One step forward, two steps back – requiring ministerial approval for all ‘non-therapeutic\' health research involving minors

The new National Health Act has clarified that children may take part in ‘non-therapeutic\' research (NTR) and the age at which they may provide independent consent to such research, viz. at legal majority. However, the Act will require consent from the Minister of Health for all research classed as NTR and involving minors regardless of the level of risk. This requirement is overly broad. It will require that low-risk research without direct benefits, which might be adequately reviewed by an accredited research ethics committee (REC), must also be reviewed by the Minister. As it currently stands this requirement serves no plausible ethical purpose, will cause delays and discourage essential research on the needs of children, and may inspire researchers and RECs alike to ‘foil the system\'. We argue that in the long term there should be comprehensive law reform for child research. However, in the short term, amendments should be made to the Act to narrow the scope of this provision. The amendment should require ministerial consent for research that is currently not approvable by an REC in terms of national ethical guidelines, namely, research that does not hold out direct benefit but presents more than a minor increase over minimal risk. If our law reform recommendations are rejected, we favour the delegation of this task to RECs because, if they receive appropriate training, they should be competent to conduct it. We accept the disadvantages, namely that the same body will review protocols twice from slightly different perspectives and that certain categories of research will remain unapprovable.South African Medical Journal Vol. 97 (2) 2007: pp.200-202

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.Â

Sequential Voxel-Based Leaflet Segmentation of Complex Lipid Morphologies

[Image: see text] As molecular dynamics simulations increase in complexity, new analysis tools are necessary to facilitate interpreting the results. Lipids, for instance, are known to form many complicated morphologies, because of their amphipathic nature, becoming more intricate as the particle count increases. A few lipids might form a micelle, where aggregation of tens of thousands could lead to vesicle formation. Millions of lipids comprise a cell and its organelle membranes, and are involved in processes such as neurotransmission and transfection. To study such phenomena, it is useful to have analysis tools that understand what is meant by emerging entities such as micelles and vesicles. Studying such systems at the particle level only becomes extremely tedious, counterintuitive, and computationally expensive. To address this issue, we developed a method to track all the individual lipid leaflets, allowing for easy and quick detection of topological changes at the mesoscale. By using a voxel-based approach and focusing on locality, we forego costly geometrical operations without losing important details and chronologically identify the lipid segments using the Jaccard index. Thus, we achieve a consistent sequential segmentation on a wide variety of (lipid) systems, including monolayers, bilayers, vesicles, inverted hexagonal phases, up to the membranes of a full mitochondrion. It also discriminates between adhesion and fusion of leaflets. We show that our method produces consistent results without the need for prefitting parameters, and segmentation of millions of particles can be achieved on a desktop machine

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.

Overweight after treatment for acute lymphoblastic leukemia in children

Objective: To determine the prevalence of overweight in childhood acute lymphoblastic leukaemia (ALL) survivors and to assess the relation between overweight and age at diagnosis, gender or treatment with cranial irradiation (CI) and/or corticosteroids. Patients and methods: Body mass index (BMI) was assessed in patients in continuous complete remission of ALL who were diagnosed between 1972 and 1993 and who were treated according to the DCLSG protocols ALL 2, 3A, 5-8 or the local ALL high-risk (GronHR) protocol. Patients were divided into three treatment groups, based on treatment with or without CI and duration of corticosteroids; group I: CI and intermittent corticosteroids for two years (n = 77); group 2: intermittent corticosteroids for two years (n = 24); group 3: two courses of corticosteroids for four weeks each (n = 47). Prevalences of overweight were compared between groups, related to gender and age at diagnosis and were compared to the growth diagrams from the Fourth Dutch Nationwide Survey 1997. Results: Until five years post-diagnosis more overweight was demonstrated in group 2 survivors; afterwards we found no differences between groups. The prevalence of overweight in boys surviving more than five yeas after diagnosis was 17.1% at age 10 and 16.7% at age 15 (Fourth Dutch Nationwide Survey respectively 7.8%; chi square p = 0.01 and 7.7%; p = 0.07), in girls 24.4% at age 10 and 28.0% at age 15 (Fourth Dutch Nationwide Survey respectively 11.8%; p = 0.03 and 9.4%; p &lt; 0.01). Overweight correlated with age at diagnosis younger than four years but not with gender. Conclusion: Childhood ALL survivors are at high risk for overweight, irrespective of CI and duration of corticosteroid treatment.</p

