Biomedical subjects
Mark Davies
Publications and source records attributed to Mark Davies.
Nine months of multicomponent behavioral treatment for ADHD and effectiveness of MTA fading procedures.
We examined 9-month data from the 14-month NIMH Multimodal Treatment Study of Children with ADHD (the MTA) as a further check on the relative effect of medication (MedMgt) and behavioral treatment (Beh) for attention-deficit/hyperactivity disorder (ADHD) while Beh was still being delivered at greater intensity than at 14-month endpoint, and conversely as a check on the efficacy of the MTA behavioral generalization/maintenance procedures. Intention-to-treat analysis at 9 months showed essentially the same results as at 14 months, after Beh had been completely faded; MedMgt and the combination (Comb) of medication and Beh were significantly superior to Beh and community care (CC) for ADHD and oppositional-defiant (ODD) symptoms, with mixed results for social skills and internalizing symptoms. All treatment-group differences examined as changes in slopes from 9 to 14 months were nonsignificant (we found general improvement for all groups). Slopes from baseline to 9 months correlated highly (r > .74, p < .0001) with slopes from baseline to 14 months for all groups. The time function from baseline to 14 months showed a significant linear, but not quadratic, trend for the main outcome measure (a composite of parent- and teacher-rated ADHD and ODD symptoms) for all groups. Findings suggest that in contrast to the hypothesized deterioration in the relative benefit of Beh between 9 and 14 months (after completion of fading), the MTA Beh generalization and maintenance procedures implemented through 9 months apparently yielded continuing improvement through 14 months, with preservation of the relative position of Beh compared to other treatment strategies.
Comparison of increasingly detailed elicitation methods for the assessment of adverse events in pediatric psychopharmacology.
OBJECTIVE: To improve the gathering of adverse events (AEs) in pediatric psychopharmacology by examining the value and acceptability of increasingly detailed elicitation methods. METHOD: Trained clinicians administered the Safety Monitoring Uniform Report Form (SMURF) to 59 parents and outpatients (mean age +/- SD = 11.9 +/- 3.2 years) in treatment, with 36% on stimulants, 29% on selective serotonin reuptake inhibitor drugs, 10% on both, and 25% on other drug combinations. The SMURF included a brief general inquiry, a drug-specific inquiry, and a comprehensive body system review (BSR). RESULTS: SMURF administration took 24.6 +/- 13.9 minutes (median, 21). The BSR took 15.5 +/- 8.1 minutes (median, 14) longer (p < .0001) than the general inquiry (4.3 +/- 5.4 minutes) and the drug-specific inquiry (4.2 +/- 2.9 minutes). The general inquiry elicited 48 AEs, the drug-specific inquiry elicited 16 additional AEs, and the BSR 129 additional AEs. Of all the clinically relevant AEs elicited by the SMURF (n = 36), 19 (53%) were elicited by the BSR. The BSR length and detail were acceptable to parents but not to clinicians. CONCLUSIONS: The BSR elicited additional clinically significant AEs that had been missed with less detailed methods. Parents, but not clinicians, rated satisfaction and acceptability of the BSR as good.
Preclinical evaluation of a vaccine based on conserved region of M protein that prevents group A streptococcal infection.
BACKGROUND & OBJECTIVES: Infection with group A Streptococcus (GAS) may result in a number of human diseases ranging from the relatively benign pharyngitis to the potentially life-threatening invasive diseases and post-infectious sequelae. We have previously defined a minimal B-cell epitope from the conserved region of the M-protein. Here we report on the immunogenicity, opsonic potential of the resulting sera and the level of protection induced by this peptide in comparison to a pepsin extract of the M protein. METHODS: Inbred mice were immunized with peptides derived from the M protein. Sera were collected from the immunized mice and its opsonic potential determined for M1 and M6 GAS strains. Mice were then intranasally challenged with a virulent M1 GAS strain to determine the protective efficacy of the peptides. RESULTS: The peptides induced significant antibody responses when delivered subcutaneously and immunized mice demonstrated significantly enhanced survival compared to control groups following challenge. INTERPRETATION & CONCLUSION: The data obtained in the present study indicated that the chimeric peptide J8 from the conserved region of the M protein could form the basis for an anti-streptococcal vaccine in future.
Clostridial infection of the abdominal aorta.
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Response to methylphenidate in children with attention deficit hyperactivity disorder and manic symptoms in the multimodal treatment study of children with attention deficit hyperactivity disorder titration trial.
