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The ability to effectively increase the base of support is crucial to prevent from falling due to stability disturbances and has been commonly assessed using the forward-directed lean-and-release test. With this multicentre study we examined whether the assessment of stability recovery performance using two different forward lean-and-release test protocols is reliable in adults over a wide age range. Ninety-seven healthy adults (age from 21 to 80 years) were randomly assigned to one out of two lean angle protocols: gradual increase to maximal forward-lean angle (maximal lean angle; n = 43; seven participants were excluded due to marker artefacts) or predefined lean angle (single lean angle; n = 26; 21 participants needed to be excluded due to multiple stepping after release or marker artefacts). Both protocols were repeated after 0.5 h and 48 h to investigate intra- and inter-session reliability. Stability recovery performance was examined using the margin of stability at release (MoS RL ) and touchdown (MoS TD ) and increase in base of support (BoS TD ). Intraclass correlation coefficients (confidence intervals at 95%) for the maximal lean angle and for the single lean angle were respectively 0.93 (0.89-0.96) and 0.94 (0.89-0.97) in MoS RL , 0.85 (0.77-0.91) and 0.67 (0.48-0.82) in MoS TD and 0.88 (0.81-0.93) and 0.80 (0.66-0.90) in BoS TD , with equivalence being revealed for each parameter between all three measurements (p < 0.01). We concluded that the assessment of stability recovery performance parameters in adults over a wide age range with the means of the forward lean-and-release test is reliable, independent of the used lean angle protocol., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the impact of a urinary tract infection (UTI) pocket card on preferred antibiotic prescribing for patients discharged from the emergency department (ED) with a diagnosis of cystitis., Methods: A multicenter, retrospective, pre-post study was conducted to compare outcomes following the introduction of a UTI pocket card. The primary outcome was prescribing rates for institutional first-line preferred antibiotics (cephalexin and nitrofurantoin) versus other antimicrobials for cystitis. Secondary outcomes included prescriber adherence to recommended therapy in regards to discharge dose, frequency, duration, and healthcare utilization rates., Results: The study included 915 patients in total, 407 in the preintervention group and 508 in the postintervention group. The frequency of preferred antibiotic prescribing was significantly increased after the introduction of a UTI pocket card compared to prior to its introduction (81.7% vs 72.0%, P = 0.001). Significant increases in prescribing of an appropriate antibiotic dose (78.0% vs 66.8%, P < 0.0001) and frequency (64.2% vs 47.4%, P < 0.0001) were also found post intervention. No significant differences were seen between the pre- and postintervention groups with regards to healthcare utilization rates., Conclusion: A UTI pocket card increased preferred antibiotic prescribing for cystitis in the ED. This study provides data on a successful antimicrobial stewardship intervention in the ED setting., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Differences in the adaptation processes between muscle and tendon in response to mechanical loading can lead to non-uniform mechanical properties within the muscle-tendon unit (MTU), potentially increasing injury risk. The current study analysed the mechanical properties of the triceps surae (TS) MTU in 10 young (YS; 22 ± 3 yrs) and 10 older (OS; age 65 ± 8 yrs; i.e. master) (inter)national level sprinters and 11 young recreationally active adults (YC; 23 ± 3 yrs) to detect possible non-uniformities in muscle and tendon adaptation due to habitual mechanical loading and ageing. Triceps surae muscle strength, tendon stiffness and maximal tendon strain were assessed in both legs during maximal voluntary isometric plantarflexion contractions via dynamometry and ultrasonography. Irrespective of the leg, OS and YC in comparison to YS demonstrated significantly (P < 0.05) lower TS muscle strength and tendon stiffness, with no differences between OS and YC. Furthermore, no group differences were detected in the maximal tendon strain (average of both legs: OS 3.7 ± 0.8%, YC 4.4 ± 0.8% and YS 4.3 ± 0.9%) as well as in the inter-limb symmetry indexes in muscle strength, tendon stiffness and maximal tendon strain (range across groups: -5.8 to 4.9%; negative value reflects higher value for the non-preferred leg). Thus, the findings provide no clear evidence for a disruption in the TS MTU uniformity in master sprinters, demonstrating that ageing tendons can maintain their integrity to meet the increased functional demand due to elite sports., Competing Interests: Conflict of Interest Statement KK has equity in Protendon GmbH & Co. KG, whose measurement device and software was used for the data processing and analysis in this study. No other authors declare any conflict of interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Obstacle avoidance is one of the skills required in coping with challenging situations encountered during walking. This study examined adaptation in gait stability and its interlimb transfer in a virtual obstacle avoidance task. Twelve young adults walked on a treadmill while wearing a virtual reality headset with their body state represented in the virtual environment. At random times, but always at foot touchdown, 50 virtual obstacles of constant size appeared 0.8 m in front of the participant requiring a step over with the right leg. Early, mid and late adaptation phases were investigated by pooling data from trials 1-3, 24-26 and 48-50. One left-leg obstacle appearing after 50 right-leg trials was used to investigate interlimb transfer. Toe clearance and the anteroposterior margin of stability (MoS) at foot touchdown were calculated for the stepping leg. Toe clearance decreased over repeated practice between early and late phases from 0.13 ± 0.05 m to 0.09 ± 0.04 m (mean ± SD, p < 0.05). MoS increased from 0.05 ± 0.02 m to 0.08 ± 0.02 m (p < 0.05) between early and late phases, with no significant differences between mid and late phases. No differences were found in toe clearance and MoS between the practiced right leg for early phase and the single trial of the left leg. Obstacle avoidance during walking in a virtual environment stimulated adaptive gait improvements that were related in a nonlinear manner to practice dose, though such gait adaptations seemed to be limited in their transferability between limbs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multivariate linear regression analysis (MLR) is used to unify and correlate different categories of asymmetric Cu-bisoxazoline (BOX) catalysis. The versatility of Cu-BOX complexes has been leveraged for several types of enantioselective transformations including cyclopropanation, Diels-Alder cycloadditions and difunctionalization of alkenes. Statistical tools and extensive molecular featurization has guided the development of an inclusive linear regression model, providing a predictive platform and readily interpretable descriptors. Mechanism-specific categorization of curated datasets and parameterization of reaction components allows for simultaneous analysis of disparate organometallic intermediates such as carbenes and Lewis acid adducts, all unified by a common ligand scaffold and metal ion. Additionally, this workflow permitted the development of a complementary linear regression model correlating analogous BOX-catalyzed reactions employing Ni, Fe, Mg, and Pd complexes. Comparison of ligand parameters in each model reveals the relevant structural requirements necessary for high selectivity. Overall, this strategy highlights the utility of MLR analysis in exploring mechanistically driven correlations across a diverse chemical space in organometallic chemistry and presents an applicable workflow for related ligand classes., Competing Interests: The authors declare no competing financial interest.

