Editorial: ‘The giant’s shoulders’: understanding Michael Rutter’s impact on science and society

The recent death of our colleague and friend Professor Sir Michael Rutter has quite rightly been greeted by an outpouring of gratitude and respect from distinguished commentators across the globe working in diverse fields of the basic, social and clinical sciences as well as from clinicians and policy makers. These have without exception highlighted his seminal role as a pioneer, perhaps The Pioneer, of the application of the scientific method to the study of child and adolescent mental health and disorder – the father of evidence-based Child Psychiatry and the most influential voice in the new field of Developmental Psychopathology (Stevenson, 2022). In this editorial, we will attempt to build on these commentaries. We will parse Mike’s scientific contributions to our field, in order to identify the personal characteristics and intellectual modus operandi that made him such a uniquely important figure, whose influence will resonate through the many fields he influenced for decades to come. We will also attempt something of a reframing of that contribution. Our thesis being that, although he never agitated for it politically or even stated it as a goal explicitly, Mike’s work was motivated by a desire for social reform and created the scientific catalyst for such reform to occur.     

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg-1. 2. Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 +/- 9.6 ml min-1 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. The mean residence time and half-life were 20.9 +/- 1.4 and 14.4 +/- 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 +/- 0.18 l kg-1. 3. No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4. In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5. These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.     

Session XII Male contraception

Session XII Male contraception     

An optimal three-stage design for phase II clinical trials

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H₀: p ≤ p₀ versus H₁: p ≥ p₁, where p₁ and p₀ are response rates such that E does or does not merit further testing at given levels of statistical significance (α) and power (1 ? β). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H₁ at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H₁ is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p₀, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H₀; and the total sample size and criteria for rejection of H₁ at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.     

Ethical dilemmas in today's nuclear medicine and radiology practice.

Throughout history, societies have developed their own codes of ethics, including those pertaining to the practice of medicine. In the United States, physicians have adopted a set of ethics based on religious values and historical teachings. We, as physicians, have been presented several codes of ethics, including the American Medical Association Code of Ethics and the American College of Radiology Code of Ethics. Over time, we have learned to appropriately apply these codes to our daily practice. With the advent of new technologies in imaging, we may lose sight as to the transfer of these principles to reflect current conditions. Recent history has shown a trend of new technology leading to potential misuse of this technology and further leading to stricter governmental regulations. It is the purpose of this review to give guidelines for dealing with new technologies, such as PET imaging, and we describe a radiologist's ethical responsibility in a doctor-patient relationship. A historical review of medical ethics will lead to discussions about various issues affecting radiologists and nuclear physicians. To be sure, not all ethical situations are black and white, and therefore there are many gray areas. The opinions expressed in this article are those of the authors and are based on extension of already established rules of ethical conduct.     

Effect of cisplatin chemotherapy on extracortical tissue formation in canine diaphyseal segmental replacement

The reconstruction of large bone and joint defects after the resection of malignant tumors remains a major challenge. Chemotherapy has significantly lowered the risk of metastasic disease, but complications associated with reconstructive techniques continue to result in late morbidity. In the present study, biomechanical torsion testing, gait analysis, and histomorphometric and scanning electron microscopic evaluations of 24 dogs were used to examine the effects of preoperative and postoperative administration of cisplatin on the biologic fixation of a porous-coated segmental replacement prosthesis. The chemotherapy consisted of four cycles of cisplatin administered at a dosage of 75 mg/m:² preoperatively or postoperatively. The healing was enhanced by use of an autogenous corticocancellous bone graft. The graft was placed evenly around the prosthesis and the adjacent femoral cortex. Mechanical analyses of torsional stiffness, yield strength, and maximum strength revealed no statistically significant differences between the groups at 12 weeks. Such lack of difference was mainly due to the penetration of highly organized fibrous tissue into the porous surface; this provided strong fixation of the implant to bone even in the absence of bone ingrowth. Although bone ingrowth into the prostheses was not affected, electron microscopic, histomorphometric, and radiologic analyses showed a clear difference in the formation of new bone around the prosthesis. Preoperative chemotherapy did not alter the formation of new bone, but specimens from animals treated postoperatively with cisplatin showed significantly less bone graft resorption and less new bone formation. Hence, the effect of cisplatin administration caused only a temporary delay, not a permanent effect, on extracortical capsule formation. The formation of extracortical bone and soft tissue might prevent debris-incised osteolysis and, therefore, prevent late complications by forming a tight capsule around the bone-prosthetic interface.     

Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test.

BACKGROUND: Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. METHODS: Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4. RESULTS: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. CONCLUSIONS: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association.