Practical experience of ustekinumab in the treatment of psoriasis: experience from a multicentre, retrospective case cohort study across the U.K. and Ireland.

BACKGROUND: There are limited data on the use of ustekinumab outside of clinical trials. OBJECTIVES: To assess the efficacy and safety of ustekinumab in patients with severe psoriasis attending 10 dermatology centres in the U.K. and Ireland. METHODS: A retrospective case-note review of 129 patients with psoriasis treated with ustekinumab. RESULTS: Baseline Psoriasis Area and Severity Index (PASI) was 22·9±10·1 (mean±SD). After 16weeks of treatment with ustekinumab PASI 75 (75% reduction in PASI) was observed in 63·0% (n=80/127) of patients, although four patients required concomitant therapy at the 16-week time point. Previous biologic use did show a small, non-significant trend towards treatment failure. A PASI 75 response was seen in 29·4% (n=5/17) of individuals weighing 90-100kg and treated with the standard 45mg ustekinumab dose compared with PASI 75 of 70·3%, 71·4%, 75·0% and 55·6% for weight groups <80, 80-90, 100-110 and >110kg, respectively (P=0·024). Ustekinumab therapy was well tolerated; serious adverse events were observed in 2·3% (n=3/129) of patients. CONCLUSIONS: Ustekinumab is a novel biologic agent for psoriasis. When used in everyday clinical practice it demonstrates high levels of short-term therapeutic efficacy with an acceptable short-term safety profile.

Tunable stiffness enables fast and efficient swimming in fish-like robots.

Fish maintain high swimming efficiencies over a wide range of speeds. A key to this achievement is their flexibility, yet even flexible robotic fish trail real fish in terms of performance. Here, we explore how fish leverage tunable flexibility by using their muscles to modulate the stiffness of their tails to achieve efficient swimming. We derived a model that explains how and why tuning stiffness affects performance. We show that to maximize efficiency, muscle tension should scale with swimming speed squared, offering a simple tuning strategy for fish-like robots. Tuning stiffness can double swimming efficiency at tuna-like frequencies and speeds (0 to 6 hertz; 0 to 2 body lengths per second). Energy savings increase with frequency, suggesting that high-frequency fish-like robots have the most to gain from tuning stiffness.

Control of head lice with a coconut-derived emulsion shampoo.

OBJECTIVE: To evaluate a novel coconut-derived emulsion (CDE) shampoo against head lice infestation in children. DESIGN: A school trial in which pupils were treated on days 0 and 7 and checked on days 8 and 15 and a family trial where product was applied by parents three times in 2 weeks or used as a cosmetic shampoo and checked on days 14 and days 70. SETTING: UK schools in Bristol and Western-super-Mare and families in Northern Somerset. MAIN OUTCOME MEASURE: Numbers of children free from infestation after treatment. RESULTS: In the school trial, percentage cures at day 8 were 14% (permethrin, n=7) and 61% (CDE, n=37). In the family trial where all family members were treated, cure rate was 96% (n=28), and if the shampoo was subsequently used as a cosmetic shampoo, only 1 of 12 children became re-infested after 10 weeks. CONCLUSION: CDE shampoo is a novel effective method of controlling head lice and used after treatment as a cosmetic shampoo can aid in the reduction of re-infestation.

Surveillance of AIDS in the European Community: recent trends and predictions to 1991.

Statistical modelling is applied to routine AIDS surveillance data to assess recent trends and to provide a range of short-term predictions. Several alternative functions have been fitted to half-yearly incidence data reported by the countries of the European Community by 31 December 1989 and adjusted for reporting delays. Among homosexual/bisexual men, recent trends in AIDS incidence are more nearly linear than exponential. Higher though less than exponential rates of growth are observed among intravenous drug users and among those presumed infected by heterosexual contact. Extrapolations to the end of 1991 using each of five functions provide a range of forecasts. Projections of total cumulated cases to the end of 1991 lie in the range 60,000-78,000, with 24,000-30,000 projected cases among homosexual/bisexual men, 23,000-33,000 among intravenous drug users, and 6000-8000 in the heterosexual transmission group. With the possible exception of the latter group, the lower parts of these ranges appear more probable.

AIDS in Europe: current trends and short-term predictions estimated from surveillance data, January 1981-June 1986.

European AIDS surveillance data, reported to the World Health Organization (WHO) Collaborating Centre on AIDS, Paris by 30 June 1986, have been analysed statistically to assess current trends and to provide short-term predictions. Reported case numbers were first adjusted to allow for the estimated time delays between diagnosis and reporting. The adjusted data (cases per half-year of diagnosis) were then fitted using exponential functions over selected time intervals to monitor and compare the evolution of the epidemic in individual countries and in the European Community (EC) as a whole. Predictions to mid-1988 were made by extrapolation. Results are presented for the EC and for the following individual countries: Belgium, Denmark, France, Federal Republic of Germany, Italy, The Netherlands, Spain, Sweden, Switzerland and the United Kingdom.

