Expectations and experiences of gamete donors and donor-conceived adults searching for genetic relatives using DNA linking through a voluntary register.

STUDY QUESTION: What are the experiences of donor-conceived adults and donors who are searching for a genetic link through the use of a DNA-based voluntary register service? SUMMARY ANSWER: Donor-conceived adults and donors held positive beliefs about their search and although some concerns in relation to finding a genetically linked relative were reported, these were not a barrier to searching. WHAT IS KNOWN ALREADY: Research with donor-conceived people has consistently identified their interest in learning about-and in some cases making contact with-their donor and other genetic relatives. However, donor-conceived individuals or donors rarely have the opportunity to act on these desires. STUDY DESIGN, SIZE, AND DURATION: A questionnaire was administered for online completion using Bristol Online Surveys. The survey was live for 3 months and responses were collected anonymously. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: The survey was completed by 65 donor-conceived adults, 21 sperm donors and 5 oocyte donors who had registered with a DNA-based voluntary contact register in the UK. The questionnaire included socio-demographic questions, questions specifically developed for the purposes of this study and the standardized Aspects of Identity Questionnaire (AIQ). MAIN RESULTS AND THE ROLE OF CHANCE: Motivations for searching for genetic relatives were varied, with the most common reasons being curiosity and passing on information. Overall, participants who were already linked and those awaiting a link were positive about being linked and valued access to a DNA-based register. Collective identity (reflecting self-defining feelings of continuity and uniqueness), as assessed by the AIQ, was significantly lower for donor-conceived adults when compared with the donor groups (P < 0.05), but not significantly different between linked/not linked or length of time since disclosure of donor conception (all Ps > 0.05) for donor-conceived adults. LIMITATIONS, REASONS FOR CAUTION: Participants were members of a UK DNA-based registry which is unique. It was therefore not possible to determine how representative participants were of those who did not register for the service, those in other countries or of those who do not seek information exchange or contact. WIDER IMPLICATIONS OF THE FINDINGS: This is the first survey exploring the experiences of donor-conceived adults and donors using a DNA-based voluntary register to seek information about and contact with genetic relatives and the first to measure aspects of identity using standardized measures. Findings provide valuable information about patterns of expectations and experiences of searching through DNA linking, identity and of having contact in the context of donor conception that will inform future research, practice and policy development. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained for this study. The authors have no competing interests to declare except for M.C. who was national adviser to UKDL from 2003-2013. TRIAL REGISTRATION NUMBER: Not applicable.

Process and consensus: ethical decision-making in the infertility clinic--a qualitative study.

Infertility treatment is a speciality that has attracted considerable attention both from the public and bioethicists. The focus of this attention has mainly been on the dramatic dilemmas created by theses technologies. Relatively little is known, however, about how clinicians approach and resolve ethical issues on an everyday basis. The central aim of this study is to gain insight into these neglected aspects of practice. It was found that, for the clinicians, the process by which ethical decisions were made was of key importance. It will be argued that this focus on the process of decision-making is more than just empty proceduralism but is based on and facilitates certain substantive ethical principles. In conclusion, suggestions as to how ethical decision-making processes can be supported and improved in infertility practice will be made.

Achieving guideline-based asthma control: does the patient benefit?

Asthma management guidelines define asthma control, but the outcome criteria used do not include the patient's own assessment of their health. The objective of the present study was to determine the association between the achievement of asthma control, as defined by the Global Initiative for Asthma (GINA) guidelines, and patient-assessed asthma-related quality of life (QOL), particularly whether maximal or near-maximal QOL scores were attainable. Clinical data from three studies that compared salmeterol/fluticasone propionate combination therapy (SFC) with other treatments in patients with persistent asthma were retrospectively analysed. Achievement of asthma control was determined over an 8-week period in each study according to six parameters derived from the GINA guideline treatment goals. Asthma Quality of Life Questionnaire (AQLQ) scores (a 7-point scale, where 1=severe impairment and 7=no impairment) were analysed by treatment group for well-controlled and not well-controlled patients. The analysis showed that, across a range of severities, well-controlled asthma patients had consistently higher AQLQ scores at endpoint and larger AQLQ improvements from baseline, than patients who were not well controlled. For many well-controlled patients, endpoint scores approached 7, indicating little or no impact of asthma on their QOL. However, AQLQ scores of not well-controlled patients also improved substantially in some treatment groups, particularly the SFC group. These results suggest a relationship between the achievement of guideline-based asthma control and improvements in quality of life to levels where there is little or no impact of asthma on quality of life. Guideline-based asthma control is therefore beneficial to the patient and should be tested in prospective studies.

