Research ethics committees in a tight spot: Approving consent strategies for child research that are prima facie illegal but are ethical in terms of national guidelines.

It is an internationally accepted principle that ethics norms should be applied and enforced in research with humans through ethics review by research ethics committees (RECs). This places RECs at the very heart of the system for protecting participants and enforcing their rights. In the South African ethical-legal framework for child research, there are divergent approaches to consent. That is, section 71 of the National Health Act (No. 61 of 2003) (NHA) requires mandatory parental consent for child research, and limits the authority for proxy consent to parents and legal guardians. However, national ethics guidelines authorised by section 72 of the NHA and issued by the National Health Research Ethics Council (NHREC) acting in terms of its mandate (National Department of Health, 2015) allow a more nuanced approach - i.e. self-consent by older adolescents, provided certain conditions are met, and consent by a range of parental substitutes where there are no available parents or legal guardians. We have argued elsewhere that the consent approach in section 71 is inappropriately restrictive and are of the view that the consent approach endorsed in national ethics guidelines is more defensible. An REC that elects to approve a consent strategy allowable in ethics guidelines is effectively electing to not follow section 71, which raises the question of what the consequences might be for that REC. This article examines the legal liability of RECs through three 'threads' of accountability: the NHREC, the institutions hosting RECs, and the courts. We conclude that: (i) if an REC approves a child protocol with consent strategies allowable in terms of national ethics guidelinesbut not in terms of section 71, it is unlikely that the NHREC would discipline the REC in the face of a complaint - provided the REC acted within national ethics guidelines issued by the NHREC in terms of the latter's section 72 mandate to set national norms and standards; (ii) if an REC approves a consent approach allowed for in ethics guidance, it is also unlikely that the host institution would discipline the REC in the face of a complaint - especially if the institution is aware of the REC's explicit decision to follow national ethics guidelines that are authorised by section 72 of the NHA; and (iii) an REC could only be sued by a participant in terms of the law of delict (and be liable for damages) if several demanding components are proven, such as that the harm suffered by the participant resulted directly from the REC's actions in approving a particular consent strategy for that research. Furthermore, the court may well look to national ethics guidelines in making determinations about whether an REC's conduct was wrongful for the purposes of liability in civil law. RECs are protected from being collectively liable by insurance taken out by their host institutions. We make a series of recommendations to address this issue.

Feasibility and acceptability of conducting HIV vaccine trials in adolescents in South Africa: Going beyond willingness to participate towards implementation.

BACKGROUND: HIV/AIDS remains a leading cause of death in adolescents (aged 15 - 25 years), and in sub-Saharan Africa HIV-related deaths continue to rise in this age group despite a decline in both adult and paediatric populations. This is attributable in part to high adolescent infection rates and supports the urgent need for more efficacious prevention strategies. In particular, an even partially effective HIV vaccine, given prior to sexual debut, is predicted to significantly curb adolescent infection rates. While adolescents have indicated willingness to participate in HIV vaccine trials, there are concerns around safety, uptake, adherence, and ethical and logistic issues. OBJECTIVES: To initiate a national, multisite project with the aim of identifying obstacles to conducting adolescent HIV vaccine trials in South Africa (SA). METHOD: A simulated HIV vaccine trial was conducted in adolescents aged 12 - 17 years across five SA research sites, using the already licensed Merck human papillomavirus vaccine Gardasil as a proxy for an HIV vaccine. Adolescents were recruited at community venues and, following a vaccine discussion group, invited to participate in the trial. Consent for trial enrolment was obtained from a parent or legal guardian, and participants aged 16 - 17 years were eligible only if sexually active. Typical vaccine trial procedures were applied during the five study visits, including the administration of vaccination injections at study visits 2, 3 and 4. RESULTS: The median age of participants was 14 years (interquartile range 13 - 15), with 81% between the ages of 12 and 15 years at enrolment. Overall, 98% of screened participants opted to receive the vaccine, 588 participants enrolled, and 524 (89%) attended the final visit. CONCLUSIONS: This trial showed that adolescents can be recruited, enrolled and retained in clinical prevention trials with parental support. While promising, these results were tempered by the coupling of sexual-risk eligibility criteria and the requirement for parental/guardian consent, which was probably a barrier to the enrolment of high-risk older adolescents. Further debate around appropriate consent approaches for such adolescents in HIV prevention studies is required.