Back-calculation by birth cohort, incorporating age- specific disease progression, pre-AIDS mortality and change in European AIDS case definition. European Union Concerted Action on Multinational AIDS Scenarios.

OBJECTIVES: To adapt and improve methodology for back-calculation of AIDS in Europe and to examine the feasibility of estimating past HIV incidence by birth cohort. METHODS: Empirical Bayesian back-calculation (EBBC) used Markov disease progression models, modified to allow for three diseases added to the AIDS case definition in 1993 and for pre-AIDS mortality, and estimation by penalized maximum likelihood with a neighbour prior. EBBC by 5-year birth cohort assumed a minimum age at infection and age-dependent progression rates; three versions, with varying age effects, were investigated using AIDS cases diagnosed prior to the introduction of highly active antiretroviral therapies (HAART). RESULTS: Compared with the no age-effect version, EBBC by birth cohort tended to produce flattened HIV incidence curves in country-exposure groups with < 1000 AIDS cases, reflecting effects of the neighbour prior when data become sparse. Otherwise, birth cohort analysis, with moderate effects of age on progression, gave initially increasing incidence curves and consistent patterns across countries, with the 1960-1964 cohort most affected. In the European Union, incidence is estimated to have peaked in 1983 among homosexual men and in 1988 among injecting drug users; 460000 persons were estimated to be living with HIV/AIDS at the end of 1995. CONCLUSIONS: Our improved methodology deals effectively with the change in AIDS case definition and has allowed quantitative assessments of the HIV epidemic by birth cohort using all AIDS cases diagnosed before 1996, thus providing a sound basis for public health policy at a time when estimation of more recent prevalence is compromised by the effects of HAART.

Reconstruction and prediction of the HIV/AIDS epidemic among adults in the European Union and in the low prevalence countries of central and eastern Europe.

OBJECTIVES: To reconstruct the HIV epidemic and to provide forecasts of AIDS incidence among adults in the European Union (EU) and in a group of low prevalence (LP) countries of central and eastern Europe (including the Asian republics of the former Soviet Union). METHODS: An empirical Bayesian back-calculation method was applied to AIDS incidence data reported by 31 March 1994. The HIV-infection curve was modelled as a yearly step function and a seven-stage Markov model of disease progression, incorporating effects of pre-AIDS treatment, was used. Estimation was by penalized maximum likelihood with empirical Bayesian smoothing. Data were analysed by transmission group and, within the EU, by country. Predictions of AIDS cases to 1998 were made assuming constant annual HIV incidence from 1993 onwards. RESULTS: Estimated HIV prevalences per 100,000 population aged 15-59 years were, at 31 December 1993, 198 (n = 447,800) in the EU and 2.7 (n = 6840) in the 22 LP countries, with increases of 41% (EU) and 71% (LP) between 1989 and 1993. Among homo/bisexual men in the EU, prevalence appears to have stabilized since 1989 and AIDS incidence appears to be reaching a peak. Among all prevalent HIV infections in the EU, 42% were estimated to be among injecting drug users, 25% among homo-/bisexual men and 18% among persons infected heterosexually, compared with 29%, 35% and 19%, respectively, in the LP countries. Without allowing for the 1993 revision of the case definition, annual AIDS incidence is predicted to increase, between 1994 and 1998, by 24% in the EU and by 48% in the LP countries, with the largest percentage increases among heterosexually-infected persons. CONCLUSION: The overall HIV prevalence rate is estimated to have been about 70-fold lower in the LP countries than in the EU in the early 1990s, but to be increasing much more rapidly in the former. Moreover, recent reports of rapidly increasing HIV infection rates suggest that back-calculation may seriously underestimate the size of the epidemic in the LP countries. Implementation of effective preventive measures is urgent if large-scale epidemics are to be avoided in the presently LP countries of the European region.

The HIV epidemic associated with injecting drug use in Europe: geographic and time trends.

