Maternal Smoking and Congenital Heart Defects, National Birth Defects Prevention Study, 1997-2011.

OBJECTIVES: To assess associations between maternal smoking and congenital heart defects (CHDs) in offspring. STUDY DESIGN: We performed a retrospective case-control study using data for cases of CHD (n = 8339) and nonmalformed controls (n = 11 020) from all years (1997-2011) of the National Birth Defects Prevention Study. Maternal self-reported smoking 1 month before through 3 months after conception was evaluated as a binary (none, any) and categorical (light, medium, heavy) exposure. Multivariable logistic regression was used to estimate aOR and 95% CIs. Stratified analyses were performed for septal defects according to maternal age, prepregnancy body mass index, and maternal race/ethnicity. RESULTS: Multiple CHDs displayed modest associations with any level of maternal periconceptional smoking independent of potential confounders; the strongest associations were for aggregated septal defects (OR, 1.5; 95% CI, 1.3-1.7), tricuspid atresia (OR, 1.7; 95% CI, 1.0-2.7), and double outlet right ventricle (DORV) (OR, 1.5; 95% CI, 1.1-2.1). Tricuspid atresia and DORV also displayed dose-response relationships. Among heavy smokers, the highest odds were again observed for tricuspid atresia (aOR 3.0; 95% CI, 1.5-6.1) and DORV (aOR 1.5; 95% CI, 1.1-2.2). Heavy smokers ≥35 years old more frequently had a child with a septal defect when compared with similarly aged nonsmokers (aOR 2.3; 95% CI, 1.4-3.9). CONCLUSIONS: Maternal periconceptional smoking is most strongly associated with septal defects, tricuspid atresia, and DORV; the risk for septal defects is modified by maternal age.

Efficacy of standardizing fibrinolytic therapy for parapneumonic effusion.

BACKGROUND: While chest tube placement with pleural fibrinolytic medication is the established treatment of pediatric empyema, treatment failure is reported in up to 20% of these children. OBJECTIVE: Standardizing fibrinolytic administration among interventional radiology (IR) physicians to improve patient outcomes in pediatric parapneumonic effusion. MATERIALS AND METHODS: We introduced a hospital-wide clinical pathway for parapneumonic effusion (1-2 mg tissue plasminogen activator [tPA] twice daily based on pleural US grade); we then collected prospective data for IR treatment May 2017 through February 2020. These data included demographics, co-morbidities, pediatric intensive care unit (PICU) admission, pleural US grade, culture results, daily tPA dose average, twice-daily dose days, skipped dose days, pleural therapy days, need for chest CT/a second IR procedure/surgical drainage, and length of stay. We compared the prospective data to historical controls with IR treatment from January 2013 to April 2017. RESULTS: Sixty-three children and young adults were treated after clinical pathway implementation. IR referrals increased (P = 0.02) and included higher co-morbidities (P = 0.005) and more PICU patients (P = 0.05). Mean doses per day increased from 1.5 to 1.9 (P < 0.001), twice-daily dose days increased from 38% to 79% (P < 0.001) and median pleural therapy days decreased from 3.5 days to 2.5 days (P = 0.001). No IR patients needed surgical intervention. No statistical differences were observed for gender/age/weight, US grade, need for a second IR procedure or length of stay. US grade correlated with greater positive cultures, need for chest CT/second IR procedure, and pleural therapy days. CONCLUSION: Interventional radiology physician standardization improved on a clinical pathway for fibrinolysis of parapneumonic effusion. Despite higher patient complexity, pleural therapy duration decreased. There were no chest tube failures needing surgical drainage.

Dodecafluoropentane Emulsion in Acute Ischemic Stroke: A Phase Ib/II Randomized and Controlled Dose-Escalation Trial.