Feasibility and acceptability of conducting HIV vaccine trials in adolescents in South Africa: Going beyond willingness to participate towards implementation

Background. HIV/AIDS remains a leading cause of death in adolescents (aged 15 - 25 years), and in sub-Saharan Africa HIV-related deaths continue to rise in this age group despite a decline in both adult and paediatric populations. This is attributable in part to high adolescent infection rates and supports the urgent need for more efficacious prevention strategies. In particular, an even partially effective HIV vaccine, given prior to sexual debut, is predicted to significantly curb adolescent infection rates. While adolescents have indicated willingness to participate in HIV vaccine trials, there are concerns around safety, uptake, adherence, and ethical and logistic issues.Objectives. To initiate a national, multisite project with the aim of identifying obstacles to conducting adolescent HIV vaccine trials in South Africa (SA).Method. A simulated HIV vaccine trial was conducted in adolescents aged 12 - 17 years across five SA research sites, using the already licensed Merck human papillomavirus vaccine Gardasil as a proxy for an HIV vaccine. Adolescents were recruited at community venues and, following a vaccine discussion group, invited to participate in the trial. Consent for trial enrolment was obtained from a parent or legal guardian, and participants aged 16 - 17 years were eligible only if sexually active. Typical vaccine trial procedures were applied during the five study visits, including the administration of vaccination injections at study visits 2, 3 and 4.Results. The median age of participants was 14 years (interquartile range 13 - 15), with 81% between the ages of 12 and 15 years at enrolment. Overall, 98% of screened participants opted to receive the vaccine, 588 participants enrolled, and 524 (89%) attended the final visit.Conclusions. This trial showed that adolescents can be recruited, enrolled and retained in clinical prevention trials with parental support. While promising, these results were tempered by the coupling of sexual-risk eligibility criteria and the requirement for parental/guardian consent, which was probably a barrier to the enrolment of high-risk older adolescents. Further debate around appropriate consent approaches for such adolescents in HIV prevention studies is required

Addressing legal and policy barriers to male circumcision for adolescent boys in South Africa.

With millions of adolescents becoming infected with HIV globally, it is essential that barriers to much-needed interventions are reduced for at-risk adolescents. In this article we review the legal and policy framework in South Africa for adolescent access to male circumcision. We are of the view that the framework does confer protection for adolescent boys while enabling access to male circumcision; however, we identify ambiguities and tensions that exist between the Children's Act, regulations and national guidelines. We recommend reform to further enable access by this vulnerable group to this prevention modality.

But is this really the 'parent' or 'guardian'? Practical strategies for consent to child research in South Africa.

Research ethics committees (RECs) in South Africa may require consent from a parent or legal guardian for child research. In instances where an REC determines that parental or guardianship consent is required, how far should researchers go to establish if the accompanying adult is in fact the parent or guardian? Should researchers accept disclosures at face value, probe assertions that are made, or even call for supporting documentation? In this article we set out the facts research staff should possess, propose key questions they could ask, and recommend practical steps for uncertain cases. We recognise that a parental/guardianship consent strategy may not be appropriate in all instances, but do not debate that issue in this article. This article is confined to practical advice for researchers wishing to implement a parental or guardianship consent approach.

Boni mores and consent for child research in South Africa.