OBJECTIVE: Recent reports raise concern that children with attention deficit hyperactivity disorder (ADHD) and some manic symptoms may worsen with stimulant treatment. This study examines the response to methylphenidate in such children. METHODS: Data from children participating in the 1-month methylphenidate titration trial of the Multimodal Treatment Study of Children with ADHD were reanalyzed by dividing the sample into children with and without some manic symptoms. Two "mania proxies" were constructed using items from the Diagnostic Interview Schedule for Children (DISC) or the Child Behavior Checklist (CBCL). Treatment response and side effects are compared between participants with and without proxies. RESULTS: Thirty-two (11%) and 29 (10%) participants fulfilled criteria for the CBCL mania proxy and DISC mania proxy, respectively. Presence or absence of either proxy did not predict a greater or lesser response or side effects. CONCLUSION: Findings suggest that children with ADHD and manic symptoms respond robustly to methylphenidate during the first month of treatment and that these children are not more likely to have an adverse response to methylphenidate. Further research is needed to explore how such children will respond during long-term treatment. Clinicians should not a priori avoid stimulants in children with ADHD and some manic symptoms.
An open trial of fluoxetine for adolescents with bulimia nervosa.
OBJECTIVE: This open clinical trial examined the feasibility, tolerability, and efficacy of treating adolescents who suffer from bulimia nervosa with fluoxetine. METHODS: Ten adolescents, ages 12-18 years received 8 weeks of fluoxetine 60 mg/day with supportive psychotherapy. Primary outcome measures included frequencies of binge eating and purging and ratings on the Clinical Global Impressions-Improvement scale (CGI-I). Secondary outcome measures included self-report measures of eating disorder, depression, and anxiety symptoms. Safety and tolerability of this dose of fluoxetine were also assessed. RESULTS: Average weekly binges decreased significantly from 4.1 +/- 3.8 to 0 (p < 0.01). Average weekly purges decreased significantly from 6.4 +/- 5.2 to 0.4 +/- 0.9 (p < 0.005). All patients improved on the CGI-I scale, with 20% rated as much improved, 50% improved, and 30% slightly improved. All subjects tolerated the 60-mg dose of fluoxetine, and there were no dropouts due to adverse effects from the medication. DISCUSSION: Fluoxetine is generally well tolerated and may be an effective treatment option for adolescents with bulimia nervosa.
Recall of childhood psychopathology more than 10 years later.
OBJECTIVE: This study investigated recall in a sample of depressed, anxious, and normal children followed up as adults. Strengths of this study were that the length of the retest interval was substantial, follow-up information was collected by blind interviewers, and childhood diagnoses were clearly documented. METHOD: The sample consisted of 144 subjects with a childhood diagnosis of depression, 48 with a childhood diagnosis of anxiety, and 128 normal controls. Best-estimate diagnoses assigned at follow-up were compared with childhood primary diagnoses. RESULTS: Reliability and sensitivity were fair for major depressive disorder (mean = 0.46 and 50%, respectively) and any depression (mean = 0.57 and 65%, respectively). Reliability and sensitivity were relatively lower for anxiety (mean = 0.32 and 43%, respectively). Sensitivity for any diagnosis was good (mean = 71%). Specificity was good among all diagnostic categories (range = 73%-100%). Results suggest better diagnostic recall for females than for males. Recall was slightly better for subjects who were older than age 12 during their original episode. Age-of-onset reliability was poor (major depressive disorder = 0.22, any depression = 0.22, and any anxiety = -0.13). CONCLUSIONS: Recall of any childhood disorder is moderately reliable and accurate. Recall of a specific disorder is less accurate. Depression was more likely to be recalled than anxiety. High specificity suggests that participants were not biased to report disorders not present in childhood.
Searching for moderators and mediators of pharmacological treatment effects in children and adolescents with anxiety disorders.
OBJECTIVE: To examine whether age, gender, ethnicity, type of anxiety disorder, severity of illness, comorbidity, intellectual level, family income, or parental education may function as moderators and whether treatment adherence, medication dose, adverse events, or blinded rater's guess of treatment assignment may function as mediators of pharmacological treatment effect in children and adolescents with anxiety disorders. METHOD: The database of a recently reported double-blind placebo-controlled trial of fluvoxamine in 128 youths was analyzed. With a mixed-model random-effects regression analysis of the Pediatric Anxiety Rating Scale total score, moderators and mediators were searched by testing for a three-way interaction (strata by treatment by time). A two-way interaction (strata by time) identified predictors of treatment outcome. RESULTS: No significant moderators of efficacy were identified, except for lower baseline depression scores, based on parent's (but not child's) report, being associated with greater improvement (p < .001). Patients with social phobia (p < .05) and greater severity of illness (p < .001) were less likely to improve, independently of treatment assignment. Blinded rater's guess of treatment assignment acted as a possible mediator (p < .001), but improvement was attributed to fluvoxamine, regardless of actual treatment assignment. Treatment adherence tended to be associated (p = .05) with improvement. CONCLUSIONS: In this exploratory study, patient demographics, illness characteristics, family income, and parental education did not function as moderators of treatment effect. Social phobia and severity of illness predicted less favorable outcome. Attribution analyses indicated that study blindness remained intact. The presence of concomitant depressive symptoms deserves attention in future treatment studies of anxious children.