PURPOSE: This randomized, placebo-controlled, double-blind, dose-escalation acute ischemic stroke trial was designed to demonstrate maximum tolerated dose, characterize adverse events (AEs), and explore clinical outcomes when intravenous dodecafluoropentane emulsion (DDFPe) was used as neuroprotection. METHODS: Acute ischemic stroke patients (n = 24) with National Institutes of Health Stroke Scale (NIHSS) score of 2-20 were randomized to either 3 doses of intravenous DDFPe or placebo, 1 every 90 minutes, starting within 12 hours of symptom onset. Doses were given without affecting standard stroke care. Each of the 3 dose cohorts included 8 patients, with 2 receiving placebo and 6 receiving DDFPe. Primary outcomes were serious adverse events (SAEs), AEs, NIHSS score, and modified Rankin Score (mRS). RESULTS: No dose-limiting toxicities were encountered, and no maximum tolerated dose was defined. One unrelated delayed death occurred in a DDFPe patient, and another occurred in the placebo group. Group SAEs and AEs were similar in incidence and severity. Early initiation of DDFPe treatment resulted in better NIHSS score response than late initiation (P = .03). Thirty- and 90-day mRS after high-dose therapy suggested clinical improvement (P = .01 and P = .03, respectively). However, the significance of differences in clinical outcomes was limited by small patient numbers and differences in stroke severity between cohorts. CONCLUSIONS: Intravenous DDFPe appears to be safe at all doses tested. Clinical improvements in NIHSS score and mRS were significant but compromised by small sample size.

Stratifying fibrinolytic dosing in pediatric parapneumonic effusion based on ultrasound grade correlation.

BACKGROUND: Complicated pleural effusion prolongs the hospital course of pneumonia. Chest tube placement with instillation of fibrinolytic medication allows efficient drain output and decreases hospital stay. OBJECTIVE: To evaluate experience with lower fibrinolytic dose for parapneumonic effusions and to assess potential dose stratification based on a simple ultrasound grading system. MATERIALS AND METHODS: We retrospectively reviewed the medical record to identify children and young adults who received fibrinolytic therapy for parapneumonic effusion and had chest tube placement by an interventional radiology service at a single children's hospital. We assessed tissue plasminogen activator (tPA) dosing and treatment duration, as well as the need for a second pleural procedure or surgical drainage. Diagnostic US images were classified as showing less than 50% pleural echogenicity (grade 1) or greater than 50% pleural echogenicity (grade 2) and were correlated with clinical parameters. RESULTS: Of 32 patients with parapneumonic effusion, all except one received at least some 1-mg tPA doses. Dosing was solely 1-mg tPA in 81% of subjects; 19% of subjects also received 2-mg tPA doses. Mean fibrinolytic duration was 3.1 days for grade 1 effusions compared to 5.4 days for grade 2 effusions. A second pleural procedure was required in 15.6% of children. Pleural drainage with fibrinolytic therapy was successful in 97%; only one child required surgical drainage. Grade 2 US differed significantly from grade 1 US, with grade 2 occurring in younger patients (P < 0.0001), smaller patients (P < 0.0001), those needing a second procedure (P = 0.001), those with positive pleural culture or polymerase chain reaction test (P = 0.006), and those with longer treatment duration (P = 0.03). CONCLUSION: A lower 1-mg dosing regimen of tissue plasminogen activator was effective in all children with less complex (grade 1 US imaging) parapneumonic effusions. Grade 2 US images correlated with younger and smaller children, presence of a pleural organism, and longer or more complicated chest tube duration.

Giant osteoclast formation and long-term oral bisphosphonate therapy.

BACKGROUND: Bisphosphonates decrease bone resorption and are commonly used to treat or prevent osteoporosis. However, the effect of bisphosphonates on their target cells remains enigmatic, since in patients benefiting from therapy, little change, if any, has been observed in the number of osteoclasts, which are the cells responsible for bone resorption. METHODS: We examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods. RESULTS: The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01). Moreover, the number of osteoclasts increased as the cumulative dose of the drug increased (r=0.50, P<0.001). Twenty-seven percent of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling. CONCLUSIONS: Long-term alendronate treatment is associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that are undergoing protracted apoptosis.

Dodecafluoropentane emulsion decreases infarct volume in a rabbit ischemic stroke model.