Consent is required for almost all health research. In order for consent to be valid a number of requirements must be met including that the consent cannot be contra bonos mores or contrary to public policy. This principle has its roots in the common law and it is used to ensure that the consent to harm, or the risk of harm, is permitted or ought to be permitted by the legal order. Recently, it has also become a statutory requirement embedded in the consent obligations relating to non-therapeutic health research with minors. Section 71 of the National Health Act provides that the Minister of Health (or potentially his or her delegated authority) must provide consent to non-therapeutic research with minors. However, such consent may not be granted if 'the reasons for the consent to the research or experimentation are contrary to public policy'. Limited work has been done on how to determine when consent to health research with children would be contrary to public policy. This article attempts to begin the debate by describing the boni mores principle, setting out some of the general factors that could be used to assess whether consent is consistent with it and suggesting how they could be applied to health research. The article concludes by stating that simply requiring proxy consent for non-therapeutic health research with children is insufficient as it cannot always be assumed that proxy consenters will act in the best interests of the child. Thus the boni mores principle acts as a limit on autonomy in order to protect the child participant. It is further submitted that establishing when consent to health research is consistent with public policy requires an assessment of whether the research is consistent with constitutional values, prevailing legal norms regarding children, and an assessment of the legal convictions of the community.

A randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-resistant major depression.

BACKGROUND: Although several studies have reported that repetitive transcranial magnetic stimulation (rTMS) treatment has demonstrable efficacy in patients with depression, the parameters needed to optimize therapeutic efficacy remain unclear. To this end we determined the efficacy of low-frequency right rTMS to the dorsolateral prefrontal cortex (DLPFC) compared to two forms of bilateral rTMS to the DLPFC: (1) sequential low-frequency right-sided followed by high-frequency left-sided rTMS and (2) sequential low-frequency rTMS to both hemispheres. METHOD: A total of 219 patients with treatment-resistant depression (TRD) were randomized to a 4-week course of rTMS applied with one of the three treatment conditions. Outcomes were assessed with standard rating scales. RESULTS: Overall, slightly more than 50% of the patients achieved clinical response criteria. There was no substantial difference in response between the unilateral and bilateral treatment groups. Successful response to rTMS was predicted by a greater degree of baseline depression severity. CONCLUSIONS: There is no substantial difference in efficacy between unilateral right-sided rTMS and the two forms of bilateral rTMS assessed in the study. Furthermore, our results call into question the specificity between frequency and laterality and rTMS response.

Provision of HIV treatment in HIV preventive vaccine trials: a developing country perspective.

HIV treatment for participants who become infected during HIV vaccine trials has been the focus of ethical controversy. The obligations of sponsors to ensure that participants have access to antiretrovirals have been a particular focus of this debate. This paper presents three arguments that have been made in this regard, and some of their limitations, in anticipation of HIV vaccine trials in South Africa. The first argument is that HIV risk behaviour increases in such trials, and HIV infection can be viewed as a research-related injury, justifying sponsor provision of treatment on grounds of compensation for harm. We conclude that risk-behaviour studies to date do not show general increases in risk behaviour that could constitute the basis for a general obligation. Participation may well adversely impact on risk behaviour for some individuals, and conceivably this could be demonstrated. This argument may, therefore, have merit at the individual level; however, it seems a weak platform from which to argue that sponsors should treat all HIV infections acquired during trials. The second argument is that treatment should be provided based on distributive justice. We conclude that traditional concepts of "distributive justice" in research appear limited in justifying obligations of sponsors to ensure access to antiretrovirals. Further, using research initiatives to reduce global health care inequities is controversial, and even proponents may disagree about the fairest use of finite resources. The third argument is that sponsors should ensure antiretroviral access on grounds of beneficence; namely, the maxim that if one can do something beneficial without sacrificing anything of comparable significance, it ought to be done. Thus, sponsors should provide more interventions than those minimally required to conduct the research. However, beneficence may demand levels of altruism that exceeds what is reasonable. While the latter arguments may provide stronger justifications than the first, it is difficult to use these arguments to establish that sponsor provision of antiretrovirals to infected individuals is obligatory.