Cardiorespiratory interaction (CRI) has been intensively studied in adult sleep, yet not in preterm infants, in particular across different sleep states including wake (W), active sleep (AS), and quiet sleep (QS). The aim of this study was to quantify the interaction between cardiac and respiratory activities in different sleep states of preterm infants. The postmenstrual age (PMA) of preterm infants was also taken into consideration. The CRI during sleep was analyzed using a visibility graph (VG) method, enabling the nonlinear analysis of CRI in a complex network. For each sleep state, parameters quantifying various aspects of the CRI characteristics from constructed VG network including mean degree ( D m ) and its variability ( D sd ), clustering coefficient (CC m ) and its variability (CC sd ), assortativity coefficient (AC), and complexity ( D SE ) were extracted from the CRI networks. The interaction effect of sleep state and PMA was found to be statistically significant on all CRI parameters except for AC and D SE . The main effect between sleep state and CRI parameters was statistically significant except for CC m , and that between PMA and CRI parameters was statistically significant except for D SE . In conclusion, the CRI of preterm infants is associated with sleep states and PMA in general. For preterm infants with a larger PMA, CRI has a more clustered pattern during different sleep states, where QS shows a more regular, stratified, and stronger CRI than other states. In the future, these parameters can be potentially used to separate sleep states in preterm infants. NEW & NOTEWORTHY The interaction between cardiac and respiratory activities is investigated in preterm infant sleep using an advanced nonlinear method (visibility graph) and some important characteristics are shown to be significantly different across sleep states, which has not been studied before.