PURPOSE: To assess the efficacy of dodecafluoropentane emulsion (DDFPe), a nanodroplet emulsion with significant oxygen transport potential, in decreasing infarct volume in an insoluble-emboli rabbit stroke model. MATERIALS AND METHODS: New Zealand White rabbits (N = 64; weight, 5.1 ± 0.50 kg) underwent angiography and received embolic spheres in occluded internal carotid artery branches. Rabbits were randomly assigned to groups in 4-hour and 7-hour studies. Four-hour groups included control (n = 7, embolized without treatment) and DDFPe treatment 30 minutes before stroke (n = 7), at stroke onset (n = 8), and 30 minutes (n = 5), 1 hour (n = 7), 2 hours (n = 5), or 3 hours after stroke (n = 6). Seven-hour groups included control (n = 6) and DDFPe at 1 hour (n = 8) and 6 hours after stroke (n = 5). DDFPe dose was a 2% weight/volume intravenous injection (0.6 mL/kg) repeated every 90 minutes as time allowed. After euthanasia, infarct volume was determined by vital stains on brain sections. RESULTS: At 4 hours, median infarct volume decreased for all DDFPe treatment times (pretreatment, 0.30% [P = .004]; onset, 0.20% [P = .004]; 30 min, 0.35% [P = .009]; 1 h, 0.30% [P = .01]; 2 h, 0.40% [P = .009]; and 3 h, 0.25% [P = .003]) compared with controls (3.20%). At 7 hours, median infarct volume decreased with treatment at 1 hour (0.25%; P = .007) but not at 6 hours (1.4%; P = .49) compared with controls (2.2%). CONCLUSIONS: Intravenous DDFPe in an animal model decreases infarct volumes and protects brain tissue from ischemia, justifying further investigation.

Successful microbubble sonothrombolysis without tissue-type plasminogen activator in a rabbit model of acute ischemic stroke.

BACKGROUND AND PURPOSE: Microbubbles (MB) combined with ultrasound (US) have been shown to lyse clots without tissue-type plasminogen activator (tPA) both in vitro and in vivo. We evaluated sonothrombolysis with 3 types of MB using a rabbit embolic stroke model. METHODS: New Zealand White rabbits (n=74) received internal carotid angiographic embolization of single 3-day-old cylindrical clots (0.6 × 4.0 mm). Groups included: (1) control (n=11) embolized without treatment; (2) tPA (n=20); (3) tPA+US (n=10); (4) perflutren lipid MB+US (n=16); (5) albumin 3 µm MB+US (n=8); and (6) tagged albumin 3 µm MB+US (n=9). Treatment began 1 hour postembolization. Ultrasound was pulsed-wave (1 MHz; 0.8 W/cm²) for 1 hour; rabbits with tPA received intravenous tPA (0.9 mg/kg) over 1 hour. Lipid MB dose was intravenous (0.16 mg/kg) over 30 minutes. Dosage of 3 µm MB was 5 × 109 MB intravenously alone or tagged with eptifibatide and fibrin antibody over 30 minutes. Rabbits were euthanized at 24 hours. Infarct volume was determined using vital stains on brain sections. Hemorrhage was evaluated on hematoxylin and eosin sections. RESULTS: Infarct volume percent was lower for rabbits treated with lipid MB+US (1.0%± 0.6%; P=0.013), 3 µm MB+US (0.7% ± 0.9%; P=0.018), and tagged 3 µm MB+US (0.8% ± 0.8%; P=0.019) compared with controls (3.5%± 0.8%). The 3 MB types collectively had lower infarct volumes (P=0.0043) than controls. Infarct volume averaged 2.2% ± 0.6% and 1.7%± 0.8% for rabbits treated with tPA alone and tPA+US, respectively (P=nonsignificant). CONCLUSIONS: Sonothrombolysis without tPA using these MB is effective in decreasing infarct volumes. Study of human application and further MB technique development are justified.

Preoperative sclerotherapy of facial venous malformations: impact on surgical parameters and long-term follow-up.