HIV vaccine research - South Africa's ethical-legal framework and its ability to promote the welfare of trial participants

An effective ethical-legal framework for the conduct of research is critical. We describe five essential components of such a system; review the extent to which these components have been realised in South Africa; present brief implications for the ethical conduct of clinical trials of HIV vaccines in South Africa and make recommendations. The components of an effective ethical-legal system that we propose are the existence of scientific ethical and policy-making structures that regulate research; research ethics committees (RECs) that ethically review research; national ethical guidelines and standards; laws protecting research participants; and mechanisms to enforce and monitor legal rights and ethical standards. We conclude that the ethical-legal framework has; for the most part; the necessary institutions; and certain necessary guidelines but does not have many of the laws needed to protect and promote the rights of persons participating in research; including HIV vaccine trials. Recommendations made include advocacy measures to finalise and implement legislation; development of regulations; analysis and comparison of ethical guidelines; and the development of measures to monitor ethical-legal rights at trial sites

Postmastectomy reconstruction of the previously augmented breast: diagnosis, staging, methodology, and outcome.

Although many of the health and safety issues associated with breast augmentation have been thoroughly discussed over the past decade, the literature is remarkably silent regarding postmastectomy reconstruction of the previously augmented breast. A retrospective review of the senior author's reconstructive practice was performed for the years 1983 through March of 1999, revealing 21 women who underwent postmastectomy breast reconstruction after previous breast augmentation. For purposes of measuring aesthetic results, these 21 patients were matched to a carefully selected control group of 15 patients. They were also compared with other, larger populations, including 777 of the senior author's other breast reconstructions, the breast cancer registry at the Lombardi Cancer Center in Washington, D.C., and several large, published epidemiologic studies. The interval between the previous augmentation and the diagnosis of breast cancer ranged from 9 months to 18 years, with a mean of 9.3 years. None of the previous augmentation implants was ruptured at the time of mastectomy. Of the nine patients with previous subpectoral augmentation, cancer was detected mammographically in five (56 percent), whereas of the 12 patients with previous subglandular augmentation, cancer was first detected mammographically in only three (25 percent). This difference was not statistically significant (p = 0.2). Overall, eight of the study patients' tumors (38 percent) were first detected mammographically, which is similar to other published reports of breast cancer patients in the general population. Seventy-one percent of the 21 study patients were node-negative, which also compares favorably with other published series. Sixteen of the women with previous augmentation (76 percent) had purely prosthetic reconstructions. Flaps were used in the other five reconstructions (23 percent): three latissimus dorsi flaps (14 percent) and two transverse rectus abdominis musculocutaneous flaps (9 percent). All five flaps were used in patients who had undergone radiation therapy. Throughout the senior author's entire reconstructive practice history, transverse rectus abdominis musculocutaneous flaps were more frequently used [282 of 777 nonaugmented reconstructions (36 percent)], whereas latissimus dorsi flaps were less frequently used [17 of 777 nonaugmented reconstructions (2.2 percent)] (p < 0.001). The cosmetic results of the breast reconstructions in the previously augmented study group were generally good-to-excellent, with a mean score by blinded observers of 3.35 of a possible 4.0. These results were comparable to or better than those in the matched controls, who scored a mean of 3.0.

Antibiotic-resistant bacteria in pediatric chronic sinusitis.

