Approaching the motional ground state of a 10-kg object.

The motion of a mechanical object, even a human-sized object, should be governed by the rules of quantum mechanics. Coaxing them into a quantum state is, however, difficult because the thermal environment masks any quantum signature of the object's motion. The thermal environment also masks the effects of proposed modifications of quantum mechanics at large mass scales. We prepared the center-of-mass motion of a 10-kilogram mechanical oscillator in a state with an average phonon occupation of 10.8. The reduction in temperature, from room temperature to 77 nanokelvin, is commensurate with an 11 orders-of-magnitude suppression of quantum back-action by feedback and a 13 orders-of-magnitude increase in the mass of an object prepared close to its motional ground state. Our approach will enable the possibility of probing gravity on massive quantum systems.

Tunable narrow-linewidth laser at 2†µm wavelength for gravitational wave detector research.

We present and characterize a narrow-linewidth external-cavity diode laser at 2 µm, and show that it represents a low-cost, high-performance alternative to fiber lasers for research into 2 µm photonic technologies for next-generation gravitational-wave detectors. A linewidth of 20 kHz for a 10 ms integration time was measured without any active stabilization, with frequency noise of ∼ 15 Hz/Hz between 3 kHz and 100 kHz. This performance is suitable for the generation of quantum squeezed light, and we measure intensity noise comparable to that of master oscillators used in current gravitational wave interferometers. The laser wavelength is tunable over a 120 nm range, and both the frequency and intensity can be modulated at up to 10 MHz by modulating the diode current. These features also make it suitable for other emerging applications in the 2 µm wavelength region including gas sensing, optical communications and LIDAR.

Quantum-Enhanced Advanced LIGO Detectors in the Era of Gravitational-Wave Astronomy.

The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).

Squeezed vacuum phase control at 2 µm.

We demonstrate phase control for vacuum-squeezed light at a 2 µm wavelength, which is a necessary technology for proposed future gravitational wave observatories. The control scheme allowed examination of noise behavior at frequencies below 1 kHz and indicated that squeezing below this frequency was limited by dark noise and scattered light. We directly measure 3.9±0.2 dB of squeezing from 2 kHz to 80 kHz and 14.2±0.3 dB of antisqueezing relative to the shot noise level. The observed maximum level of squeezing is currently limited by photodetector quantum efficiency and laser instabilities at this new wavelength for squeezed light. Accounting for all losses, we conclude the generation of 11.3 dB of squeezing at the optical parametric oscillator.

Fee-for-service cancer rehabilitation programs improve health-related quality of life.

BACKGROUND: Rigorously applied exercise interventions undertaken in a research setting result in improved health-related quality of life (hrqol) in cancer survivors, but research to demonstrate effective translation of that research to practice is needed. The objective of the present study was to determine the effect of fee-for-service cancer rehabilitation programs in the community on hrqol and on self-reported physical activity and its correlates. METHODS: After enrolment and 17 ± 4 weeks later, new clients (n = 48) to two fee-for-service cancer rehabilitation programs completed the 36-Item Short Form Health Survey (rand-36: rand Corporation, Santa Monica, CA, U.S.A.), the Godin Leisure-Time Exercise Questionnaire, and questions about physical activity correlates. Normal fee-for-service operations were maintained, including a fitness assessment and individualized exercise programs supervised in a group or one-on-one setting, with no minimum attendance required. Fees were associated with the assessment and with each exercise session. RESULTS: Of the 48 participants, 36 (75%) completed both questionnaires. Improvements in the physical functioning, role physical, pain, and energy/fatigue scales on the rand-36 exceeded minimally important differences and were of a magnitude similar to improvements reported in structured, rigorously applied, and free research interventions. Self-reported levels of vigorous-intensity (p = 0.021), but not moderate-intensity (p = 0.831) physical activity increased. The number of perceived barriers to exercise (p = 0.035) and the prevalence of fatigue as a barrier (p = 0.003) decreased. Exercise self-efficacy improved only in participants who attended 11 or more sessions (p = 0.002). Exercise enjoyment did not change (p = 0.629). CONCLUSIONS: Enrolment in fee-for-service cancer rehabilitation programs results in meaningful improvements in hrqol comparable to those reported by research interventions, among other benefits. The fee-for-service model could be an effective model for delivery of exercise to more cancer survivors.

Optomechanical design and construction of a vacuum-compatible optical parametric oscillator for generation of squeezed light.

With the recent detection of gravitational waves, non-classical light sources are likely to become an essential element of future detectors engaged in gravitational wave astronomy and cosmology. Operating a squeezed light source under high vacuum has the advantages of reducing optical losses and phase noise compared to techniques where the squeezed light is introduced from outside the vacuum. This will ultimately provide enhanced sensitivity for modern interferometric gravitational wave detectors that will soon become limited by quantum noise across much of the detection bandwidth. Here we describe the optomechanical design choices and construction techniques of a near monolithic glass optical parametric oscillator that has been operated under a vacuum of 10(-6) mbar. The optical parametric oscillator described here has been shown to produce 8.6 dB of quadrature squeezed light in the audio frequency band down to 10 Hz. This performance has been maintained for periods of around an hour and the system has been under vacuum continuously for several months without a degradation of this performance.

