Adaptive designs in critical care trials: a simulation study.

BACKGROUND: Adaptive clinical trials are growing in popularity as they are more flexible, efficient and ethical than traditional fixed designs. However, notwithstanding their increased use in assessing treatments for COVID-19, their use in critical care trials remains limited. A better understanding of the relative benefits of various adaptive designs may increase their use and interpretation. METHODS: Using two large critical care trials (ADRENAL. CLINICALTRIALS: gov number, NCT01448109. Updated 12-12-2017; NICE-SUGAR. CLINICALTRIALS: gov number, NCT00220987. Updated 01-29-2009), we assessed the performance of three frequentist and two bayesian adaptive approaches. We retrospectively re-analysed the trials with one, two, four, and nine equally spaced interims. Using the original hypotheses, we conducted 10,000 simulations to derive error rates, probabilities of making an early correct and incorrect decision, expected sample size and treatment effect estimates under the null scenario (no treatment effect) and alternative scenario (a positive treatment effect). We used a logistic regression model with 90-day mortality as the outcome and the treatment arm as the covariate. The null hypothesis was tested using a two-sided significance level (α) at 0.05. RESULTS: Across all approaches, increasing the number of interims led to a decreased expected sample size. Under the null scenario, group sequential approaches provided good control of the type-I error rate; however, the type I error rate inflation was an issue for the Bayesian approaches. The Bayesian Predictive Probability and O'Brien-Fleming approaches showed the highest probability of correctly stopping the trials (around 95%). Under the alternative scenario, the Bayesian approaches showed the highest overall probability of correctly stopping the ADRENAL trial for efficacy (around 91%), whereas the Haybittle-Peto approach achieved the greatest power for the NICE-SUGAR trial. Treatment effect estimates became increasingly underestimated as the number of interims increased. CONCLUSIONS: This study confirms the right adaptive design can reach the same conclusion as a fixed design with a much-reduced sample size. The efficiency gain associated with an increased number of interims is highly relevant to late-phase critical care trials with large sample sizes and short follow-up times. Systematically exploring adaptive methods at the trial design stage will aid the choice of the most appropriate method.

A lifestyle intervention programme for the prevention of Type 2 diabetes mellitus among South Asian women with gestational diabetes mellitus [LIVING study]: protocol for a randomized trial.

AIM: This study aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable. METHODS: Women with GDM (diagnosed by oral glucose tolerance test using the International Association of the Diabetes and Pregnancy Study Groups criteria) will be recruited from 16 hospitals in India, Sri Lanka and Bangladesh. Participants will undergo a repeat oral glucose tolerance test at 6 ± 3 months postpartum and those without Type 2 diabetes, a total sample size of 1414, will be randomly allocated to the intervention or usual care. The intervention will consist of four group sessions, 84 SMS or voice messages and review phone calls over the first year. Participants requiring intensification of the intervention will receive two additional individual sessions over the latter half of the first year. Median follow-up will be 2 years. The primary outcome is the proportion of women with a change in glycaemic category, using the American Diabetes Association criteria: (i) normal glucose tolerance to impaired fasting glucose, or impaired glucose tolerance, or Type 2 diabetes; or (ii) impaired fasting glucose or impaired glucose tolerance to Type 2 diabetes. Process evaluation will explore barriers and facilitators of implementation of the intervention in each local context, while trial-based and modelled economic evaluations will assess cost-effectiveness. DISCUSSION: The study will generate important new evidence about a potential strategy to address the long-term sequelae of GDM, a major and growing problem among women in South Asia. (Clinical Trials Registry of India No: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry No: SLCTR/2017/001; and ClinicalTrials.gov Identifier No: NCT03305939).

Near-field observation of surface plasmon polaritons launched by V-shaped nanorods on a gold surface.

By scanning near-field optical microscopy, we study the propagation of surface waves created by V-shaped nanorods deposited on a gold thin film. The nanorods launch surface plasmon polaritons that interfere with the incident light, producing interference patterns. The angle of the V-shaped rods varies from 110° to 180° (straight rod). We observe that the near-field distribution strongly depends on the angle of the V. For angles close to straight rods, a hot spot is visible, whereas for a narrower angle, the surface plasmon waves are launched in specific directions. The experimental results are in good qualitative agreement with numerical simulations performed with a simple analytical model that considers the rods as a sum of isolated surface plasmon sources.

The efficacy of lowering glycated haemoglobin with a gliclazide modified release-based intensive glucose lowering regimen in the ADVANCE trial.