BACKGROUND: Limited information exists on emerging bacterial resistance patterns in pediatric chronic sinusitis. METHODS: A retrospective review (1995 to 1998) of the aerobic microbiology of chronic sinusitis in children at a tertiary care children's hospital was conducted. One hundred nineteen children (mean age, 4.9 years) with maxillary sinusitis of >8 weeks duration and no known immunodeficiency or cystic fibrosis who underwent antral irrigation were included. RESULTS: One hundred sixty-one of 240 (67%) aerobic cultures were positive, yielding 274 isolates. Eighty-eight positive cultures were polymicrobial. The most frequent isolates were nontypable Haemophilus influenzae (24%), Streptococcus pneumoniae (19%), Moraxella catarrhalis (17%), coagulase-negative Staphylococcus (6%), alpha-streptococci (6%), diphtheroids (5%), Staphylococcus aureus (3%) and Neisseria spp. (3%). Rates of nonsusceptibility of Streptococcus pneumoniae were 64% for penicillin (24% high grade resistance), 40% for cefotaxime, 18% for clindamycin and 0% for vancomycin. Rates of nonsusceptibility of S. pneumoniae did not change significantly during the study period. Thirty-nine percent of H. influenzae isolates were beta-lactamase-positive and 44% were nonsusceptible to ampicillin (41% high grade resistance). Beta-lactamase positivity of H. influenzae decreased during the study period (P = 0.06). All M. catarrhalis isolates tested were beta-lactamase-positive. CONCLUSION: This study indicates that the aerobic pathogens in pediatric chronic sinusitis include bacteria typical of acute sinusitis as well as organisms more characteristic of chronic disease. Moreover it highlights the significant role of antibiotic-resistant aerobes, including multiply resistant S. pneumoniae, in pediatric chronic sinusitis.

Hospital and emergency department use by young low-income children.

BACKGROUND: Limited data are available concerning determinants of health care service usage by low-income young children. OBJECTIVES: To explore predictors of hospitalization and emergency department (ED) use by young children of low-income families by using the Aday and Andersen Access Framework. METHODS: Low-income women (n = 474) with a child younger than 6 years completed a structured face-to-face interview at human service offices or Women, Infants, and Children (WIC) clinics in four central Ohio counties. Women were considered low-income if they or their child were Medicaid eligible or uninsured. Data were collected for both the mother and the index child on sociodemographic status, health services use, health status, and access to care. RESULTS: Fifteen percent of the children had been hospitalized the previous year, and half had an ED visit. Hospitalization was significantly related to maternal hospitalization the previous year (OR = 2.5), child age younger than 1 year old (OR = 2.1) and more than two chronic conditions (OR = 2.2). Maternal ED usage in the last year (OR = 2.2), Medicaid fee for service plan (OR = 1.7), and rural residence (OR = 2.0) were predictive of ED use. CONCLUSIONS: Predisposing characteristics (maternal hospital/ED use) were predictive of both hospitalization and ED use by the index child. Enabling characteristics (fee-for-service Medicaid plan, rurality) were only predictive of ED use, and need characteristics (child's health) were only predictive of hospitalization. Further research to explore linkages between maternal and child use of health care services as well as the effect of changes in health care access, managed care, and other innovations on hospitalization and ED use in young, low-income children is recommended.

Rearrangement of extracellular matrix during cluster formation by human luteinising granulosa cells in culture.

Human ovarian granulosa cells were cultured on a basement membrane preparation (Matrigel) to investigate the role of extracellular matrix components in granulosa cell cluster formation. Time-lapse videomicroscopy of these cultures revealed a rapid aggregation of cells which was initiated during the first 2-4 h of culture so that by 8 h most of the granulosa cells were incorporated into clusters. Further amalgamation then occurred with the transfer of cells along 'bridges' between combining clusters. The clustering process, which was complete by about 24 h, was accompanied by reorganisation of matrix which was visualised by immunolabelling of laminin. Clustering cells appeared to gather matrix which became distributed around the clusters. Confocal microscopy showed matrix to be present over the surface of each cluster as well as around the base apparently anchoring the aggregate to the culture surface. Results suggest the potential for active rearrangement of matrix by granulosa-derived cells during corpus luteum development.

Post-varicella epiglottitis and necrotizing fasciitis.