Rapid stepping to preserve stability is a crucial action in avoiding a fall. It is also an important measure in the assessment of fall-resisting skills. We examined whether volitional step execution correlates with recovery stepping performance after sudden balance loss for adults of different ages. In addition, we investigated whether volitional step performance can discriminate between individuals with high and low balance recovery capabilities, i.e. between those making single versus multiple steps after balance perturbation. Healthy adults (28 young, 43 middle-aged and 26 older; 24 ± 4, 52 ± 5 and 72 ± 5 years respectively) performed a single step in the anterior direction volitionally in response to a mechanical stimulus to the heel. In a second stepping task, participants experienced sudden anterior balance loss in a lean-and-release protocol. For both tasks, an optical motion capture system was used to assess stepping kinematics. We found on average 28% shorter reaction times, 46% faster maximal step velocities and 48% higher rates of increase in base of support across all participants after sudden balance loss compared to volitional stepping (p < 0.001). There was a significant age-related decline in recovery stepping performance after sudden balance loss: 24/26 older, 15/43 middle-aged and none of the younger adults required two or more steps to regain balance (p < 0.001). Multiple- compared to single-steppers had on average 23% shorter step lengths and 12% lower maximal step velocities for the lean-and-release task (p < 0.01). Multiple-steppers also had reduced rates of increase in base of support for both stepping tasks (14% for balance recovery and 11% for volitional stepping). Furthermore, in examining the relationship between the results of the two tasks, only weak to moderate correlations were observed for step velocity and rate of increase in base of support (0.36 ≤ r ≤ 0.52; p < 0.001). Thus, performance in volitional step execution has a low potential to explain variability in recovery response after sudden balance loss in adults across the lifespan and hence seems less suitable to be used to identify deficiencies in reactive stepping responses necessary to cope with sudden balance disturbances., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The generalization of related asymmetric processes in organocatalyzed reactions is an ongoing challenge due to subtle, noncovalent interactions that drive selectivity. The lack of transferability is often met with a largely empirical approach to optimizing catalyst structure and reaction conditions. This has led to the development of diverse structural catalyst motifs and inspired unique design principles in this field. Bifunctional hydrogen bond donor (HBD) catalysis exemplifies this in which a broad collection of enantioselective transformations has been successfully developed. Herein, we describe the use of data science methods to connect catalyst and substrate structural features of an array of reported enantioselective bifunctional HBD catalysis through an iterative statistical modeling process. The computational parameters used to build the correlations are mechanism-specific based on the proposed transition states, which allows for analysis into the noncovalent interactions responsible for asymmetric induction. The resulting statistical models also allow for extrapolation to out-of-sample examples to provide a prediction platform that can be used for future applications of bifunctional hydrogen bond donor catalysis. Finally, this multireaction workflow presents an opportunity to build statistical models unifying various modes of activation relevant to asymmetric organocatalysis.

Background: PF-06649751 is a novel, oral, non-catechol-based, D1/D5 dopamine receptor partial agonist under investigation for the treatment of motor symptoms associated with Parkinson's disease., Methods: A 15-week, phase II, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy and safety of flexible-dose PF-06649751 in subjects with early stage Parkinson's disease (ClinicalTrials.gov identifier: NCT02847650)., Results: Enrollment was terminated early for reasons unrelated to the trial. Overall, 57 subjects received study medication (PF-06649751 = 29; placebo = 28) and 47 completed the study (PF-06649751 = 25; placebo = 22). Despite early termination, the study met its primary endpoint with the PF-06649751 group showing statistically significant improvement from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score at week 15 compared with placebo. Mean (SE) change in MDS-UPDRS Part III score was -9.0 (1.54) for PF-06649751 and -4.3 (1.65) for placebo. This corresponds to an improvement versus placebo of 4.8 for the PF-06649751 group (two-sided p  = 0.0407; 90% CI = 1.0, 8.6). Statistically significant improvement in MDS-UPDRS-III score was also observed at all assessment time points prior to week 15. The safety profile of PF-06649751 was similar to that observed in prior studies, with the majority of adverse events (AEs) reported as mild or moderate. The most common AEs in the PF-06649751 group were nausea, headache, dry mouth, somnolence, and tremor., Conclusions: Once-daily dosing of oral PF-06649751 resulted in significant improvement of motor symptoms and was generally well tolerated in subjects with early stage Parkinson's disease., Competing Interests: Conflict of interest statement: JW and YZ are full-time employees of, and own stock or stock options, in Pfizer Inc. DG and SD were full-time employees of Pfizer Inc. at the time the study was conducted, and own stock in Pfizer Inc. DG is named on the patent for PF-06649751 (though all rights are assigned to Pfizer Inc). RR has no potential conflicts to disclose. Medical writing support provided by Matt Soulsby of Engage Scientific was funded by Pfizer. RR reports no financial relationships with commercial interests. JW, and YZ have received salary as full-time employees of Pfizer Inc. and own stock in Pfizer Inc. SD and DG have received salary as full-time employees of Pfizer Inc., and subsequently Cerevel Therapeutics, and own stock in Pfizer Inc., (© The Author(s), 2020.)

Cobalt pyridine-diimine (PDI) complexes catalyze the reductive spirocyclopropanation of terminal 1,3-dienes. gem -Dichlorocycloalkanes serve as carbene precursors and Zn is used as a terminal electron source. The reaction is effective for a range of gem -dichloro partners including those containing sulfur and nitrogen heterocycles. An example of an intramolecular Rh-catalyzed [5 + 2]-cycloaddition of a vinyl spirocyclopropane is demonstrated, providing rapid access to a complex tricyclic framework. Overall, this catalyst system is capable of suppressing the kinetically facile 1,2-hydride shift, which has hampered the development of Simmons-Smith reactions using Zn carbenoids possessing β-hydrogen atoms.