PURPOSE: To analyze the operative benefit of preoperative sclerotherapy of facial venous malformations and assess long-term patient outcome. MATERIALS AND METHODS: Preoperative sclerotherapy was performed in 24 consecutive patients referred before resection of facial venous malformation. Pretreatment imaging was reviewed for malformation dimensions (length, width, and height), and volumes were estimated. Sclerotherapy was performed with 3% sodium tetradecyl in the first 15 patients and 98% dehydrated alcohol in the remaining 9 patients. Operative blood loss, operative time, transfusion requirement, and hospital stay were recorded. Operative time per lesion volume and operative blood loss per lesion volume were calculated. Results were compared with 15 historical control patients who underwent resection of facial venous malformations without preoperative sclerotherapy. Long-term follow-up of study and control patients was performed. RESULTS: Compared with controls, patients undergoing preoperative venous sclerotherapy were significantly older (P = .0206) and had larger lesions in all three dimensions (height, P = .0002; length, P = .0010; width, P = .0004). Patients receiving sclerotherapy had shorter operative time per lesion volume (P < .0001) and reduced blood loss per lesion volume (P < .0001). Neither hospital stay nor the need for blood transfusion differed from the control patients (P = .2449 and P = .6857). Mild periprocedural complications were encountered in 12.5% of cases, and nerve paresis occurred in 8.3% of cases. Long-term follow-up revealed retreatment was required in 2 of 24 patients (8.3%). CONCLUSIONS: Preoperative sclerotherapy of venous malformations was associated with less operative time per lesion volume and less operative blood loss per lesion volume. Long-term follow-up revealed a low need for retreatment.

Physiologic effects of retinopathy of prematurity screening examinations.

PURPOSE: Preterm infants weighing less than 1500 g routinely undergo a series of eye examinations to screen for retinopathy of prematurity (ROP). While these examinations are important for the prevention of blindness, infants may suffer adverse physiologic events during and after the examination. The procedure includes administration of mydriatic eye drops that may be absorbed systemically and physical manipulation of the eye that is accompanied by stress and pain. The purpose of the study was to monitor changes in infant health status and adverse physiologic events in the 2 days after ROP eye screening. SUBJECTS: The study used 50 preterm infants with a mean gestational age of 32 weeks, undergoing their first ROP examination in a NICU located in a university medical center. DESIGN: This pilot study used a prospective, descriptive design. METHODS: Physiologic changes and illness events were recorded before and for 2 days after the eye examination, using tools that tracked parameters of respiratory, cardiovascular, gastrointestinal, and neurological status. Data were collected directly from daily audits of medical records. McNemar's test for comparing paired proportions and the signed rank test were used for comparing significance of physiologic changes before and after the ROP eye examination. PRINCIPAL RESULTS: Apnea events increased significantly (P = .04) in the 24- to 48-hour period after the eye examination compared with apnea events before the eye examination. These results were based on 39 infants who were not receiving ventilator support. There was a significant difference in the frequency of oxygen desaturation events between infants with and without apnea (0-24 hours after examination, P < .002; 25-48 hours after examination, P < .001). There were no significant differences in heart rate, cyanosis, gastric residuals, or seizures after the eye examinations. CONCLUSIONS: The ROP examinations may be associated with increased apnea, a clinically significant problem. Nursing implications include careful monitoring of infants during and after ROP eye examinations, discharge teaching for caregivers, and continued research on nursing interventions to prevent adverse physiologic events.

The effect of tai chi on cognition in elders with cognitive impairment.

This one-arm pilot study investigated the effect of tai chi on cognition in elders with cognitive impairment. Although no significant difference existed between pre- and post-test performance on all cognition measures, a dose-response relationship was demonstrated between attendance and some cognition measures.

The false discovery rate: a key concept in large-scale genetic studies.