The aim of these analyses was to examine the efficacy of the intensive gliclazide MR-based glucose lowering regimen used in the ADVANCE trial in lowering the level of glycated haemoglobin (HbA1c). All 11,140 randomised patients were included in analyses of treatment efficacy. Treatment efficacy was also examined in subgroups defined by baseline characteristics and treatments. At the end of 5 years follow-up, the mean HbA1c was reduced from 7.5% at baseline to 6.5% in those on intensive glucose control and to 7.3% in those on standard glucose control. With intensive glucose lowering greater proportions achieved HbA1c levels of < or =7.0%, < or =6.5% and < or =6.0%. With intensive glucose lowering substantial reductions in HbA1c were observed across subgroups defined by baseline age, sex, duration of diabetes, BMI, HbA1c or treatment regimen (p<0.0001). The main independent predictors of reduction in HbA1c during follow-up were baseline HbA1c, duration of diabetes and BMI. There was no weight gain in the intensive glucose control group and severe hypoglycaemia was uncommon, though more frequent than in the standard control group. Intensive glucose control with a gliclazide MR-based regimen was well tolerated and consistently effective in lowering HbA1c across a broad range of patient with type 2 diabetes.

Linear to radial polarization conversion in the THz domain using a passive system.

This paper addresses a passive system capable of converting a linearly polarized THz beam into a radially polarized one. This is obtained by extending to THz frequencies and waveguides an already proven concept based on mode selection in optical fibers. The approach is validated at 0.1 THz owing to the realization of a prototype involving a circular waveguide and two tapers that exhibits a radially polarized beam at its output. By a simple homothetic size reduction, the system can be easily adapted to higher THz frequencies.

New growth charts for Libyan preschool children.

To draw up new growth charts for Libyan children under 5 years of age, a cross-sectional survey was carried out in urban and rural areas in 2 regions of the Libyan Arab Jamahiriya from June 1999 to February 2000. Using WHO cluster sampling methodology, 1473 infants and children of both sexes aged between 0 and 59 months were selected from residential areas, maternal and child health centres, kindergartens and the delivery section of hospitals. Growth charts for weight-for-age, height-for-age and weight-for-height were plotted and smoothed, to provide reference curves for clinical, epidemiological and research purposes. In addition, mean Z-scores were analysed by sociodemographic variables collected from interviews with parents. Factors with a strong influence on childhood growth patterns were child's age, mother's education level and sex.

New growth charts for Libyan preschool children

To draw up new growth charts for Libyan children under 5 years of age, a cross-sectional survey was carried out in urban and rural areas in 2 regions of the Libyan Arab Jamahiriya from June 1999 to February 2000. Using WHO cluster sampling methodology, 1473 infants and children of both sexes aged between 0 and 59 months were selected from residential areas, maternal and child health centres, kindergartens and the delivery section of hospitals. Growth charts for weight-for-age, height for-age and weight-for-height were plotted and smoothed, to provide reference curves for clinical, epidemiological and research purposes. In addition, mean Z-scores were analysed by sociodemographic variables collected from interviews with parents. Factors with a strong influence on childhood growth patterns were child's age, mother's education level and sex

Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.

BACKGROUND: Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. METHODS: The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925. FINDINGS: After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline. INTERPRETATION: Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

French adolescent attitudes towards informal care for physical and emotional or relational problems.

UNLABELLED: The objective of this study was to determine adolescents' attitudes concerning the use of self-care and traditional medicines. A self-administered anonymous questionnaire with open-ended questions was completed by 543 adolescents aged 15-19 y. The results showed that the most frequent self-care activity for general health problems, in more than three-quarters of them, was self-medication; 14% of them resorted to minor home treatment such as taking care of wounds, bandaging or massages. Instructions for use were mentioned by 69% of adolescents as a way of choosing self-prescribed drugs. Natural medicines were used by 32% of the girls and 23% of the boys, mainly herbal teas or plant-based medicines, followed by homoeopathy. Self-care for emotional and relational problems mainly involved thinking about the problem and questioning themselves about their own behaviour or about the way they are. They also mentioned activities such as sports, going out, listening to music, watching television, and trying to think about something else by keeping themselves occupied. Natural medicines were used by 19% of the girls and 13% of the boys. Plant-based medicines or herbal teas were used most often, followed by drugs or alcohol, with homoeopathy in third place. CONCLUSION: Self-care and alternative medicines were used by adolescents in this study for physical as well as for emotional or relational problems. Their use did not reflect dissatisfaction with physicians and hospital treatment or an objection to formal services, but rather was a choice of these approaches for their own specific characteristics. They were also viewed as being less harmful than conventional treatment.

Nutritional status of Libyan children in 2000 compared with 1979.