Objective: To date, mainly obtrusive methods (e.g. adhesive electrodes in electroencephalography or electrocardiography) have been necessary to determine the preterm infant sleep states. As any obtrusive measure should be avoided in preterm infants because of their immature skin development, we investigated the possibility of automated sleep staging using electrocardiograph signals from non-adhesive capacitive electrocardiography., Approach: Capacitive electrocardiography data from eight different patients with a mean gestational age of 30  ±  2.5 weeks are compared to manually annotated reference signals from classic adhesive electrodes. The sleep annotations were performed by two trained observers based on behavioral observations., Main Results: Based on these annotations, classification performance of the preterm infant active and quiet sleep states, based on capacitive electrocardiography signals, showed a kappa value of 0.56  ±  0.20. Adding wake and caretaking into the classification, a performance of kappa 0.44  ±  0.21 was achieved. In-between sleep state performance showed a classification performance of kappa 0.36  ±  0.12. Lastly, a performance for all sleep states of kappa 0.35  ±  0.17 was attained., Significance: Capacitive electrocardiography signals can be utilized to classify the central preterm infant sleep states, active and quiet sleep. With further research based on our results, automated classification of sleep states can become an essential instrument in future intensive neonatal care for continuous brain maturation monitoring. In particular, being able to use capacitive electrocardiography for continuous monitoring is a significant contributor to reducing disruption and harm for this extremely fragile patient group.

Prolonged monitoring of infant sleep is paramount for parents and healthcare professionals for interpreting and evaluating infants' sleep quality. Wake-sleep patterns are often studied to assess this. Video cameras have received a lot of attention in infant sleep monitoring because they are unobtrusive and easy to use at home. In this paper, we propose a method using motion data detected from infrared video frames (video-based actigraphy) to identify wake and sleep states. The motion, mostly caused by infant body movement, is known to be substantially associated with infant wake and sleep states. Two features were calculated from the video-based actigraphy, and a Bayesian-based linear discriminant classification model was employed to classify the two states. Leave-one-subject-out cross validation was performed to validate our proposed wake and sleep classification model. From a total of 11.6 h of infrared video recordings of 10 healthy term infants in a laboratory pilot study, we achieved a reliable classification performance with a Cohen's kappa coefficient of 0.733 ± 0.204 (mean ± standard deviation) and an overall accuracy of 92.0% ± 4.6%.

Dimethylcyclopropanes are valuable synthetic targets that are challenging to access in high yield using Zn carbenoid reagents. Herein, we describe a cobalt-catalyzed variant of the Simmons-Smith reaction that enables the efficient dimethylcyclopropanation of 1,3-dienes using a Me 2 CCl 2 /Zn reagent mixture. The reactions proceed with high regioselectivity based on the substitution pattern of the 1,3-diene. The products are vinylcyclopropanes, which serve as substrates for transition-metal-catalyzed ring-opening reactions, including 1,3-rearrangement and [5+2] cycloaddition. Preliminary studies indicate that moderately activated monoalkenes are also amenable to dimethylcyclopropanation under the conditions of cobalt catalysis., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Because herbicide resistance evolves in very large populations over periods of many years, modelling is an important tool for investigating the dynamics of the problem. The Diversity model tracks the simultaneous evolution of resistance to multiple herbicides, using multiple genetic pathways, in several weed species at once. Tracking multiple species and simultaneous resistances is an important development in resistance modelling. We used the Diversity model to test weed management strategies for new cropping cotton varieties with multiple herbicide tolerances ('triple-stacked' varieties), in an Australian context., Results: The diversity required for long-term control of three key weeds in Australian cotton goes beyond using three herbicides, especially where there is already a substantial background of existing resistance to one or more of these herbicides. Assuming some glyphosate resistance is already present, simulations showed that glyphosate-resistant summer grass populations reach 20 000 seeds m -2 within 12 years using the triple-stack herbicides (glyphosate, glufosinate and dicamba) and a minimum of other tactics. Adding three pre-emergent modes of action plus cultivation to the system effectively controls glyphosate-resistant grasses for over 30 years. In conditions where resistance genes are as frequent as 1 in 100, however, highly fecund weeds such as Conyza bonariensis are hard to control beyond 15 years even with very highly diverse management., Conclusions: Stacked herbicide tolerances in new crop varieties offers potential for increased herbicide diversity, but existing glyphosate-resistant weed populations need substantial extra management beyond what a glyphosate/glufosinate/dicamba resistance stack provides. More diverse systems can provide robust management over 30 years in the absence of very high levels of background resistance to other herbicides. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