Overweight after treatment for acute lymphoblastic leukemia in children

Objective: To determine the prevalence of overweight in childhood acute lymphoblastic leukaemia (ALL) survivors and to assess the relation between overweight and age at diagnosis, gender or treatment with cranial irradiation (CI) and/or corticosteroids. Patients and methods: Body mass index (BMI) was assessed in patients in continuous complete remission of ALL who were diagnosed between 1972 and 1993 and who were treated according to the DCLSG protocols ALL 2, 3A, 5-8 or the local ALL high-risk (GronHR) protocol. Patients were divided into three treatment groups, based on treatment with or without CI and duration of corticosteroids; group I: CI and intermittent corticosteroids for two years (n = 77); group 2: intermittent corticosteroids for two years (n = 24); group 3: two courses of corticosteroids for four weeks each (n = 47). Prevalences of overweight were compared between groups, related to gender and age at diagnosis and were compared to the growth diagrams from the Fourth Dutch Nationwide Survey 1997. Results: Until five years post-diagnosis more overweight was demonstrated in group 2 survivors; afterwards we found no differences between groups. The prevalence of overweight in boys surviving more than five yeas after diagnosis was 17.1% at age 10 and 16.7% at age 15 (Fourth Dutch Nationwide Survey respectively 7.8%; chi square p = 0.01 and 7.7%; p = 0.07), in girls 24.4% at age 10 and 28.0% at age 15 (Fourth Dutch Nationwide Survey respectively 11.8%; p = 0.03 and 9.4%; p &lt; 0.01). Overweight correlated with age at diagnosis younger than four years but not with gender. Conclusion: Childhood ALL survivors are at high risk for overweight, irrespective of CI and duration of corticosteroid treatment.</p

Overweight after treatment for acute lymphoblastic leukemia in children

Objective: To determine the prevalence of overweight in childhood acute lymphoblastic leukaemia (ALL) survivors and to assess the relation between overweight and age at diagnosis, gender or treatment with cranial irradiation (CI) and/or corticosteroids. Patients and methods: Body mass index (BMI) was assessed in patients in continuous complete remission of ALL who were diagnosed between 1972 and 1993 and who were treated according to the DCLSG protocols ALL 2, 3A, 5-8 or the local ALL high-risk (GronHR) protocol. Patients were divided into three treatment groups, based on treatment with or without CI and duration of corticosteroids; group I: CI and intermittent corticosteroids for two years (n = 77); group 2: intermittent corticosteroids for two years (n = 24); group 3: two courses of corticosteroids for four weeks each (n = 47). Prevalences of overweight were compared between groups, related to gender and age at diagnosis and were compared to the growth diagrams from the Fourth Dutch Nationwide Survey 1997. Results: Until five years post-diagnosis more overweight was demonstrated in group 2 survivors; afterwards we found no differences between groups. The prevalence of overweight in boys surviving more than five yeas after diagnosis was 17.1% at age 10 and 16.7% at age 15 (Fourth Dutch Nationwide Survey respectively 7.8%; chi square p = 0.01 and 7.7%; p = 0.07), in girls 24.4% at age 10 and 28.0% at age 15 (Fourth Dutch Nationwide Survey respectively 11.8%; p = 0.03 and 9.4%; p &lt; 0.01). Overweight correlated with age at diagnosis younger than four years but not with gender. Conclusion: Childhood ALL survivors are at high risk for overweight, irrespective of CI and duration of corticosteroid treatment.</p

Round Spermatid Injection Rescues Female Lethality of a Paternally Inherited Xist Deletion in Mouse

In mouse female preimplantation embryos, the paternal X chromosome (Xp) is silenced by imprinted X chromosome inactivation (iXCI). This requires production of the noncoding Xist RNA in cis, from the Xp. The Xist locus on the maternally inherited X chromosome (Xm) is refractory to activation due to the presence of an imprint. Paternal inheritance of an Xist deletion (XpΔXist) is embryonic lethal to female embryos, due to iXCI abolishment. Here, we circumvented the histone-to-protamine and protamine-to-histone transitions of the paternal genome, by fertilization of oocytes via injection of round spermatids (ROSI). This did not affect initiation of XCI in wild type female embryos. Surprisingly, ROSI using ΔXist round spermatids allowed survival of female embryos. This was accompanied by activation of the intact maternal Xist gene, initiated with delayed kinetics, around the morula stage, resulting in Xm silencing. Maternal Xist gene activation was not observed in ROSI-derived males. In addition, no Xist expression was detected in male and female morulas that developed from oocytes fertilized with mature ΔXist sperm. Finally, the expression of the X-encoded XCI-activator RNF12 was enhanced in both male (wild type) and female (wild type as well as XpΔXist) ROSI derived embryos, compared to in vivo fertilized embryos. Thus, high RNF12 levels may contribute to the specific activation of maternal Xist in XpΔXist female ROSI embryos, but upregulation of additional Xp derived factors and/or the specific epigenetic constitution of the round spermatid-derived Xp are expected to be more critical. These results illustrate the profound impact of a dysregulated paternal epigenome on embryo d