Varicella is a nearly ubiquitous acquired childhood disease. Infectious complications of varicella can be life- or limb-threatening. These complications appear 3 to 4 days after the appearance of varicella exanthem and are heralded by fever, pain, and erythema of the overlying skin. Airway complications of varicella are rare, rapidly evolving, and, unfortunately, difficult to visualize. We report a child who presented with a unique combination of varicella-induced airway complications-acute epiglottitis and subsequent necrotizing fasciitis of the head and neck. varicella, epiglottitis, necrotizing fasciitis, group A beta-hemolytic streptococcus, nasopharyngoscopy.

Ethical issues in HIV vaccine trials in South Africa.

In this review we describe the ethical issues central to local and international debates about HIV vaccine trials. These issues include the physiological and psycho-social risks of trial participation, the preventative interventions to be provided to participants, access to treatment for participants who seroconvert, access to an effective vaccine after the trial, the role of placebo-controlled trials, and obtaining informed consent.

Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3'-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage.

Mammalian polynucleotide kinases catalyze the 5'-phosphorylation of nucleic acids and can have associated 3'-phosphatase activity, predictive of an important function in DNA repair following ionizing radiation or oxidative damage. The sequences of three tryptic peptides from a bovine 60-kDa polypeptide that correlated with 5'-DNA kinase and 3'-phosphatase activities identified human and murine dbEST clones. The 57.1-kDa conceptual translation product of this gene, polynucleotide kinase 3'-phosphatase (PNKP), contained a putative ATP binding site and a potential 3'-phosphatase domain with similarity to L-2-haloacid dehalogenases. BLAST searches identified possible homologs in Caenorhabditis elegans, Schizosaccharomyces pombe, and Drosophila melanogaster. The gene was localized to chromosome 19q13.3-13.4. Northern analysis indicated a 2-kilobase mRNA in eight human tissues. A glutathione S-transferase-PNKP fusion protein displayed 5'-DNA kinase and 3'-phosphatase activities. PNKP is the first gene for a DNA-specific kinase from any organism. PNKP expression partially rescued the sensitivity to oxidative damaging agents of the Escherichia coli DNA repair-deficient xth nfo double mutant. PNKP gene function restored termini suitable for DNA polymerase, consistent with in vivo removal of 3'-phosphate groups, facilitating DNA repair.

Purification of a polynucleotide kinase from calf thymus, comparison of its 3'-phosphatase domain with T4 polynucleotide kinase, and investigation of its effect on DNA replication in vitro.

Mammalian polynucleotide kinases (PNKs) carry out 5'-phosphorylation of nucleic acids. Although the cellular function(s) of these enzymes remain to be delineated, important suggestions have included a role in DNA repair and, more recently, in DNA replication. Like T4 PNK, some preparations of mammalian PNKs have been reported to have an associated 3'-phosphatase activity. Previously, we have identified in calf thymus glands an apparently novel PNK with a neutral to alkaline pH optimum that lacked 3'-phosphatase activity. In this report, we describe purification of another bovine PNK, SNQI-PNK, with a slightly acidic pH optimum that copurifies with a 3'-phosphatase activity. The enzyme appears to be a monomer of 60 kDa. Mammalian DNA replication reactions were supplemented with T4 PNK or SNQI-PNK, and no significant effect on DNA replication in vitro was observed. Database searches support the earlier mapping of the 3'-phosphatase activity of T4 PNK to the C-terminus and suggest that the 3'-phosphatase domain of T4 PNK is related to the protein superfamily of L-2-haloacid dehalogenases. Exopeptidase digestion experiments were carried out to compare the SNQI-PNK enzyme with T4 PNK and led to the inference that the domain organization of the bovine polypeptide may differ from that of the T4 enzyme.

Fungal mastoiditis in immunocompromised children.

The immunocompromised host is subject to a variety of opportunistic infections. Mycotic infections, including invasive fungal sinusitis, are a dreaded complication in immune deficient children. Fungal mastoiditis has rarely been described in this population. Our experience with 2 cases of fungal mastoiditis in immunocompromised children is reviewed. Case histories describing aggressive medical management with and without surgical intervention and a review of the literature are presented.