A [ i -Pr PDI]CoBr 2 complex (PDI = pyridine-diimine) catalyzes Simmons-Smith-type reductive cyclopropanation reactions using CH 2 Br 2 in combination with Zn. In contrast to its non-catalytic variant, the cobalt-catalyzed cyclopropanation is capable of discriminating between alkenes of similar electronic properties based on their substitution patterns: monosubstituted > 1,1-disubstituted > ( Z )-1,2-disubstituted > ( E )-1,2-disubstituted > trisubstituted. This property enables synthetically useful yields to be achieved for the monocyclopropanation of polyalkene substrates, including terpene derivatives and conjugated 1,3-dienes. Mechanistic studies implicate a carbenoid species containing both Co and Zn as the catalytically relevant methylene transfer agent.

As an approach of unobtrusive assessment of neonatal sleep state we aimed at an automated sleep state coding based only on heart rate variability obtained from electrocardiography used for regular patient monitoring. We analyzed active and quiet sleep states of preterm infants between 30 and 37weeks postmenstrual age. To determine the sleep states we used a nonlinear kernel support vector machine for sleep state separation based on known heart rate variability features. We used unweighted and weighted misclassification penalties for the imbalanced distribution between sleep states. The validation was performed with leave-one-out-cross-validation based on the annotations of three independent observers. We analyzed the classifier performance with receiver operating curves leading to a maximum mean value for the area under the curve of 0.87. Using this sleep state separation methods, we show that automated active and quiet sleep state separation based on heart rate variability in preterm infants is feasible., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Heterogeneous semiconductors are underexploited as photoredox catalysts in organic synthesis relative to their homogeneous, molecular counterparts. Here, we report the use of metal/TiO 2 particles as catalysts for light-induced dehydrogenative imine transformations. The highly oxophilic nature of the TiO 2 surface promotes the selective binding and dehydrogenation of alcohols in the presence of other oxidizable and Lewis basic functional groups. This feature enables the clean photogeneration of aldehyde equivalents that can be utilized in multicomponent couplings.