Gamete donation and anonymity: the ethical and legal debate.

The British government is currently considering whether to review the law on information provision for donor offspring. This paper therefore provides an overview of the current international legal situation relating to donor anonymity and a review of the key arguments and evidence on both sides of the debate. While the British government is considering all aspects of information giving, both identifying and non-identifying donor information, this paper will focus on the most contentious issue: the provision of information that would identify the donor. The current legal situation in the UK and internationally is examined, drawing attention to a possible international trend towards more information giving. The evolution of the present British system is outlined and it is asked whether some of the concerns and values that gave rise to the practice of anonymous donation are still relevant today. Looking at the concept of a child's right to know their biological identity it examines the possible basis of such a right and its potential conflict with the perceived interests of the child's parents. Finally, some of the practical obstacles to non-anonymous donation are evaluated. The paper concludes that a review of the British law is both timely and desirable.

Beneath the rhetoric: the role of rights in the practice of non-anonymous gamete donation.

The use of rights based arguments to justify claims that donor offspring should have access to information identifying their gamete donor has become increasingly widespread. In this paper, I do not intend to revisit the debate about the validity of such rights. Rather, the purpose is to examine the way such alleged rights have been implemented by those legislatures that have allowed access to identifying information. I will argue that serious inconsistencies exist between the claim that donor offspring have a right to know the identity of their gamete donor and the way such a right is currently met in practice. I hope to show that in systems where non-anonymous donation is practised, an understanding of the proclaimed right of donor offspring to know their genetic identity is one composed of two different rights--the right to know the circumstances of their conception and the right to information identifying the gamete donor--can provide important insights into this important area of public policy.

Ignorance is bliss? HIV and moral duties and legal duties to forewarn.

In 1997, a court in Cyprus jailed Pavlos Georgiou for fifteen months for knowingly infecting a British woman, Janet Pink, with HIV-1 through unprotected sexual intercourse. Pink met Georgiou in January 1994 whilst on holiday. She discovered that she had contracted the virus from him in October 1994 but continued the relationship until July 1996 when she developed AIDS. She returned to the UK for treatment and reported Georgiou to the Cypriot authorities. There have been a number of legal cases involving deliberate transmission of HIV, but most have involved forced exposure to infected bodily fluids for example, rape or biting, and have been dealt with using the existing legislation for rape or assault. While it is often difficult to prove responsibility for transmission in cases of forced exposure to HIV, it is even more contentious in cases like those of Janet Pink where an individual has consented to sex but claims that he/she was not forewarned of his/her partner's HIV-positive status. At present there is no specific criminal offence of having unprotected sexual intercourse without disclosing one's HIV-positive status but a prosecution could possibly be brought under any one of a number of existing offences. Perhaps a change of policy needs to be considered. The Home Office has issued a consultation document which outlines a proposal that will allow the criminalization of intentional transmission of diseases, like HIV, that are likely to cause serious harm. This revised legislation would cover all other potentially fatal diseases (including salmonella and legionnaire's disease, for instance) but seems primarily to be targeted at HIV transmission. Should transmission of HIV through consensual sex, without the HIV-positive status of the individual being disclosed, be an offence? This question, and that of whether there is a moral obligation to disclose a positive HIV status prior to having a sexual relationship is the subject of this paper.

Troglitazone in combination with sulphonylurea improves glycaemic control in Type 2 diabetic patients inadequately controlled by sulphonylurea therapy alone. Troglitazone Study Group.

AIM: The aim of this study was to investigate the effectiveness of troglitazone (a peroxisome proliferator-activated receptor-gamma agonist developed primarily for the treatment of Type 2 diabetes mellitus (DM)), 100 or 200mg/day, in terms of glycaemic control, lipid profile and tolerability, when given in addition to existing sulphonylurea therapy. METHODS: A 16-week, randomized, parallel-group placebo-controlled trial in 259 Type 2 diabetic patients already on sulphonylurea therapy. RESULTS: At week 16, adjusted geometric mean HbA1c with troglitazone 100mg (7.7%; P=0.023) and 200mg (7.4%; P<0.001) was lower with sulphonylurea alone (8.2%). At all weeks, adjusted geometric mean fasting serum glucose levels were lower in both troglitazone groups, compared with sulphonylurea alone (P=0.007 to P<0.001). At week 16, both troglitazone groups showed reductions in immune reactive insulin compared with sulphonylurea alone (200mg, 13%; P=0.032: 100mg, 5%; NS). Troglitazone reduced serum levels of nonesterified fatty acids at week 16 (100 g, 12%; P=0.042) and at all weeks (200mg, 17-24%; P=0.014 to P<0.001). The incidence of drug-related adverse events was similar in all groups (23-24% of patients). There was no apparent association between hypoglycaemia and the addition of troglitazone to sulphonylurea therapy. CONCLUSIONS: Troglitazone 100 or 200 mg added to usual sulphonylurea therapy in patients with Type 2 DM is associated with a significant improvement in glycaemic control, without altering the adverse-event profile of the sulphonylurea.