BACKGROUND: In experimental research, a statistical test is often used for making decisions on a null hypothesis such as that the means of gene expression in the normal and tumor groups are equal. Typically, a test statistic and its corresponding P value are calculated to measure the extent of the difference between the two groups. The null hypothesis is rejected and a discovery is declared when the P value is less than a prespecified significance level. When more than one test is conducted, use of a significance level intended for use by a single test typically leads to a large chance of false-positive findings. METHODS: This paper presents an overview of the multiple testing framework and describes the false discovery rate (FDR) approach to determining the significance cutoff when a large number of tests are conducted. RESULTS: The FDR is the expected proportion of the null hypotheses that are falsely rejected divided by the total number of rejections. An FDR-controlling procedure is described and illustrated with a numerical example. CONCLUSIONS: In multiple testing, a classical "family-wise error rate" (FWE) approach is commonly used when the number of tests is small. When a study involves a large number of tests, the FDR error measure is a more useful approach to determining a significance cutoff, as the FWE approach is too stringent. The FDR approach allows more claims of significant differences to be made, provided the investigator is willing to accept a small fraction of false-positive findings.

Challenges in tailored intervention research.

Although individuals and nurses value tailored health interventions, incorporating tailored interventions into research is fraught with pitfalls. This manuscript provides guidance on addressing challenges on developing, implementing, and evaluating tailored interventions (TIs). The initial step in designing TIs involves selecting the individual characteristics on which to tailor the intervention. After selecting critical characteristics for tailoring, researchers must decide how to assess these characteristics. Then researchers can use manuals, algorithms, or computer programs to tailor an intervention and maintain treatment fidelity. If desired outcomes are not achieved, focus groups or individual interviews may be conducted to gather information to improve the intervention for specific individuals/groups. Then, incorporating study arms of TIs in intervention studies, investigators may compare TIs with standardized interventions statistically and clinically. We believe TIs may have better outcomes, promote better adherence, and be more cost efficient.

The effect of tai chi on knee osteoarthritis pain in cognitively impaired elders: pilot study.

This article reports a pilot study of the effect of tai chi (TC), a pharmacological adjunct and mild aerobic exercise, on osteoarthritic knee pain in elders with cognitive impairment (CI). The TC program included a warm-up, 12-form Sun-style TC, and a cool-down period, for a total of 20-40 minutes per session, twice a week for 15 weeks. The results showed no significant differences in knee pain after the TC intervention in 7 elders with CI. However, more minutes of TC attendance were related to improved pain scores (Spearman's rho=.78, P < .05). Greater accuracy in TC performance was also correlated with improvements in pain scores (Spearman's rho = .70, P=.08). Of 4 elders who participated in TC practice regularly (more than 20 sessions), 3 showed clinically important improvements, but 3 elders who participated in no sessions or only a few sessions showed no improvement.

Periodic leg movements predict total sleep time in persons with cognitive impairment and sleep disturbance.

STUDY OBJECTIVE: To determine if periodic leg movements predict total sleep time at night in elders with cognitive impairment and sleep disturbance. DESIGN: Descriptive cross-sectional secondary analysis using data from an observational study and baseline data from a randomized, controlled clinical trial. SETTINGS: Private homes, nursing homes, and assisted living facilities. PARTICIPANTS: One hundred and two persons with a mean age of 81.8 years, cognitive impairment, and sleep disturbance. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: We measured sleep variables using 1 night of attended polysomnography in each participant's usual sleep setting. We assessed 10 characteristics associated with sleep disturbance (periodic leg movement index, time in bed, apnea-hypopnea index, oxygen saturation nadir, age, sex, living arrangement, cognitive status, painful conditions, and depression) with multiple linear regression analyses to determine the predictors of total sleep time. Of the 102 participants, 56.9% were men, and 64.7% lived in nursing homes or assisted living facilities. Their mean Mini-Mental State Examination score was 17.3. In addition, 21.6% had 1 or more painful conditions, and 45.1% were diagnosed with depression. Participants' mean periodic leg movement index was 17.3 with 34 (33.3%) having a periodic leg movement index greater than 15. Time in bed at night exceeded 8 hours, yet participants averaged only 5.5 hours of sleep. They had a mean apnea-hypopnea index of 18.3, with a mean oxygen saturation nadir of 86.4%. Periodic leg movement index, time in bed, and age explained 43.6% of the variance in total sleep time. CONCLUSIONS: Frequent periodic leg movements, less time in bed, and older age are associated with less sleep at night in this population.