Sleep is important for the development of preterm infants. During sleep, neural connections are formed and the development of brain regions is triggered. In general, various rudimentary sleep states can be identified in the preterm infant, namely active sleep (AS), quiet sleep (QS) and intermediate sleep (IS). As the infant develops, sleep states change in length and organization, with these changes as important indicators of brain development. As a result, several methods have been deployed to distinguish between the different preterm infant sleep states, among which polysomnography (PSG) is the most frequently used. However, this method is limited by the use of adhesive electrodes or patches that are attached to the body by numerous cables that can disturb sleep. Given the importance of sleep, this review explores more unobtrusive methods that can identify sleep states without disturbing the infant. To this end, after a brief introduction to preterm sleep states, an analysis of the physiological characteristics associated with the different sleep states is provided and various methods of measuring these physiological characteristics are explored. Finally, the advantages and disadvantages of each of these methods are evaluated and recommendations for neonatal sleep monitoring proposed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Vanutide Cridificar (ACC-001), a novel investigational immunotherapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease (AD)., Objectives: To evaluate the immunogenicity, safety and impact of ACC-001 with Quillaja saponaria (QS-21) adjuvant on the reduction of brain fibrillar amyloid burden, assayed by positron emission tomography (PET) imaging, in patients with mild to moderate AD., Design: Randomized, phase 2, interventional study., Trial Registration: ClinicalTrials.gov Identifier: NCT01284387., Participants: Individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination scores 18-26; measurable amyloid burden in the expected range, on the screening 18F-florbetapir PET scan; and a Rosen modified Hachinski ischemic score ≤4)., Intervention: Participants were randomized to 3 μg or 10 μg ACC-001 (each in combination with 50 μg QS-21) or placebo (without QS-21)., Measurements: Primary endpoint was the change from baseline to week 104 in cerebral amyloid burden as measured by the global cortical average (GCA) standard value uptake ratio (SUVR) based on the brain 18F-florbetapir PET composite cortical SUVR between each ACC-001+QS-21 dose compared with placebo. Secondary endpoints included safety, immunogenicity and pharmacodynamics. Exploratory endpoints included cognitive and functional efficacy, and health outcome measures., Results: Of 126 randomized patients (placebo: 40; ACC-001 3 µg+QS-21: 43; and ACC-001 10 µg+QS-21: 43), 125 received study treatment; 92 (73%) completed the study. Change in 18F-florbetapir PET GCA SUVR, was not significantly different between either of the two ACC-001+QS-21 treatment groups and placebo (3 μg +QS-21 vs. placebo diff=-0.03, p=0.54; 10 μg +QS-21 vs. placebo diff=-0.08, p=0.07), but the trend was numerically consistent with a dose response. The geometric mean peak anti-Aβ IgG titers were slightly higher in the 10 μg than the 3 μg group. The proportion of responders was similar in both dose groups of ACC-001+QS-21. The cerebrospinal fluid (CSF) p-tau changes from baseline in both active treatment groups were not statistically different from placebo, but were numerically consistent with a dose response (3 μg +QS-21 vs. placebo diff=-3.2, p=0.57; 10 μg +QS-21 vs. placebo diff=-7.0, p=0.19). The vMRI showed statistically significant faster treatment-related decrease in brain volume in the 10 μg group but was not significant in the 3 μg group, compared with placebo (3 μg diff =-1.3 mL/year, p=0.50; 10 μg diff=-4.2 mL/year, p=0.02). Measured plasma Aβ levels increased in parallel with peak anti-Aβ titers after each injection. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) were more frequent in patients who received ACC-001+QS-21 than placebo (6% vs. 0%) but none were symptomatic. The most common treatment-emergent adverse events in the active groups were injection reactions, and occurred more frequently in the ACC-001+QS-21 groups than the placebo (48% vs 8%), the majority of which were mild and transient., Conclusions: Primary biomarker efficacy endpoints were not statistically significant in either dose group. The numerical decreases in 18F-florbetapir PET GCA SUVR suggests a dose-related trend for greater reductions in fibrillar amyloid burden in the ACC-001+QS-21 10 µg group compared with placebo. Likewise, while not significant, there was a numerical trend of decreased CSF p-tau levels with ACC-001, possibly consistent with a downstream effect in the ACC-001+QS-21 group. Insufficient antibody titers or quality, insufficient power to detect a difference, or too short duration of follow up may be reasons why a statistically significant response was not observed. Brain volume measures showed faster volume loss in the 10 µg treatment group, similar to the effect seen in few earlier AD immunotherapy trials which may suggest removal of amyloid and resultant decrease in inflammation. No new, unexpected safety signals were detected., Competing Interests: Dr. Honig was an investigator for this study. He received research funding, but no personal compensation for this study. He has received personal compensation from Janssen in his role as a member of the Steering Committee of a different Janssen study. Drs. Ketter, Lu, Di, Novak and Brashear are employees of Janssen Research and Development, LLC and hold stocks in the company. Dr. Liu and Ms. Shadman were at Janssen Research and Development, LLC during the time the study was conducted, but now are affiliated with Prothena and Amgen respectively. Drs. Werth and LePrince Leterme are employees of Pfizer Clinical Sciences. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision on where to publish these data.

Sleep apnea is a sleep disorder distinguished by repetitive absence of breathing. Compared with the traditional expensive and cumbersome methods, sleep apnea diagnosis or screening with physiological information that can be easily acquired is needed. This paper describes algorithms using heart rate variability (HRV) to automatically detect sleep apneas as long as it can be easily acquired with unobtrusive sensors. Because the changes in cardiac activity are usually hysteretic than the presence of apneas with a few minutes, we propose to use the delayed HRV features to identify the episodes with sleep apneic events. This is expected to help improve the apnea detection performance. Experiments were conducted with a data set of 23 sleep apnea patients using support vector machine (SVM) classifiers and cross validations. Results show that using eleven HRV features with a time delay of 1.5 minutes rather than the features without time delay for SA detection, the overall accuracy increased from 74.9% to 76.2% and the Cohen's Kappa coefficient increased from 0.49 to 0.52. Further, an accuracy of 94.5% and a Kappa of 0.89 were achieved when applying subject-specific classifiers.

This study compared cortisol concentrations yielded using three saliva collection methods (passive drool, salivette, and sorbette) in both in vitro and in vivo conditions, as well as method acceptability for a sample of children (n = 39) with High Functioning Autism Spectrum Disorders. No cortisol concentration differences were observed between passive and sorbette samples obtained in vitro or in vivo. The salivette derived concentration was lower than the other two methods for the in vitro derived comparisons but did not differ from the other methods when collected in vivo. Cross-day comparison for the salivettes was also found to differ significantly, whereas the cross-day comparisons did not differ for the passive method or the sorbette method. Overall, passive drool and sorbettes were found to produce similar and stable readings of cortisol, whereas the salivette yielded unstable and variable concentrations. Ratings suggested that the children generally perceived all methods as acceptable.