Priority setting and evidence based purchasing.

The purpose of this paper is to consider the role that values play in priority setting through the use of EBP. It is important to be clear about the role of values at all levels of the decision making process. At one level, society as a whole has to make decisions about the kind of health provision that it wants. As is generally accepted, these priority setting questions cannot be answered by medical science alone but involve important judgements of value. However, as I hope to show values come into priority setting questions at another level, one not often explicitly recognised in much of the literature: that of the very definition of the effectiveness of treatments. This has important consequences for patient care. If we do not recognise that the effectiveness of a treatment involve subjective elements--a patient's own assessment of the value of the treatment--then this could lead to the belief that we can purchase one treatment that is the most effective for all patients. This might result in a detrimental reduction in the range of options that a patient is given with some patients not receiving the treatment that is most effective for them.

Practical issues in equivalence trials.

Equivalence trials aim to show that two treatments have equivalent therapeutic effects. The approach is to define, in advance, a range of equivalence -d to +d for the treatment difference such that any value in the range is clinically unimportant. If the confidence interval for the difference, calculated after the trial, lies entirely within the interval, then equivalence is claimed. Glaxo Wellcome has carried out a series of trials using this methodology to assess new formulations of inhaled beta-agonists and inhaled steroids in asthma. Eleven of these trials are used to review some practical issues in equivalence trials. For the series of asthma trials, a range for peak expiratory flow rate (PEF) from -15 to +15 l/min was chosen to be the range of equivalence. This fitted well with physicians' opinions and with previously demonstrated differences between active and placebo. The choice of the size of the confidence interval should depend on the medical severity of the clinical endpoints under consideration and the level of risk acceptable in assuming equivalence if a difference of potential importance exists. From this point of view, a recommendation in the CPMP Note for Guidance on Biostatistics that 95 per cent confidence intervals should be used is inappropriate. Intent-to-treat (ITT) and per-protocol (PP) analyses were compared for the eleven asthma trials. Confidence intervals were always wider for the PP analysis and this was entirely due to the smaller number of subjects included in the PP analysis. There was no evidence that the ITT analyses were more conservative in their estimates of treatment difference. The need to demonstrate equivalence in both an ITT and a PP analysis in a regulatory trial increases the regulatory burden on drug developers. The relative importance of the two analyses will depend on the definitions used in particular therapeutic areas. Demonstrating equivalence in one population with strong support from the other would be preferred from the Industry viewpoint. In trials with regulatory importance, prior agreement with regulators on the role of ITT and PP populations should be sought. Trial designs will need to take account of the estimated size of the PP population if adequate power is needed for both analyses. Careful design in the series of asthma trials, particularly identifying a population of patients with potential to improve, resulted in notable increases in lung function during the course of the trials for both treatments. This provided reassurance that equivalence was not due to a lack of efficacy for both treatments. In one trial equivalence was demonstrated overall but a treatment by country interaction was noted. However, this interaction could not be attributed to differences in patient characteristics or baseline data between the countries. Study conduct was also similar in the different countries. The conclusion was that the interaction was spurious and that the trial provided good evidence of equivalence.

Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group.

