Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

OBJECTIVE: The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD: In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS: Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS: Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

Effect of antenatal treatment of maternal periodontitis on early childhood neurodevelopment.

OBJECTIVE: To determine if antenatal treatment of maternal periodontitis affects early childhood neurodevelopment. STUDY DESIGN: We evaluated neurodevelopment of 331 24-month-old children born to women who participated in a randomized trial of antenatal (167) or postpartum (164) treatment of periodontitis. Children within groups defined by maternal treatment were designated as high risk for abnormal neurodevelopment (n = 96; birth at ≤34(6)/7 weeks' gestation or small for gestational age following birth at term) or low risk (n = 235; appropriate birth weight and ≥37 weeks' gestation). We measured neurodevelopment using the Bayley Scale of Infant and Toddler Development III (BSID III) and neurological examination. Treatment effect was analyzed using a chi-square or Fisher exact test. Between-group mean scores were compared using Student t test. RESULTS: There were no differences in the incidence of neuromotor or sensory (visual or hearing) impairment or scores on the BSID III between groups. Low-risk children in the antenatal treatment group had higher language scores than those in the postpartum treatment group (92.9 versus 89.2; p = 0.05). CONCLUSION: Antenatal treatment of maternal periodontitis does not appear to affect neurodevelopment at 24 months of age. The slight improvement in language development in low-risk children may be an artifact or not clinically relevant.

Effects of periodontal therapy on rate of preterm delivery: a randomized controlled trial.

OBJECTIVE: To test the effects of maternal periodontal disease treatment on the incidence of preterm birth (delivery before 37 weeks of gestation). METHODS: The Maternal Oral Therapy to Reduce Obstetric Risk Study was a randomized, treatment-masked, controlled clinical trial of pregnant women with periodontal disease who were receiving standard obstetric care. Participants were assigned to either a periodontal treatment arm, consisting of scaling and root planing early in the second trimester, or a delayed treatment arm that provided periodontal care after delivery. Pregnancy and maternal periodontal status were followed to delivery and neonatal outcomes until discharge. The primary outcome (gestational age less than 37 weeks) and the secondary outcome (gestational age less than 35 weeks) were analyzed using a chi test of equality of two proportions. RESULTS: The study randomized 1,806 patients at three performance sites and completed 1,760 evaluable patients. At baseline, there were no differences comparing the treatment and control arms for any of the periodontal or obstetric measures. The rate of preterm delivery for the treatment group was 13.1% and 11.5% for the control group (P=.316). There were no significant differences when comparing women in the treatment group with those in the control group with regard to the adverse event rate or the major obstetric and neonatal outcomes. CONCLUSION: Periodontal therapy did not reduce the incidence of preterm delivery. LEVEL OF EVIDENCE: I.

Results from the Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease.

BACKGROUND: In the Periodontitis and Vascular Events (PAVE) pilot study, periodontal therapy was provided as an intervention in a secondary cardiac event prevention model through five coordinated cardiac-dental centers. METHODS: Subjects were randomized to either community care or protocol provided scaling and root planing to evaluate effects on periodontal status and systemic levels of high-sensitivity C-reactive protein (hs-CRP). RESULTS: After 6 months, there was a significant reduction in mean probing depth and extent of 4- or 5-mm pockets. However, there were no significant differences in attachment levels, bleeding upon probing, or extent of subgingival calculus comparing subjects assigned to protocol therapy (n = 151) to those assigned to community care (n = 152). Using intent-to-treat analyses, there was no significant effect on serum hs-CRP levels at 6 months. However, 48% of the subjects randomized to community care received preventive or periodontal treatments. Secondary analyses demonstrated that consideration of any preventive or periodontal care (i.e., any treatment) compared to no treatment showed a significant reduction in the percentage of people with elevated hs-CRP (values >3 mg/l) at 6 months. However, obesity nullified the periodontal treatment effects on hs-CRP reduction. The adjusted odds ratio for hs-CRP levels >3 mg/l at 6 months for any treatment versus no treatment among non-obese individuals was 0.26 (95% confidence interval: 0.09 to 0.72), adjusting for smoking, marital status, and gender. CONCLUSION: This pilot study demonstrated the critical role of considering obesity as well as rigorous preventive and periodontal care in trials designed to reduce cardiovascular risk.