Ethanol exposure of neonatal rats does not increase biomarkers of oxidative stress in isolated cerebellar granule neurons.

Oxidative stress is a candidate mechanism for ethanol neuropathology in fetal alcohol spectrum disorders. Oxidative stress often involves production of reactive oxygen species (ROS), deterioration of the mitochondrial membrane potential (MMP), and cell death. Previous studies have produced conflicting results regarding the role of oxidative stress and the benefit of antioxidants in ethanol neuropathology in the developing brain. This study investigated the hypothesis that ethanol neurotoxicity involves production of ROS with negative downstream consequences for MMP and neuron survival. This was modeled in neonatal rats at postnatal day 4 (P4) and P14. It is well established that granule neurons in the rat cerebellar cortex are more vulnerable to ethanol neurotoxicity on P4 than at later ages. Thus, it was hypothesized that ethanol produces more oxidative stress and its negative consequences on P4 than on P14. A novel experimental approach was used in which ethanol was administered to animals in vivo (gavage 6g/kg), granule neurons were isolated 2-24h post-treatment, and ROS production and relative MMP were immediately assessed in the viable cells. Cells were also placed in culture and survival was measured 24h later. The results revealed that ethanol did not induce granule cells to produce ROS, cause deterioration of neuronal MMP, or cause neuron death when compared to vehicle controls. Further, granule neurons from neither P4 nor P14 animals mounted an oxidative response to ethanol. These findings do not support the hypothesis that oxidative stress is obligate to granule neuron death after ethanol exposure in the neonatal rat brain. Other investigators have reached a similar conclusion using either brain homogenates or cell cultures. In this context, it is likely that oxidative stress is not the sole and perhaps not the principal mechanism of ethanol neurotoxicity for cerebellar granule neurons during this stage of brain development.

Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer's Disease: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVE: Apathy is a common behavioral problem in Alzheimer's disease. Apathy has profound consequences, such as functional impairment, higher service utilization, higher caregiver burden, and increased mortality. The authors' objective was to study the effects of methylphenidate on apathy in Alzheimer's disease. METHOD: A 12-week, prospective, double-blind, randomized, placebo-controlled trial (methylphenidate versus placebo) was conducted in community-dwelling veterans (N=60) with mild Alzheimer's disease. The primary outcome for apathy (Apathy Evaluation Scale-Clinician) and secondary outcomes for cognition (Mini-Mental State Examination, Modified Mini-Mental State Examination), functional status (activities of daily living, instrumental activities of daily living), improvement and severity (Clinical Global Impressions Scale [CGI]), caregiver burden (Zarit Burden Scale), and depression (Cornell Scale for Depression in Dementia) were measured at baseline and at 4, 8, and 12 weeks. RESULTS: Participants were all men (77 years old, SD=8). After adjusting for baseline, the methylphenidate group had significantly greater improvement in apathy than the placebo group at 4 weeks, 8 weeks, and 12 weeks. At 12 weeks, there was also greater improvement in cognition, functional status, caregiver burden, CGI scores, and depression in the methylphenidate group compared with the placebo group. CONCLUSIONS: Methylphenidate improved apathy in a group of community-dwelling veterans with mild Alzheimer's disease. Methylphenidate also improved cognition, functional status, caregiver burden, CGI scores, and depression.

Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study.

Apathy is a common and disabling behavioral concomitant of many neurodegenerative conditions. The presence of apathy with Mild Cognitive Impairment (MCI) is linked with heightened rates of conversion to Alzheimer's disease. Improving apathy may slow the neurodegenerative process. The objective was to establish the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving apathy in older adults with MCI. An 8-week, double-blind, randomized, sham-controlled cross-over study was conducted in nine subjects (66 ± 9 years) with apathy and MCI. Subjects were randomized to rTMS or sham treatment (5 days/week) for 2 weeks following which they underwent a 4-week treatment-free period. Subjects then crossed-over to receive the other treatment for 2 weeks. The primary (apathy (AES-C)) and secondary (cognition (3MS & MMSE), executive function (TMT-A & TMT-B), and clinical global impression (CGI)) outcomes were assessed at baseline, 2, 6, and 8 weeks. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment at 2 weeks. There was significantly greater improvement in 3MS, MMSE, TMT-A, and CGI-I with rTMS compared to the sham treatment. This study establishes that rTMS is efficacious in improving apathy in subjects with MCI.