The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) is being revised. A proposed revision hotly debated is to remove what is known as the exclusionary criterion and allow clinicians to diagnose a person with a major depressive episode within the early days and weeks following a death. The Executive Committee of the Association for Death Education and Counseling (ADEC) commissioned its Scientific Advisory Committee (SAC) to examine the debate over removing the exclusionary criterion and provide a written report. The DSM-IV-TR classifies bereavement as a clinical condition that is not a mental disorder. The exclusionary criterion states that within the first 2 months of the onset of bereavement a person should not be diagnosed as having major depression unless certain symptoms not characteristic of a normal grief reaction are present. We note these symptoms when discussing the exclusionary criterion. In the report we identify the features that comprise the exclusionary criterion, examine reasons (including research conclusions and clinical concerns) given for retaining and for eliminating the exclusionary criterion, offer extensive comments from experienced licensed clinicians about the issues involved, discuss diagnostic and treatment implications, and offer specific recommendations for ADEC to implement.

The use of a clinical utility index (CUI) was proposed in order to compare two calcium channel alpha2delta ligands that were in development for the treatment of insomnia. The important attributes included in the CUI were two measures of residual sedation and five measures of efficacy (wake after sleep onset, sleep quality, sleep latency, and sleep stages (stage 1 and stages 3-4)). Dose-response analyses were conducted on each end point, and a sensitivity analysis was conducted to determine a clinically meaningful difference in CUI. Nonparametric bootstrap parameters were used to build confidence intervals (CIs). Peak CUI (80% CI) was 0.345 (0.25-0.43), observed at a dose of approximately 30 mg with the lead compound and 0.436 (0.35-0.52) observed at >600-mg dose for the backup. Although CUI was slightly greater for the backup, peak CUI values were observed at doses that were not considered viable, and therefore development of the ligand was discontinued. The use of the CUI allowed an efficient, quantitative, and transparent decision.

Epidemiological and large scale treatment studies within smoking research have utilized many one-item screening items to examine the influence of current depressive symptoms on smoking behavior and quitting. Little is known about that concurrent validity of screening items that may reflect depression vulnerability independent of current symptoms. The present paper evaluated the concurrent validity of two one-item screening items that were essential for diagnosing past episodes of major depression. Screening questions were administered to seventy-seven nicotine dependent participants via a telephone screening interview. Smokers then returned to the laboratory for a comprehensive structured assessment of depressive vulnerability. Vulnerability measures were clinician-diagnosed history of major depressive disorder and other self-reported depressive vulnerability factors. Telephone screening items accurately classified a clinician-diagnosed history of major depression, and predicted the number of recurrent depressive episodes, self-reported rumination, and self-reported depression-proneness (all p<0.05). Results support the utility of one-item screening questions as a "proxy" of a depressive vulnerability for smoking treatment studies that are not designed for comprehensive assessment procedures.

Introduction: The effects of any drug treatment on cognitive function are typically studied in groups of subjects. Observations made about the behavior of the drug, in the study sample, are then generalized to the population from which the sample was drawn. However, the magnitude and pharmacodynamic qualities of the response to many central nervous system-active drugs are known to vary in the population. Therefore, it is useful to consider statistical models for the detection of cognitive change in response to a drug treatment in individual subjects., Materials and Methods: In this report, we first outline the statistical assumptions and requirements for the reliable estimation of clinically relevant individual change in cognition. We then used the sedative benzodiazepine, alprazolam, as a pharmacologic challenge in healthy volunteer subjects to test our statistical model, using a parallel groups placebo-controlled study design. After treatment, the nature and severity of alprazolam-induced cognitive change was determined for each individual., Results: Our proposed method and analysis showed an excellent sensitivity and specificity for alprazolam-related cognitive deterioration in individuals., Discussion and Conclusions: These findings, although preliminary, suggest that statistically reliable decisions about the effects of sedative drugs on cognition can be made for individuals.

While there is no doubt that benzodiazepine administration leads to transient cognitive impairment in healthy adults, the nature and magnitude of such impairment has not been well described. The cognitive effects of a single dose of alprazolam 0.5 and 1 mg were therefore assessed in 36 healthy adults on measures of psychomotor function, visual attention, working memory, planning and learning in a double-blind parallel-groups study. Measures of these different cognitive functions were selected on the basis of their brevity and because they yielded distributions of performance data that were without skew, floor or ceiling effects of range restriction (i.e. normal distributions). With data satisfying the assumptions for parametric analysis, measures of effect size could be computed in addition to significance testing, thus allowing for direct and meaningful comparison between the different performance measures used. Alprazolam 0.5 mg reduced only the speed of attentional performance although the magnitude of this reduction was large (d = 0.8). At 1.0 mg, impairments in psychomotor function, equivalent to that seen for attentional function at the lower dose, were observed. In addition, moderate (d approx = 0.5) impairments in working memory, and learning also became obvious. When considered together, these results suggest that low-dose alprazolam primarily alters visual attentional function. At the higher dose psychomotor functions also become impaired, and it is likely that the combination of these led to the observed moderate impairments in higher level executive and memory processes. The current study also illustrates a method for directly comparing the magnitude of change in cognitive function between measures with different performance metrics., (Copyright 2005 John Wiley & Sons, Ltd.)