Parent-defined target symptoms respond to risperidone in RUPP autism study: customer approach to clinical trials.
OBJECTIVE: A consumer-oriented efficacy assessment in clinical trials should measure changes in chief complaint and consumer request (symptoms of most concern to patient/caregiver), which may be diluted in change scores of multisymptom scales. METHOD: In the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network 8-week double-blind trial of risperidone versus placebo, the chief concerns of parents were collected at 0, 4, and 8 weeks (endpoint), in addition to standardized primary measures. Blinded clinical judges rated change from baseline to 4 and 8 weeks on a 9-point scale (1 = normalized, 5 = unchanged, 9 = disastrous); 94 participants had usable data. RESULTS: The most common symptoms identified by parents were tantrums, aggression, and hyperactivity. Interrater reliability was excellent. Mean ratings at endpoint were 2.8 +/- 1.2 on risperidone and 4.5 +/- 1.3 on placebo (p <.001). Ratings were collinear with Clinical Global Impression-Improvement and Aberrant Behavior Checklist Irritability subscale (primary dimensional measure). Effect size d was 1.4, compared to 1.2 on the Aberrant Behavior Checklist Irritability subscale. Effect sizes varied twofold by symptom category, largest for self-injury (2.11) and tantrums (1.95). CONCLUSIONS: Risperidone was superior to placebo in reducing symptoms of most concern to parents of autistic children with irritable behavior. Rating individualized participant-chosen target symptoms seems a reliable, sensitive, efficient, and consumer-friendly way to assess treatment effect and might have clinical application.
How can we improve the assessment of safety in child and adolescent psychopharmacology?
OBJECTIVE: To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. METHOD: Strengths and limitations of current methodology were reviewed and possible alternatives examined. RESULTS: Research on the validity of safety evaluation has been extremely limited. No evidence-based "gold standard" exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered. CONCLUSION: The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common "core," to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.
Review of safety assessment methods used in pediatric psychopharmacology.
OBJECTIVE: Elicitation is an essential and critical step in ascertaining adverse events (AEs). This report reviews elicitation methods used in published clinical trials of psychopharmacological agents in children. METHOD: Pediatric psychopharmacology reports were reviewed for safety methods in the Medline database. Studies were included if they were published 1980 or later, provided data on AEs, and described the ascertainment methodology used for determining them. RESULTS: A review of 196 pediatric psychopharmacology articles depicting safety assessments in clinical studies over the past 22 years revealed that there was no common method used for eliciting or reporting AE data. CONCLUSION: The current inconsistency in safety data ascertainment is a major limitation that likely impairs the ability to promptly and accurately identify drug-induced AEs. Research on how best to standardize safety methods should be considered a priority in pediatric psychopharmacology.
Developing methodologies for monitoring long-term safety of psychotropic medications in children: report on the NIMH conference, September 25, 2000.
OBJECTIVE: To improve the methods for long-term assessment of drug-associated side effects and advance knowledge of the safety profile of psychotropic medications in children and adolescents. METHOD: A multidisciplinary, interactive workshop was hosted by the National Institute of Mental Health (NIMH) and the Research Units on Pediatric Psychopharmacology network. Participants were experts in child and adolescent psychiatry, psychopharmacology, pharmacoepidemiology, and statistics from academia, the pharmaceutical industry, the Food and Drug Administration (FDA), and the NIMH. Evaluation of drug safety was examined from five perspectives: research design and methods, industry, regulatory requirements, bioethics, and practice settings. For each of these areas, special emphasis was placed on identifying barriers and generating solutions. RESULTS: A major obstacle is the lack of standardization of the methods used for collecting safety data. The limitations of both randomized clinical trials and passive postmarketing surveillance in assessing long-term safety were recognized. The need to consider alternative approaches, such as registries and trend analysis of population-based databases, was highlighted. Recommendations were proposed together with possible approaches to implementation. CONCLUSIONS: A concerted effort by academic researchers, industry, FDA, practitioners, and NIMH is needed to standardize methods and lay the foundations for systematic research on the long-term safety of psychotropic medications in children.