Effects of muscle strength training and megestrol acetate on strength, muscle mass, and function in frail older people.

OBJECTIVES: To determine the independent and combined effects of progressive resistance muscle strength training (PRMST) and megestrol acetate (MA) on strength, muscle mass, and function in older recuperative care patients. DESIGN: Double-blind, randomized, controlled intervention using a two-by-two factorial design and conducted between 1999 and 2001. SETTING: University-affiliated Department of Veterans Affairs hospital. PARTICIPANTS: Twenty-nine patients (mean age 79.4 +/- 7.4, 90% white) aged 65 and older and had recent functional decline. INTERVENTIONS: After randomization to one of four treatment groups (low-resistance exercises plus 800 mg per day of MA or a placebo or high-intensity PRMST plus 800 mg/d of MA or placebo), subjects received training and the drug or placebo for 12 weeks. MEASUREMENTS: Change in muscle strength, mid-thigh muscle area, and aggregate functional performance score as assessed using analysis of covariance. RESULTS: Five subjects withdrew from the study before its completion. Based on intent-to-treat analyses, subjects who received high-intensity PRMST and placebo experienced the greatest strength gains. The addition of MA was associated with worse outcomes than with high-intensity exercise training alone, especially with regard to the leg exercises. Post hoc analysis demonstrated that subjects who received high-intensity PRMST and placebo experienced significantly greater percentage increases in leg strength than subjects in either of the MA treatment groups (P<.05 for each comparison). There was also a significant negative effect of MA on physical function. In general, subjects who received MA experienced a deterioration in aggregate physical function scores, whereas the remaining subjects improved (-0.80+/-0.40 vs 0.48+/-0.41, P=.04). There was not a significant interaction between exercise and MA for any outcome. CONCLUSION: High-intensity PRMST is a safe and well-tolerated exercise regimen for frail elderly patients. The addition of MA appears to blunt the beneficial effects of PRMST, resulting in less muscle strength and functional performance gains.

Home-Based Exercise Program Improves Balance and Fear of Falling in Community-Dwelling Older Adults with Mild Alzheimer's Disease: A Pilot Study.

BACKGROUND/OBJECTIVE: Balance problems are common in older adults with Alzheimer's disease (AD). The objective was to study the effects of a Wii-Fit interactive video-game-led physical exercise program to a walking program on measures of balance in older adults with mild AD. METHODS: A prospective randomized controlled parallel-group trial (Wii-Fit versus walking) was conducted in thirty community-dwelling older adults (73±6.2 years) with mild AD. Home-based exercises were performed under caregiver supervision for 8 weeks. Primary (Berg Balance Scale, BBS) and secondary outcomes (fear of falls and quality of life) were measured at baseline, 8 weeks (end of intervention), and 16 weeks (8-weeks post-intervention). RESULTS: At 8 weeks, there was a significantly greater improvement (average inter-group difference [95% CI]) in the Wii-Fit group compared to the walking group in BBS (4.8 [3.3-6.2], p < 0.001), after adjusting for baseline. This improvement was sustained at 16 weeks (3.5 [2.0-5.0], p < 0.001). Analyses of the secondary outcome measures indicated that there was a significantly greater improvement in the Wii-Fit group compared to walking group in Activity-specific Balance Confidence scale (6.5 [3.6-9.4], p < 0.001) and Falls Efficacy Scale (-4.8 [-7.6 to -2.0], p = 0.002) at 8 weeks. However, this effect was not sustained at 16 weeks. Quality of life improved in both groups at 8 weeks; however, there were no inter-group differences (p = 0.445). CONCLUSION: Home-based, caregiver-supervised Wii-Fit exercises improve balance and may reduce fear of falling in community-dwelling older adults with mild AD.