis (incidence rates 2 cases per 100 000 injections DTP and 6 per 100 000 children given three doses of DTP) and between the pertussis component of DTP and protracted inconsolable crying (incidence rates 0’ 1 to 6% recipients of a DTP injection). There was insufficient evidence to indicate a causal relation with chronic neurological damage, learning disabilities, and attention deficit disorder. The IOM team was not asked to examine febrile seizures, afebrile seizures, or epilepsy, but did so because these are considered by some to be components of encephalopathy. The conclusion was that the evidence indicates a causal relation between DTP vaccine and febrile seizures but not between DTP vaccine and afebrile seizures. The evidence was insufficient for conclusions to be drawn about epilepsy. CP, Fineberg HV Adverse events following pertussis and rubella vaccine. Summary of a report of the Institute of Medicine. JAMA 1992; 267: 392-96. 2. Alderslade R, Bellman MH, Rawson NSB, Ross EM, Miller DL. The National Childhood Encephalopathy Study. In: Whooping cough: Reports from the Committee on Safety of Medicine and Joint Committee of Vaccination and Immunisation. London: HM Stationery Office. 1981: 79-169. 1. Howson
Infections in intensive
care
Patients in intensive care, already severely ill, are at greatly increased risk ofnosocomial infections, the prevalence in intensivecare units (ICUs) ranging from 13 to 42% compared with 5-10% for hospital-acquired infections in general.1 The first step towards reducing this alarmingly high rate of infection is to improve knowledge of the patterns of infections. The European Prevalence of Infection in Intensive Care (EPIC) study, funded by Roussel Uclaf, has been set up to gather information on the prevalence of infections in ICUs, demographic profiles of infected patients, risk factors (eg, the use of immunosuppressive drugs and invasive procedures), pathogens, and antibiotics prescribed. EPIC is hoping to recruit at least 20% of ICUs in 17 European countries to take part in a one-day point prevalence study, on April 29. Many infections could probably be prevented with simple measures, such as the enforcement of basic handwashing techniques, but even more fundamental is the need to ensure that all members of the ICU team are aware of the extent of infection and have the necessary information to develop priorities for infection control. A report of three separate outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) infection in a Dutch university hospitaP shows the extreme measures sometimes needed to eradicate a resistant organism. The Scutari strategy of isolating infected patients did not work, and SALT (Staph aureus limitation technique) was regarded as unacceptable because it applies less rigorous controls to colonised patients than infected ones. Vandenbroucke-Grauls et al chose instead a more vigorous "search and destroy" approach, which involved isolation of infected patients, search for symptom-free carriers, keeping track of known carriers through hospital records, and isolation and screening of patients coming from other hospitals with MRSA. Further information on the EPIC study is available from Medical Action Communications, Action International House, Crabtree Office Village, Eversley Way, Thorpe, Egham, Surrey TW20 8RY, UK (telephone 0784 434353, fax 0784 431323).
1. Daschner F Nosocomial infections
in intensive care units. Intensive Care Med 1985; 11: 284-87. 2. Vandenbroucke-Grauls CM, Frenay HME, van Klingeren B, Savelkoul TF. Control of epidemic methicillin-resistant Staphylococcus aureus in a Dutch university hospital. Eur J Clin Microbiol Infect Dis 1990; 10: 6-11.