Rationale and design issues of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study.

OBJECTIVE: Our goal is to determine if antimicrobial prophylaxis with trimethoprim/sulfamethoxazole prevents recurrent urinary tract infections and renal scarring in children who are found to have vesicoureteral reflux after a first or second urinary tract infection. DESIGN, PARTICIPANTS, AND METHODS: The Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study is a double-blind, randomized, placebo-controlled trial. Six hundred children aged 2 to 72 months will be recruited from both primary and subspecialty care settings at clinical trial centers throughout North America. Children who are found to have grades I to IV vesicoureteral reflux after the index febrile or symptomatic urinary tract infection will be randomly assigned to receive daily doses of either trimethoprim/sulfamethoxazole or placebo for 2 years. Scheduled follow-up contacts include in-person study visits every 6 months and telephone interviews every 2 months. Biospecimens (urine and blood) and genetic specimens (blood) will be collected for future studies of the genetic and biochemical determinants of vesicoureteral reflux, recurrent urinary tract infection, renal insufficiency, and renal scarring. RESULTS: The primary outcome is recurrence of urinary tract infection. Secondary outcomes include time to recurrent urinary tract infection, renal scarring (assessed by dimercaptosuccinic acid scan), treatment failure, renal function, resource utilization, and development of antimicrobial resistance in stool flora. CONCLUSIONS: The RIVUR study will provide useful information to clinicians about the risks and benefits of prophylactic antibiotics for children who are diagnosed with vesicoureteral reflux after a first or second urinary tract infection. The data and specimens collected over the course of the study will allow researchers to better understand the pathophysiology of recurrent urinary tract infection and its sequelae.

The Periodontitis and Vascular Events (PAVE) pilot study: recruitment, retention, and community care controls.

BACKGROUND: Population-based clinical and laboratory studies have reported findings providing support for a possible relationship between periodontal disease and cardiovascular disease. The Periodontitis and Vascular Events (PAVE) pilot study was conducted to investigate the feasibility of a randomized secondary prevention trial to test whether treatment of periodontal disease reduces the risk for cardiovascular disease. METHODS: Five clinical centers recruited participants who had documented coronary heart disease and met study criteria for periodontal disease. Eligible participants were randomized to receive periodontal therapy provided by the study or community dental care. Follow-up telephone calls and clinic visits were planned to alternate at 3-month intervals after randomization, with all participants followed until at least the 6-month clinic visit. Participants were followed for adverse events and periodontal and cardiovascular outcomes. RESULTS: A total of 303 participants were randomized. Recruitment that involved active participation of a cardiologist with responsibility for the patients worked best among the strategies used. Of those who had not withdrawn, 93% completed the 6-month contact. During follow-up, 11% of the 152 subjects in the community dental care group reported receiving periodontal therapy outside of the study. CONCLUSIONS: If appropriate recruitment strategies are used, this pilot study demonstrated that it is feasible to conduct a secondary prevention trial of periodontal therapy in patients who have had coronary heart disease. If a community dental care group is used, sample size estimation needs to take into account that a non-trivial proportion of participants in this group may receive periodontal therapy outside of the study.

The Periodontitis and Vascular Events (PAVE) pilot study: adverse events.