Objective: To create skin cancer risk profiles that could be used to predict sun protection among Midwest beachgoers., Method: Cluster analysis was used with study participants (N=239), who provided information about sun protection motivation and behavior, perceived risk, burn potential, and tan importance. Participants were clustered according to their risk profiles; 4 distinct risk profiles emerged., Results: Analyses revealed that risk profiles were significantly different on sun protection motivation and behavior and marginally different in terms of sun tanning behavior., Conclusion: Given the complexity of risk factors, an examination of clusters, rather than factors in isolation, may more accurately depict sun protection behavior.

Discontinuing nicotine intake usually results in weight gain partially due to heightened energy intake from between-meal snacks. This experiment tested the hypothesis that the reinforcing value of palatable carbohydrate-rich snacks increases for female smokers during nicotine deprivation. Eighteen smokers and 18 nonsmokers completed a concurrent-schedules operant computer task on two separate days. Smokers were bioverified abstinent at the second testing. The operant task allowed participants to earn points redeemable for either carbohydrate snacks or money on concurrent variable-ratio schedules of reinforcement. There were five different probabilities of earning points redeemable for snacks (8%, 16%, 25%, 50%, 75%), while the probability of earning points redeemable for money remained fixed at 25%. Reward value of snacks was measured by switch point: the reinforcement ratio at which the effort required to earn snacks exceeded their value to the respondent, as signified by a shift to working for money. Results showed that smokers undergoing nicotine deprivation persisted in working for snacks into leaner reinforcement schedules than nonsmokers (P=.026). Furthermore, nicotine deprivation increased smokers' allocation of effort to earn snack foods relative to their own behavior when smoking (P=.006). Variation in palatability or hunger did not explain these differences in snack reward value. Findings indicate that nicotine deprivation is associated with a heightened reward value of appealing snack foods for female smokers.

Objective: Previous work in an academic setting has found that scoring in the higher ranges for selected personality disorders on an objective assessment tool was associated with increases in psychiatric co-morbidities, decreased satisfaction with health care, and diminished health related functional status. This study examines how often patients in primary care practices exhibit traits consistent with these selected disorders and what impact this has on their health related functional status and use of health care resources., Methods: Thirteen family practices agreed to distribute questionnaires to 50 consecutive patients in the spring of 1997. Questionnaires contained instruments that assess risk for personality disorders, health related functional status, health resource use, demographics, and depression. The relationships between four specific personality disorders (borderline, dependent, schizoid and schizotypal) and other assessed variables were explored., Results: Of the 250 patients returning completed survey instruments, 80 (32%) scored in the high range for traits consistent with one of the four target personality disorders. Patients in the high risk group also were noted to have more outpatient, emergency, and inpatient visits in the previous six months. Those in the high risk group also had significantly lower scores on seven of eight measures of health related functional status., Conclusions: Patients who have several traits for borderline, dependent, schizoid, and schizotypal personality disorders are common in primary care practices. These patients utilize services at higher rates than others and are more likely to screen in the positive range for depressive symptoms and have overall lower health related functional status.

A case of lipoma of the right eighth cranial nerve in the cerebellopontine angle (CPA) is presented. The patient had a clinical, diagnostic, surgical, and postoperative course similar to that of patients with other small CPA tumors. The literature on this rare CPA tumor is reviewed and discussed.

An enzyme that catalyzes the reduction of methionine sulfoxide residues in ribosomal protein L12 has been partially purified from Escherichia coli extracts. Methionine sulfoxide present in oxidize [Met]enkephalin is also reduced by the purified enzyme. The enzyme is different from a previously reported E. coli enzyme that catalyzes the reduction of methionine sulfoxide to methionine [Ejiri, S. I., Weissbach, H. & Brot, N. (1980) Anal. Biochem. 102, 393--398]. Extracts of rat tissues, Euglena gracilis, Tetrahymena pyriformis, HeLa cells, and spinach also can catalyze the reduction of methionine sulfoxide residues in protein.