This cross-sectional study examined the growth and nutritional status of Libyan preschool children and the socioeconomic status of their parents in 2000 and compared the results with those of a similar study conducted in 1979. The investigation involved 1614 healthy children of both sexes under 5 years of age in two regions of the Libyan Arab Jamahiriya. Simple random sampling and cluster sampling techniques were used to enlist participants. Body weight, height, and head and arm circumference of the children were recorded and mothers were interviewed about their child's health and the socioeconomic status of the family. Significant improvements in nutritional status since 1979 were found that could be attributable to factors such as socioeconomic development, longer breastfeeding, greater availability of high energy foods, supplementation with semi-solid or solid foods and heavy government subsidy of basic foods.

Growth of preschool children in the Libyan Arab Jamahiriya: regional and sociodemographic differences.

This cross-sectional study was performed in two regions of the Libyan Arab Jamahiriya. The aim was to study the growth and nutritional status of children under 5 years of age and the effect of socioeconomic factors on child development. Anthropometric indices (weight-for-age, height-for-age and weight-for-height) differed in the two regions. The prevalence of stunting was significantly higher among children from mainly rural Al Jabel Al Garby (6.1%) than those from urban Tripoli (2.5%). The z-scores that correlated strongly with under-nutrition included: mother's education, child's age and sex, and region. Stunting was significantly related to age and region and to maternal education level and family size. Wasting was highly correlated with maternal education.

[Attitudes regarding the delivery of formal and informal care: comparison of French and Chilean adolescents]. / Attitudes à l'égard des soins formels et informels: comparaison d'adolescents français et chiliens.

The representations that youth have of health professionals and young people's demands in terms of the operation and administration of services create an original and complex problematic. Clearly, this originality implies the important differences from one culture to another. For this very reason, it seemed that a comparative study relating the representations and attitudes confronted when care is sought by young people from countries with different cultural contexts would assist in comprehending why adolescents have such particular ways of using--or not using--formal and self-administered health services. An original open-ended response questionnaire was jointly designed and validated by a French and Chilean team. A mutually agreed upon sample of 957 school children, adolescents aged from 14 to 19, participated in the study in France and in Chili. The following correlations were found. In the event of a sleeping problem (or other general worry that is physically manifested), the mother is the privileged confidant, and in the specific case of a relationship or emotional problem, it is usually one of the adolescents' friends. The general practitioner is the favoured professional person in the event of a purely physical problem. When confronted with an emotional problem, one-third of adolescents say that they would not consider going to a consultation. The expectations of the French toward health professionals are more often within the "emotional" arena than those of the Chileans which generally concern the "medical/technical" field. The practice of self-administered care is qualitatively similar but the French prefer taking medication whereas the Chileans prefer the "little home remedies". The use of natural medicine is more widespread among young Chileans, but the types of medicine used are similar, namely herbal teas and other plant-based remedies and homeopathy. These results have a variety of implications, especially in terms of the need for training health professionals in the consideration of emotional and relationship problems. It is desirable that the official health care sector considers the care delivered outside of it as being complementary resources, which respond to the adolescents' need for autonomy, and then integrate those contributions into its own area of financial responsibility.

Growth of preschool children in the Libyan Arab Jamahiriya: regional and sociodemographic differences

This cross-sectional study was performed in two regions of the Libyan Arab Jamahiriya. The aim was to study the growth and nutritional status of children under 5 years of age and the effect of socioeconomic factors on child development. Anthropometric indices [weight-for-age, height-for-age and weight-for-height] differed in the two regions. The prevalence of stunting was significantly higher among children from mainly rural Al Jabel Al Garby [6.1%] than those from urban Tripoli [2.5%]. The z-scores that correlated strongly with under-nutrition included: mother's education, child's age and sex, and region. Stunting was significantly related to age and region and to maternal education level and family size. Wasting was highly correlated with maternal education

Nutritional status of Libyan children in 2000 compared with 1979

This cross-sectional study examined the growth and nutritional status of Libyan preschool children and the socioeconomic status of their parents in 2000 and compared the results with those of a similar study conducted in 1979. The investigation involved 1614 healthy children of both sexes under 5 years of age in two regions of the Libyan Arab Jamahiriya. Simple random sampling and cluster sampling techniques were used to enlist participants. Body weight, height, and head and arm circumference of the children were recorded and mothers were interviewed about their child's health and the socioeconomic status of the family. Significant improvements in nutritional status since 1979 were found that could be attributable to factors such as socioeconomic development, longer breastfeeding, greater availability of high energy foods, supplementation with semi-solid or solid foods and heavy government subsidy of basic foods