Acquired constriction ring syndrome.
A case of "acquired constriction ring" or "toe-tourniquet" syndrome is presented to increase awareness of the condition in the orthopaedic community. If treated promptly, this condition has a very good prognosis and, if the diagnosis is missed, may lead to amputation. We also discuss the potential causes and presentation of this condition, along with the need for urgent surgical exploration if there are doubts over tissue viability.
Changing emergency department practice.
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Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model.
Prostate adenocarcinoma is associated with the formation of osteoblastic metastases in bone. It has been hypothesized that osteoclastic bone resorption is a critical component before the development of these osteoblastic lesions in bone. This observation has led researchers to test agents that inhibit osteoclastic activity to prevent or halt the formation of metastatic prostate cancer lesions in bone. Bisphosphonates inhibit osteoclast activity, and previous studies showed that they have the ability to reduce the osteolytic bone resorption associated with multiple myeloma and breast cancer. The objective of this study was to evaluate the efficacy of zoledronate in limiting the formation and/or progression of osteoblastic lesions produced by the injection of known prostate cancer cells (LAPC-9 and PC-3 cells) into the tibia of SCID mice. The mice were treated with either 30- micro g or 150- micro g doses of zoledronate before tumor implantation (pretreatment group), or at weekly intervals after tumor implantation (weekly treatment group), or weekly starting one month after tumor implantation (delayed-treatment group). The zoledronate was very effective in limiting the formation of osteolytic lesions in PC-3 implanted tibias by inhibiting osteoclast activity. Radiographic and histological analysis at weekly intervals revealed that osteolytic lesions developed in the control tibias by 2 weeks, and there was complete destruction of the cortical bone in much of the proximal tibias by 4 weeks. In the treatment groups, there was minimal cortical destruction noted in the weekly treatment groups at both doses, whereas mild cortical erosion was evident in the pretreatment groups, with more cortical destruction noted in the 30- micro g group compared with the 150- micro g group. Tartrate-resistant acid phosphatase (TRAP) staining showed that zoledronate decreased osteoclastic numbers and that there was a dose-dependent response. In tibias implanted with the LAPC-9 cells, the zoledronate was not effective in halting the formation of the osteoblastic lesions. Radiographic and histological analysis revealed that osteoblastic lesions either had formed or were developing in 18 of 18 of the control tibias and 36 of 36 of the treated tibias at 8 weeks regardless of dose or treatment schedule. Furthermore, TRAP staining demonstrated that osteoblastic lesions had formed in the LAPC-9 tibias under conditions in which osteoclast numbers were significantly reduced. These results suggest that osteoclast activity may not be critical for the development of osteoblastic lesions associated with prostate tumor cells. Hence, bisphosphonates may not be ideal agents to prevent the formation of osteoblastic lesions associated with prostate cancer metastases to bone.
The diagnostic accuracy of MR imaging in osteoid osteoma.
OBJECTIVE: To analyse the MR imaging appearances of a large series of osteoid osteomas, to assess the ability of MR imaging to detect the tumour, and to identify potential reasons for misdiagnosis. DESIGN AND PATIENTS: The MR imaging findings of 43 patients with osteoid osteoma were reviewed retrospectively and then compared with other imaging modalities to assess the accuracy of MR localisation and interpretation. RESULTS: The potential for a missed diagnosis was 35% based solely on the MR investigations. This included six tumours which were not seen and nine which were poorly visualised. The major determinants of the diagnostic accuracy of MR imaging were the MR technique, skeletal location, and preliminary radiographic appearances. There was a wide spectrum of MR signal appearances of the lesion. The tumour was identified in 65% of sequences performed in the axial plane. The nidus was present in only one slice of the optimal sequence in 27 patients. Reactive bone changes were present in 33 and soft tissue changes in 37 patients. CONCLUSION: Reliance on MR imaging alone may lead to misdiagnosis. As the osteoid osteoma may be difficult to identify and the MR features easily misinterpreted, optimisation of MR technique is crucial in reducing the risk of missing the diagnosis. Unexplained areas of bone marrow oedema in particular require further imaging (scintigraphy and CT) to exclude an osteoid osteoma.
Risperidone in children with autism and serious behavioral problems.
BACKGROUND: Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. METHODS: We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. RESULTS: A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.