BACKGROUND: The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) remains controversial because of a lack of placebo-controlled studies. We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD. METHODS: We used a randomised, double-blind, placebo-controlled design. We enrolled from 13 European countries, New Zealand, and South Africa, 281 outpatient current or ex-smokers, aged between 50 and 75 years. They had a forced expiratory volume in 1 s (FEV1) of between 35% and 90% of predicted normal values, a ratio of FEV1 to forced vital capacity of 70% or less and bronchodilator reversibility of less than 15%, as well as a history of chronic bronchitis. Patients were randomly assigned fluticasone propionate 500 microg (n=142) or placebo (n=139) twice daily via a metered-dose inhaler for 6 months. The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment, the number and severity of exacerbations, clinic lung function, diary card symptoms and peak expiratory flow and 6 min walking distance. FINDINGS: 51 (37%) patients in the placebo group compared with 45 (32%) in the fluticasone propionate group had had at least one exacerbation by the end of treatment (p=0.449). Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group (86% vs 60%, p<0.001). Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group (p<0.001, p=0.048, respectively), as did clinic FEV1 (p<0.001), forced vital capacity (p<0.001), and mid-expiratory flow (p=0.01). Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo (p=0.004 and p=0.016, respectively). At the end of treatment, patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo (p=0.032). Fluticasone propionate was tolerated as well as placebo, with few adverse effects and without a clinically important effect on mean serum cortisol concentration. INTERPRETATION: Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months. Inhaled corticosteroids may have an important role in the long-term treatment of COPD.

Implications of socio-cultural contexts for the ethics of clinical trials.

BACKGROUND: Health technology assesment (HTA) requires scientifically rigorous experimentation involving patients as subjects. HTA itself is required so that treatment given to patients will be both effective and efficient; this requirement is itself ethical in nature. At the same time it is essential that the methods used in HTA are ethically sound. Most healthcare researchers agree that the most effective and soundest method for assessing treatments is the randomised controlled trial (RCT). However, some researchers believe that the RCT is unethical, either in essence, or for use in some forms of medical research and HTA. Furthermore, many patients seem unable to understand the principles and purposes of the RCT, a factor which is highly detrimental for the validity of informed consent. Informed consent is the key to the ethics of medical research, both in most theories and in all codes of research conduct. Many RCTs therefore risk being unethical in practice, even if ethical in principle. AIM OF REPORT: To survey the main objections to the RCT and its alternatives. To assess the philosophical and methodological basis of these objections, and of the methods recommended for addressing them. To identify areas where objections are founded in social or cultural factors normally overlooked in ethical argument about the RCT methodology. To identify alternative arguments or methods which might resolve ethical conflicts in this area. HOW THE RESEARCH WAS CONDUCTED: The methods used were adapted from systematic reviews in medicine. Systematic searches of Medline, Psychlit and Sociofile CD-ROM databases; hand-searches of the major journals in general medicine and surgery, medical ethics and philosophy; and searches of books were carried out. The literature survey was restricted to articles published or abstracted in English. A database of the most relevant and useful materials was compiled, and is accessible on the Internet (http://www.liv.ac.uk/sdthomps/page1.html). RESEARCH FINDINGS: UNDERSTANDING RCTS AND THEIR ALTERNATIVES: There is some evidence of difficulty in understanding the aims and methods of RCTs, and some disquiet about elements of the RCT methodologies. These objections are well known and much discussed, and concern the use of placebo, the continuation of trials after significant differentials in benefit or harm are apparent, and randomisation. CULTURAL OR RELIGIOUS OBJECTIONS: There was an absence of evidence of cultural or religious objections to randomisation, placebo or other kinds of controlled prospective trials. This most likely reflects an absence of research rather than absence of objections. (ABSTRACT TRUNCATED)

Twenty-one percent partial hepatectomy. In vivo rat model for the study of liver regeneration.

We describe a new model of submaximal stimulation of liver regeneration in the rat. Removal of the right lateral lobes in the rat produced a 21% hepatectomy. The measurement accuracy of the incorporation rate of [14C]thymidine into DNA 24 h after 21% hepatectomy (n = 32) was less than that after the standard 34% hepatectomy (n = 32), with S.D./mean being 35% and 130%, respectively (F-test, p less than 0.025). This model was able to detect regeneration-stimulation activity present in liver cytosol extract and serum of 68% hepatectomized rats. Using this model we identified a subfraction of rat serum achieved after treatment of serum with ethanol and ion-exchange column, which had a highly stimulatory effect. Stimulation obtained with serum from hepatectomized pigs showed that these factors are not species specific.

Fibrinogen synthesis in the rat; role of the C terminal end of the gamma chain of fragment D1.

The terminal fibrinogen degradation product fragment D1 is known to regulate fibrinogen synthesis but the determinants in the D1 molecule responsible for this property are not known. The effect of fragment D1 on fibrinogen synthesis by the isolated perfused rat liver was studied using the (14C) carbonate method. Addition of 25 mg of fragment D1 to 100 ml of whole blood perfusate resulted in a significant increase in fibrinogen synthesis. When the C-terminal end of the gamma-chain of D1 was further plasmin-degraded to form fragment D3 this fibrinogen-enhancing effect was lost. Our studies suggest that the C-terminal of the gamma-chain of fragment D1 plays a role in regulating fibrinogen synthesis by the isolated rat liver.