OBJECTIVES: To evaluate the magnitude and trends of the HIV epidemic associated with injecting drug use in Europe. METHODS: AIDS cases associated with injecting drug users (IDU) diagnosed through 1995 were analysed, including IDU, homo-/bisexual IDU, heterosexual partners of IDU and children whose mothers were IDU. HIV seroprevalence studies among IDU were reviewed. RESULTS: Of the 171,932 cumulative AIDS cases, 73,119 (43%) were IDU-associated (IDU, 89.0%; homo-/bisexual IDU, 3.5%: heterosexual partners of IDU, 6.2%; children with IDU mothers, 1.4%). Over 90% of IDU-associated cases were concentrated in south-western European countries with considerably higher rates in Spain (124 cases per million in 1995) than elsewhere (Italy, 68 per million; Portugal, 42 per million; France, 38 per million). During 1990-1995, incidence increased at an average annual rate of 11% overall and > 23% in central and eastern Europe; overall, incidence increased in older persons (12%) while decreasing in those aged 13-24 years (by 6%). HIV prevalence in IDU showed considerable geographic variation across and within countries. In several countries of western Europe, prevalence decreased. In the former Soviet Union, large HIV outbreaks have recently been detected among IDU through systematic HIV testing (e.g., in Ukraine, 6750 HIV infections were diagnosed in IDU tested during 1995-1996). CONCLUSIONS: IDU have played a major role in the spread of HIV in Europe. In several western European countries, the incidence of HIV acquired through drug use has declined following high rates in mid-1980s. Studies to assess current transmission are needed and prevention efforts must be maintained. In eastern Europe, emerging epidemics reinforce the urgency for prevention.

Time trends in HIV infection among pregnant women in Europe.

OBJECTIVE: To estimate time trends in HIV prevalence among pregnant women delivering livebirths in 14 European countries using a uniform methodology. METHODS: A form of back-projection was used to estimate HIV prevalence among pregnant women based on reported cases of AIDS due to perinatally acquired HIV infection. The method used estimates the rate of progression to AIDS in children with HIV, and the rate of transmission of HIV from mother to child, derived from published studies. RESULTS: The prevalence of HIV among pregnant women delivering livebirths was estimated to be highest in Spain (2.61 per 1000 livebirths in 1992-1993), relatively high (> or = 0.3 per 1000 livebirths) throughout the period 1984-1993 in France, Italy and Switzerland, and low (< 0.2 per 1000 livebirths) in Germany, The Netherlands and Scandinavia. There were large and statistically significant increasing trends in the estimated HIV prevalence among pregnant women in Portugal (an estimated 77% increase per 2-year period), Spain (40% increase) and the United Kingdom (77% increase; all P < 0.001). Statistically significant increasing trends of a smaller magnitude were estimated for France (24% increase) and Italy (23% increase; both P < 0.001). CONCLUSIONS: Sharp increases in HIV prevalence among pregnant women were estimated for several European countries, whereas in other countries no trends in the estimated prevalence were detected.

Economic impact of the AIDS epidemic in the European Community: towards multinational scenarios on hospital care and costs.

OBJECTIVE: To underpin multinational public-health HIV/AIDS strategy planning in the European Community (EC) by integrating national studies on HIV/AIDS in scenario analysis. METHOD: Three types of data are used: routine surveillance data, information on disease progression and observational studies on the economic impact. The HIV/AIDS epidemic is simulated using two models (MIDAS and PC-Based AIDS Scenarios). Selected simulations, consistent with surveillance data, are connected to economic impact (hospital-bed needs and annual hospital costs for AIDS patients). Parameter values expressing per person-year economic impacts are derived from a structured review of publications on economic aspects of AIDS. RESULTS: Evaluation of published studies on hospital resource use and costs in EC countries shows that there are significant differences between both countries and studies, even after conversion to similar measures (for example, using purchasing power parities). These differences are partly due to factors such as the composition of the patient population. Differences in methodology may also have influenced the results. Economic impact is analysed for combinations of three factors; survival time after AIDS diagnosis, hospital inpatient days needed per person-year and corresponding hospital costs per person-year. All scenarios indicate 1995 hospital-bed needs above the 1990 level of 5400 beds. Hospital cost projections for 1995 vary (up to US$1050 million). CONCLUSIONS: (1) For economic impact assessment, there are important gaps in epidemiological and economic data, and in the methods for linking these. (2) Standardization of studies on the resource use and costs of HIV/AIDS is necessary to provide a sound basis for multinational scenarios. (3) Preliminary multinational scenarios show that by 1995 hospital-bed needs for AIDS might reach 0.45% of all hospital beds available in the EC, and that hospital cost projections for AIDS in that year will range from 0.15% to 0.30% of EC health-care expenditure.

Transfusion-associated AIDS cases in Europe: estimation of the incubation period distribution and prediction of future cases.