BACKGROUND: During the last 15 years, a substantial number of population-based, clinical, laboratory, and animal studies have been published that reported findings on the relationship between periodontal disease and cardiovascular disease. The Periodontitis and Vascular Events (PAVE) pilot study was conducted to investigate the feasibility of a randomized secondary prevention trial to test whether treatment of periodontal disease reduces the risk for cardiovascular disease. This article describes the occurrence of adverse events during the pilot study. METHODS: The PAVE pilot study was a multicenter, randomized trial comparing periodontal therapy to community dental care. Baseline and follow-up clinic visits included a periodontal examination; blood, subgingival plaque, and crevicular fluid specimen collection; and medical and dental histories. Telephone follow-up contacts were scheduled to occur 3 months after randomization and every 6 months thereafter to assess adverse events or endpoints. RESULTS: Cardiovascular adverse events occurred with similar frequency (23 versus 24 [P = 0.85] in the community control and the treatment groups, respectively). There were 15 serious adverse events (SAEs) with a non-significantly higher percentage occurring in the community care group (6.6% versus 3.3%; P = 0.19). A time-to-event analysis of patterns of SAEs indicated that subjects in the periodontal therapy group tended to be less likely to experience an SAE over the entire 25 months of the study. CONCLUSION: For those individuals who remained in the study, it appears that provision of periodontal scaling and root planing treatment to individuals with heart disease resulted in a similar pattern of adverse events as seen in the community care group, which also received some treatment.

A functional MRI study of a paced motor activation task to evaluate frontal-subcortical circuit function in bipolar depression.

The primary aim of this functional magnetic resonance imaging (fMRI) study was to test the utility of a paced motor activation task to evaluate frontal-subcortical (FSC) circuit function in bipolar depression. A secondary aim was to determine if utilizing both a motor and cognitive activation paradigm (Stroop) would provide information about the potential role of FSC dysfunction in the cognitive symptoms of bipolar depression. Analysis of the control group (n=15) alone revealed that the motor task activated FSC structures. Comparison of the control to bipolar group (n=14) revealed significant differences between the groups in striatum as well as cortical areas with FSC connections in response to the non-dominant-hand motor task. In response to the Stroop, there were significant differences between the groups in portions of the bilateral posterior cingulate and occipital cortex, but not in FSC structures. While these results must be considered preliminary, this work supports further studies of paced motor tasks to probe FSC function. Further, it suggests that the use of both a cognitive and motor task in the same study provides useful information about brain function. Finally, it supports the literature implicating FSC circuit abnormalities in bipolar disorder.

Pathways curriculum and family interventions to promote healthful eating and physical activity in American Indian schoolchildren.

BACKGROUND: Pathways, a multisite school-based study aimed at promoting healthful eating and increasing physical activity, was a randomized field trial including 1704 American Indian third to fifth grade students from 41 schools (21 intervention, 20 controls) in seven American Indian communities. METHODS: The intervention schools received four integrated components: a classroom curriculum, food service, physical activity, and family modules. The curriculum and family components were based on Social Learning Theory, American Indian concepts, and results from formative research. Process evaluation data were collected from teachers (n=235), students (n=585), and families. Knowledge, Attitudes, and Behavior Questionnaire data were collected from 1150 students including both intervention and controls. RESULTS: There were significant increases in knowledge and cultural identity in children in intervention compared to control schools with a significant retention of knowledge over the 3 years, based on the results of repeating the third and fourth grade test items in the fifth grade. Family members participated in Family Events and take-home activities, with fewer participating each year. CONCLUSION: A culturally appropriate school intervention can promote positive changes in knowledge, cultural identity, and self-reported healthful eating and physical activity in American Indian children and environmental change in school food service.

Design, implementation, and quality control in the Pathways American-Indian multicenter trial.

BACKGROUND: Pathways was the first multicenter American-Indian school-based study to test the effectiveness of an obesity prevention program promoting healthy eating and physical activity. METHODS: Pathways employed a nested cohort design in which 41 schools were randomized to intervention or control conditions and students within these schools were followed as a cohort (1,704 third graders at baseline). The study's primary endpoint was percent body fat. Secondary endpoints were levels of fat in school lunches; time spent in physical activity; and knowledge, attitudes, and behaviors regarding diet and exercise. Quality control (QC) included design of data management systems which provided standardization and quality assurance of data collection and processing. Data QC procedures at study centers included manuals of operation, training and certification, and monitoring of performance. Process evaluation was conducted to monitor dose and fidelity of the interventions. Registration and tracking systems were used for students and schools. RESULTS: No difference in mean percent body fat at fifth grade was found between the intervention and control schools. Percent of calories from fat and saturated fat in school lunches was significantly reduced in the intervention schools as was total energy intake from 24-hour recalls. Significant increases in self-reported physical activity levels and knowledge of healthy behaviors were found for the intervention school students. CONCLUSIONS: The Pathways study results provide evidence demonstrating the role schools can play in public health promotion. Its study design and QC systems and procedures provide useful models for other similar school based multi- or single-site studies.