Managing the rate of increase in average co-ancestry in a rolling front tree breeding strategy.

In breeding forest trees, as for livestock, the goal is to capture as much genetic gain as possible for the breeding objective, while limiting long- and short-term inbreeding. The Southern Tree Breeding Association (STBA) is responsible for breeding Australia's two main commercial forest tree species and has adopted algorithms and methods commonly used in animal breeding to achieve this balance. Discrete generation breeding is the norm for most tree breeding programmes. However, the STBA uses an overlapping generation strategy, with a new stream of breeding initiated each year. A feature of the species bred by the STBA (Pinus radiata and Eucalyptus globulus) is the long interval (up to 7 years) between when an individual is mated and when its progeny is first assessed in field trials and performance data included in the national performance database. Mate selection methods must therefore recognize the large pool of unmeasured progeny generated over recent years of crossing. In addition, the substantial delay between when an individual is selected in a field trial and when it is clonally copied into a mating facility (breeding arboretum) means that selection and mating must occur as a two-step process. In this article, we describe modifications to preselection and mate selection algorithms that allow unmeasured progeny (juveniles) to be recognized. We also demonstrate that the addition of hypothetical new progeny to the juvenile pool is important for computing the increase in average co-ancestry in the population. Methods outlined in this article may have relevance to animal breeding programmes where between mating and progeny measurement, new rounds of mating are initiated.

Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline: a randomized, placebo-controlled trial.

The efficacy and safety of retreatment with varenicline in smokers attempting to quit were evaluated in this randomized, double-blind, placebo-controlled, multicenter trial (Australia, Belgium, Canada, the Czech Republic, France, Germany, the United Kingdom, and the United States). Participants were generally healthy adult smokers (≥ 10 cigarettes/day) with ≥ 1 prior quit attempt (≥ 2 weeks) using varenicline and no quit attempts in ≤ 3 months; they were randomly assigned (1:1) to 12 weeks' varenicline (n = 251) or placebo (n = 247) treatment, with individual counseling, plus 40 weeks' nontreatment follow-up. The primary efficacy end point was the carbon monoxide-confirmed (≤ 10 ppm) continuous abstinence rate for weeks 9-12, which was 45.0% (varenicline; n = 249) vs. 11.8% (placebo; n = 245; odds ratio: 7.08; 95% confidence interval: 4.34, 11.55; P < 0.0001). Common varenicline group adverse events were nausea, abnormal dreams, and headache, with no reported suicidal behavior. Varenicline is efficacious and well tolerated in smokers who have previously taken it. Abstinence rates are comparable with rates reported for varenicline-naive smokers.

Thermo-optic locking of a semiconductor laser to a microcavity resonance.

We experimentally demonstrate thermo-optic locking of a semiconductor laser to an integrated toroidal optical microcavity. The lock is maintained for time periods exceeding twelve hours, without requiring any electronic control systems. Fast control is achieved by optical feedback induced by scattering centers within the microcavity, with thermal locking due to optical heating maintaining constructive interference between the cavity and the laser. Furthermore, the optical feedback acts to narrow the laser linewidth, with ultra high quality microtoroid resonances offering the potential for ultralow linewidth on-chip lasers.

Donepezil preserves cognition and global function in patients with severe Alzheimer disease.

OBJECTIVE: To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD). METHODS: Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores > or =6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving > or =1 dose of donepezil or placebo. RESULTS: Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD. CONCLUSION: Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.

Implementation of an RN/RT-initiated extubation protocol.

Widespread acceptance of the importance of discontinuing ventilator support at the earliest possible opportunity has resulted in a number of efforts to develop a standardized approach to extubation. The implementation of an extubation protocol designed for the medical/surgical intensive care unit of a university-affiliated hospital followed a series of educational sessions that were open to all members of the multidisciplinary team. As part of quality assurance monitoring, data were collected on the first 47 patients who were extubated using these criteria. A clinical outcome was defined as the percentage of patients who required reintubation within 48 hours. The protocol has been well-received by the ICU team and has become an established component of ventilator management.

The invariant chain gene intronic enhancer shows homology to class II promoter elements.

Coordinate expression of MHC class II proteins and the class II-associated invariant chain (Ii) is important for proper MHC class II functioning in Ag processing and presentation. The coordinate regulation of these genes results, in part, from the sharing of transcriptional regulatory regions between MHC class II and Ii genes; the Ii has previously been shown to have an upstream enhancer closely related to the essential class II promoter elements. We report here the characterization of a second enhancer in the Ii gene, located within the first intron. This intronic enhancer is contained within a 155-bp region, enhances transcription from the Ii minimal promoter, and also contains elements that are homologous to class II promoter elements X1, X2, and Y boxes.

Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer's disease.

Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer's disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-D-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity.

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease.

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD.

The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation.

PURPOSE: To test the hypothesis that atrophy of the hippocampal formation in nondemented elderly individuals would predict subsequent Alzheimer disease. METHOD: We studied 86 subjects at two time points, 4 years apart. At baseline all study subjects were nondemented and included 54 control subjects and 32 persons who had memory complaints and minimal cognitive impairments. All subjects received a CT scan using a protocol designed to image the perihippocampal cerebrospinal fluid (HCSF) accumulating in the fissures along the axis of the hippocampal formation. Blind to the clinical evaluations, we subjectively assessed the presence of HCSF at the baseline. Retrospectively, we examined the predicted association between baseline HCSF and clinical decline as determined across the two evaluations. RESULTS: At follow-up 25 of the 86 subjects had deteriorated and received the diagnosis of Alzheimer disease. Of the declining subjects, 23 came from the minimally impaired group, and 2 came from the control group. In the minimally impaired group the baseline HCSF measure had a sensitivity of 91% and a specificity of 89% as a predictor of decline. Both control subjects who deteriorated were also correctly identified at baseline. One of these two subjects died, and an autopsy confirmed the presence of Alzheimer disease. M(r) validation studies demonstrated that HCSF is quantitatively related to dilatation of the transverse fissure of Bichat and the choroidal and hippocampal fissures. CONCLUSION: Our findings strongly suggest that among persons with mild memory impairments, dilatation of the perihippocampal fissures is a useful radiologic marker for identifying the early features of Alzheimer disease.

Backscatter absorption gas imaging: a new technique for gas visualization.

This paper presents a new laser-based method of gas detection that permits real-time television images of gases to be produced. The principle of this technique [which is called backscatter absorption gas imaging (BAGI)] and the operation of two instruments used to implement it are described. These instruments use 5-W and 20-W CO(2) lasers to achieve gas imaging at ranges of approximately 30 and 125 m, respectively. Derivations of relevant BAGI signal equations that can be used to predict the performance of a gas imager are provided. The predictions of this model and the measured range performance of an extended-range gas imager are compared. Finally, the results of gas sensitivity measurements and imaging tests on flowing gases are presented. These can be used to generate a realistic estimate of the BAGI sensitivity expected in detecting leaks of many different vapors.

Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer's disease. Pathophysiologic implications.

Positron emission tomographic studies of cerebral glucose metabolism have shown high diagnostic specificity in distinguishing among the degenerative dementias and differentiating between Alzheimer's disease (AD) and normal aging. The current investigation was undertaken to characterize the regional glucose metabolic deficits in AD, using cross-sectional and longitudinal study designs. All subjects met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 45) or were normal (n = 20), and the AD subjects were subdivided into incipient and mild AD and moderate plus moderately severe subgroups based on the Global Deterioration Scale. The subjects underwent a non-contrast computed tomographic scan and a positron emission tomographic (PETT VI) scan. The AD subjects (n = 14) and normal control subjects (n = 15) received evaluations 2 to 3 years after baseline study. The brain regions that show glucose metabolic deficits cross-sectionally (temporal and parietal association areas, with lesser degrees of deficit in subcortical gray matter structures), over the stages of AD, also show further deficits longitudinally within the same AD subjects. The reduction in glucose metabolism is greater than would be expected from the degree of brain atrophy. The glucose metabolic deficits are discussed in the context of neuropathologic findings and neurotransmitter deficits in AD.

Mini-Mental State exam scores vary with education in blacks and whites.

Previous studies have suggested that education and race may affect performance on standardized mental status tests. In order to more clearly define these relationships, a prospective longitudinal study was devised to answer two questions: (1) whether race or level of education affects scores on the Mini-Mental State (MMS) exam in non-demented people and (2) what numerical cutpoints maximize the sensitivity and specificity of utilizing the MMS to help diagnose dementia in blacks of varying educational attainment. A total of 100 white and 258 black individuals, recruited from two city hospital primary care geriatric clinics, were evaluated and subsequently followed longitudinally over a 2 1/2 year period in order to assess accurately the presence or absence of dementia. In the non-demented, total MMS scores and performance on each item of the MMS were analyzed, revealing that people with an 8th grade or less education consistently had significantly (P less than .01) worse results than the better educated (9th grade or better) on borough, attention items, recall of table and dog, copying, sentence writing, phrase repeating, and total score. Furthermore, a total of 25% of the lower education group had an MMS score in the 18-23 range, traditionally thought to suggest dementia. There were no consistently significant differences between blacks and whites of equal education. In the better educated groups, using a score of 23 or less to define dementia maximizes the sensitivity and specificity of using the MMS in this diagnosis at 93% and 100%, respectively. In the lower education group, using 17 or less to define dementia maximizes sensitivity and specificity at 81% and 100%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)