European data on transfusion-associated (TA) AIDS cases reported by December 31, 1989 have been analyzed using both parametric and nonparametric methods. Parametric estimates of the median incubation period of TA AIDS in adults vary from 6.5 to 11 years according to the type of distribution assumed (Weibull or gamma) and the latest year of diagnosis included (1987 or 1988). The latter finding may reflect a lengthening of the incubation period due to increasing treatment of HIV-infected patients prior to the development of AIDS. It is predicted that, by the end of 1991, between 2,000 and 3,000 cases of AIDS will have been diagnosed in Europe among adults infected by transfusion between 1978 and 1985 (when systematic screening of donated blood was introduced in most western countries). It is not possible, however, to predict how many further cases may arise among those transfused more recently in countries in which screening was introduced at a later date.

Use of the allogeneic TCR repertoire to enhance anti-tumor immunity.

It is well established that antigen-specific T lymphocytes can inhibit tumor growth in humans and in mice, leading to complete tumor elimination in some cases. However, in many cases T cell immunity is unable to successfully control tumor progression. Since tumors are derived from normal tissues, most antigens are shared with normal tissues, although expression levels are usually elevated in malignant cells. Nevertheless, low-level expression in normal cells can be sufficient to render autologous T cells tolerant and thus unable to mount effective immune responses against tumors. Here, we review how allogeneic T cells can be used to isolate T cells that effectively recognise and kill tumor cells, but not normal cells with low level of antigen expression. The TCR of allogeneic T cells can be introduced into patient T cells to equip them with anti-tumor specificity that may not be present in the autologous T cell repertoire.

Physical therapy in lung transplantation.

Lung transplantation requires the skillful attention of a health care team to provide optimal results. The physical therapist is an integral part of this team, providing expertise in exercise testing and prescription in all phases, from initial evaluation through postoperative rehabilitation and beyond. In addition, the physical therapist promotes effective ventilation, offers techniques for enhanced coughing and mucociliary clearance, and provides treatment of the musculoskeletal system. Lung transplantation is reserved for patients in whom all other treatments have been exhausted. It is important for the physical therapist to stay abreast of the evolving field of lung transplantation, including medications and complications. The physical therapist has a critical role in helping lung transplant recipients achieve optimal function, increased survival, and improved quality of life.

Rates of regression and progression of dysplastic lesions in the nasal mucosa in nickel workers: a Markov model approach.

Nasal epithelial dysplasia is considered a precancerous state. From 1976 through 1989, regular screening for such lesions has been performed among workers at the Falconbridge nickel refinery in Kristiansand. The longitudinal data thus obtained have been evaluated to ascertain to what extent, if any, pre-existing dysplasia can regress when exposure to nickel is reduced. A total of 418 pairs of observations were available from 243 workers. Interpretation of the data is complicated by the fact that dysplasia may remain undetected in small biopsies and the probability of detection of existing dysplasia was, therefore, incorporated into the two-state Markov model. Transition probability rates were estimated by maximum likelihood. The results suggest that regression of dysplasia has taken place and that regression rates increased with time. This finding probably reflects a decreased exposure resulting from a combination of a reduction in airborne nickel, improved personal hygiene and allocation of workers with dysplasia to work in areas with lower nickel exposure. Our results indicate that the chance of developing carcinomas related to nickel exposure is reduced. There are, however, indications that dysplasias continue to develop at a low rate.

Hospital care for persons with AIDS in the European Union.

This study estimates the current and future hospital resources for AIDS patients in the European Union (EU), using multinational scenario analysis (EU Concerted Action BMH1-CT-941723). In collaboration with another EU-project ('Managing the Costs of HIV Infection'), six national European studies on the utilization of hospital care for AIDS have been selected to provide the data for our analysis. The selection criteria involve recentness, quality, comparability, accessibility and representativeness. Baseline hospital resource utilization is estimated for hospital inpatient days and outpatient contracts, using a standardized approach controlling for two severity stages of AIDS (chronic stage and late stage). The epidemiological part of the study is based on standard models for backcalculating HIV incidence and projecting AIDS incidence, prevalence and mortality. In the next step, baseline resource utilization is linked to epidemiological information in a mixed prevalence and mortality-based approach. Several scenarios render different future epidemiological developments and hospital resource needs. For the year 1999, hospital bed needs of 10,000-12,700 in the EU are indicated, representing an increase of 20-60% compared to the estimated current (1995) level. The projected range for 1999 corresponds to a maximum of 0.65% of all hospital beds available in the EU. The growth in the number of outpatient hospital contacts is projected to possibly exceed that of inpatient days up to 1.82 million in 1999. Our methodology illustrates that estimation of current and future hospital care for AIDS has to be controlled for severity stages, to prevent biases. Further application of the multinational approach is demonstrated through a 'what-if' analysis of the potential impact of combination triple therapy for HIV/AIDS. Estimation of the economic impact of other diseases could as well benefit from the severity-stages approach.