Effect of fibrinogenolytic products D and E on fibrinogen and albumin synthesis in the rat.

Previous studies are in conflict over the effect of infusing mixed fibrinogen-fibrin degradation products on fibrinogen synthesis, as determined by changes in fibrinogen concentration or by incorporation of labeled amino acids into fibrinogen. We have injected purified homologous fragments D1 and E into rats and measured their fibrinogen and albumin synthetic rates by the [14C]carbonate technique, a method that provides quantitative estimates of hepatic secretory protein synthesis. Fibrinogen fractional synthetic rates were increased 2.5 times in animals injected with fragment D1, compared with saline-injected controls. No increase were observed in fragment E-injected animals. Neither fragment produced changes in albumin synthesis. Fragment D increased plasma fibrinogen concentration, but did not raise plasma haptoglobin levels. These results suggest that fragment D is a regulator of fibrinogen synthesis.

Insulin, glucagon and liver regeneration.

Partially hepatectomized rats receiving intragastric amino acids synthesize less DNA than similar rats receiving intragastric water alone. In the present study insulin and glucagon levels were measured in rats receiving amino acids or water alone. In both groups of rats insulin levels were depressed and glucagon levels elevated. These findings suggest that insulin and glucagon do not play a major role in the regulation of liver regeneration after partial hepatectomy in the rat.

The effect of intragastric feeding with amino acids on liver regeneration after partial hepatectomy in the rat.

The incorporation of 14C-thymidine into DNA was measured at 4-hr intervals from 16 to 32 hr after partial hepatectomy in groups of rats. Rats forcefed solutions of amino acids or branched-chain amino acids showed a significant reduction in the DNA specific activity 24 hr after partial hepatectomy when compared to rats forced fed an equal volume of water. Intragastric feeding with ketoanalogues of the branched-chain amino acids did not alter thymidine incorporation into DNA significantly. The finding that intragastric feeding depresses DNA synthesis after partial hepatectomy contrasts with our studies indicating increased synthesis of albumin in partially hepatectorized animals receiving similar feeding and indicates different control mechanisms for DNA and albumin synthesis.

Stimulation of albumin synthesis by keto analogues of amino acids.

(1) The effect of ketoanalogues of branched-chain amino acids on albumin synthesis was examined in two biological systems using the [14C]carbonate technique. (2)alpha-Ketocaproic acid, the ketoanalogue of leucine, was able to reverse the reduced synthesis rate observed when isolated livers, from well-nourished animals were perfused with blood from rats deprived of dietary protein for 48 h. (3) A mixture of ketoanalogues of the three branched-chain amino acids, leucine, isoleucine and valine, was able to increase albumin synthesis per unit dry liver weight to above normal levels when administered intragastrically to rats 16 h after partial hepatectomy.

Stimulation of albumin synthesis by amino acids following partial hepatectomy in the rat.

Albumin synthesis was measured, in vivo, in rats 16 hours after partial hepatectomy or after sham operation. When albumin synthesis was expressed in terms of whole body weight, partially hepatectomized rats synthesized significantly less than sham-operated rats. However, when albumin synthesis was expressed as a function of dry liver weight, the two groups synthesized similar amounts. Intragastric hyperalimentation with amino acids significantly increased albumin synthesis in partially hepatectomized rats.

Albumin synthesis and catabolism following partial hepatectomy in the rat. The effects of amino acids and adrenocortical steroids on albumin synthesis after partial hepatectomy.

Plasma albumin levels were measured in partially hepatectomized, sham operated and control rats. The levels fell in both the partially hepatectomized and sham operated groups; while the latter group returned to normal within a few days, the low plasma albumin in the partially hepatectomized animals was sustained. Albumin synthesis rates in the isolated perfused rat liver were measured in the three groups of animals at varying intervals after partial hepatectomy. There was a significant depression of albumin synthesis rate in terms of both liver and whole animal weights when compared to the sham operated and control animals. This depression was almost completely reversed by the addition of arginine, asparagine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan and valine added together to 10 times their normal plasma concentrations. The addition of hydrocortisone had no effect on the albumin synthesis rate after partial hepatectomy. Studies in vivo in the three groups of animals (partially hepatectomized, sham operated and control animals) revealed a fall in the albumin catabolic rate after partial hepatectomy coinciding with the fall in the albumin synthesis rate. An hypothesis whereby the amino acids may have their stimulatory effect is proposed.