Impact of the Pathways food service intervention on breakfast served in American-Indian schools.

BACKGROUND: Pathways was a multisite, multicomponent obesity prevention intervention for American-Indian schoolchildren. The goal of the school breakfast and lunch component was to reduce fat content of school meals to 30% or fewer calories from fat without compromising dietary quality. METHODS: An intensive 3-year intervention was implemented with school food service staff. Five consecutive days of school breakfast menu and recipe information was collected at 20 control and 19 intervention schools at four time intervals. Data were analyzed at nutrient and (in final year) food levels. RESULTS: Average total fat decreased in intervention schools from 16.0 grams at baseline to 13.6 grams by end of study, compared with 16.6 and 16.7 grams at baseline and final measurement in control schools (P<0.030). Percentage of calories from saturated fat were also significantly reduced from 12.0 to 8.9%, compared with 12.1 to 10.6% in control schools (P<0.014). There were no significant differences in total energy or other nutrients by treatment condition across four time points. Food-level data revealed a consistent pattern of more lower-fat items served in intervention schools compared to control schools. CONCLUSIONS: Pathways was successful in achieving its overall goal of reducing dietary fat in meals served for school breakfasts.

The effects of the Pathways Obesity Prevention Program on physical activity in American Indian children.

BACKGROUND: Inadequate opportunities for physical activity at school and overall low levels of activity contribute to the high prevalence of overweight and obesity in American-Indian children. METHODS: A school-based physical activity intervention was implemented which emphasized increasing the frequency and quality of physical education (PE) classes and activity breaks. Changes in physical activity were assessed using the TriTrac-R3D accelerometer in a subsample of 580 of the students (34%) randomly selected from the Pathways study cohort. Baseline measures were completed with children in second grade. Follow-up measurements were obtained in the spring of the fifth grade. RESULTS: Intervention schools were more active (+6.3 to +27.2%) than control schools at three of the four sites, although the overall difference between intervention and control schools (approximately 10%) was not significant (P>0.05). Boys were more active than girls by 17 to 21% (P < or =.01) at both baseline and follow-up. CONCLUSIONS: Despite the trend for greater physical activity at three of four study sites, and an overall difference of approximately 10% between intervention and control schools, high variability in accelerometer AVM and the opportunity to measure physical activity on only 1 day resulted in a the failure to detect the difference as significant.

Pathways process evaluation results: a school-based prevention trial to promote healthful diet and physical activity in American Indian third, fourth, and fifth grade students.

BACKGROUND: Pathways was a large-scale, multisite, 3-year, study testing a school-based intervention designed to lower percent body fat in American Indian children. METHODS: At the 21 intervention schools process evaluation data were collected for training of school personnel; implementation of the classroom and physical activity curricula; implementation of the project's food service guidelines in the school cafeterias; adult participation in the family events; and, students' perceived exposure to the Pathways interventions. RESULTS: Students received about 93% of the classroom curriculum lessons. The minimum requirement of physical education being taught three times per week for at least 30 minutes duration was achieved by the fifth grade. The implementation of the food service behavioral guidelines increased from 51% in the third grade to 87% in the fifth grade. The family events had lower than anticipated adult participation. The participation rates were 45% during the third grade, and 41 and 63% during the fourth and fifth grades, respectively. There was a significant difference between intervention and control students' perceived exposure to Pathways type interventions. CONCLUSION: The Pathways interventions were successfully implemented with good reach, high extent, and fidelity.