III-nitride m-plane violet narrow ridge edge-emitting laser diodes with sidewall passivation using atomic layer deposition.

A novel deep-ridge laser structure with atomic-layer deposition (ALD) sidewall passivation was proposed that enhances the optical characteristics of 8-µm ridge width III-nitride violet lasers on freestanding m-plane GaN substrates. The internal loss was determined using the variable stripe length method, where the laser structure with ALD sidewall passivation showed lower internal loss compared to the conventional shallow-ridge laser design. ALD sidewall passivation plays a critical role in device improvements; compared to the lasers without ALD sidewall passivation, the lasers with ALD sidewall passivation yield improved optoelectrical performance and longer lifetime under continuous-wave operation at high current density. This work demonstrates the importance of ALD sidewall passivation to laser performance, which enables high energy efficiency.

Spontaneous attentional failures reflect multiplicative interactions of chronic sleep loss with acute sleep loss and circadian misalignment.

OBJECTIVES: Acute and chronic sleep loss and circadian timing interact such that, depending on their combination, small or very large performance decrements are observed in tasks of attention. Here, we tested whether such nonlinear interactions extend to a physiological measure of spontaneous visual attentional failures, indicating a fundamental principle of sleep-wake regulation. METHODS: Nine healthy volunteers completed an in-laboratory 3-week forced desynchrony protocol consisting of 12 consecutive 42.85-hour cycles with a sleep-wake ratio of 1:3.3. The protocol induced increasing chronic sleep loss, while extended wake (32.85 hours) and sleep episodes (10 hours) occurred at multiple circadian phases. Attentional failure rate was quantified from continuous electrooculograms (number of 30-second epochs with slow eye movements/h of wakefulness) as a function of time since scheduled wake (acute sleep loss), week of study (chronic sleep loss), and circadian (melatonin) phase. RESULTS: During the first ∼8 hours awake, attentional failure rate was low, irrespective of the week. During the following wake hours, attentional failure rate increased steadily but at a faster rate in weeks 2 and 3 compared to week 1. The effects of acute and chronic sleep loss on attentional failure rate were magnified during the biological night compared to the biological day. CONCLUSIONS: A single extended sleep episode can only temporarily reverse attentional impairment associated with chronic sleep loss. Multiplicative effects of acute and chronic sleep loss-further amplified during the biological night-substantiate the interaction of 2 homeostatic response mechanisms and caution against underestimating their disproportionate combined impact on performance, health, and safety.

Treatment of Geriatric Acetabular Fractures-A Concise Review of the Literature.

Optimal management of acetabular fractures (AF) in the elderly has not been defined clearly. The incidence of such fractures is rising in the aging population. Advancements in implant technology have improved the longevity of combined or staggered total hip arthroplasty procedures for this patient population, thus allowing earlier weight bearing and continued functional independence. Perioperative/postoperative complication rates remain significantly high in all treatment arms. Overall, the best outcomes with the lowest complication rates are achieved when AF are treated by a surgeon or a team of surgeons who specialize in both orthopedic traumatology and adult reconstruction.

Does the Use of Intraoperative Pressure Sensors for Knee Balancing in Total Knee Arthroplasty Improve Clinical Outcomes? A Comparative Study With a Minimum Two-Year Follow-Up.

BACKGROUND: It is undetermined whether using sensors for knee balancing in total knee arthroplasty (TKA) improves patient outcomes. The purpose of this study was to compare clinical outcomes of sensor balance (SB) with manual balance (MB) TKA with a minimum two-year follow-up. METHODS: A consecutive series of 207 MB TKAs was compared with 222 SB TKAs between April 2014 and April 2017. A single surgeon performed all surgeries, using the same prosthesis. The primary end point was the aggregated mean change in four subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS4) between preoperative and two-year time points. Secondary outcomes included mean differences between groups in all five KOOS subscales, proportions of knee balancing procedures, and rates of reoperations including revisions and manipulations for stiffness. RESULTS: The mean changes in the KOOS4 aggregated means for MB TKA (42.4; standard deviation, 29.1) and SB TKA (41.5; standard deviation, 25.0) were not significantly different (mean difference, 0.9; 95% confidence interval: -2.6 to 4.4, P = .62). There were significantly more balancing procedures in the SB group (55.9% versus 16.9%; P < .01). There were no significant differences in the number of reoperations (1.4% SB versus 1.4% MB; P = .71) or manipulations for stiffness (3.7% SB versus 4.4% MB; P = .69). CONCLUSION: The use of sensors in TKA to achieve knee balance did not result in improved clinical outcomes, despite significantly increasing the number of surgical interventions required to achieve a balanced knee. Sensors did not alter the rates of revision surgery or requirements for manipulation. It remains to be determined whether precise soft-tissue balancing improves prosthetic survivorship and joint biomechanics.

High performance of a semipolar InGaN laser with a phase-shifted embedded hydrogen silsesquioxane (HSQ) grating.

Single-frequency blue laser sources are of interest for an increasing number of emerging applications but are still difficult to implement and expensive to fabricate and suffer from poor robustness. Here a novel and universal grating design to realize distributed optical feedback in visible semiconductor laser diodes (LDs) was demonstrated on a semipolar InGaN LD, and its unique effect on the laser performance was investigated. For the first time, to the best of our knowledge, a low threshold voltage, record-high power output, and ultra-narrow single-mode lasing were simultaneously obtained on the new laser structure with a thinner p-GaN layer and a third-order phase-shifted embedded dielectric grating. Under continuous-wave operation, such 450 nm lasers achieved 35 dB side-mode suppression ratio, less than 2 pm FWHM, and near 400 mW total output power at room temperature.

Demonstration of GaN-based vertical-cavity surface-emitting lasers with buried tunnel junction contacts.

We report III-nitride vertical-cavity surface-emitting lasers (VCSELs) with buried tunnel junction (BTJ) contacts. To form the BTJs, GaN TJ contacts were etched away outside the aperture followed by n-GaN regrowth for current spreading. Under pulsed operation, a BTJ VCSEL with a 14 µm diameter aperture showed a lasing wavelength of 430 nm, a threshold current of ∼20 mA (12 kA/cm2), and a maximum output power of 2.8 mW. Under CW operation, an 8 µm aperture VCSEL showed a differential efficiency of 11% and a peak output power of ∼0.72 mW.

Demonstration of blue semipolar (202¯1¯) GaN-based vertical-cavity surface-emitting lasers.

We successfully demonstrated an electrically injected blue(202¯1¯)semipolar vertical-cavity surface-emitting laser with a 5λ cavity length, an ion implanted aperture, and a dual dielectric DBR design. The peak power under pulsed operation was 1.85 mW, the threshold current was 4.6 kA/cm2 , and the differential efficiency was 2.4% for the mode at 445 nm of a device with a 12 µm aperture. Lasing was achieved up to a 50% duty cycle and the thermal impedance was estimated to be 1800 K/W. The lasing emission was found to be 100% plane polarized along the a-direction.

Continuous-wave operation of a semipolar InGaN distributed-feedback blue laser diode with a first-order indium tin oxide surface grating.

A novel approach to realize DFB gratings on GaN based laser diodes is presented and continuous-wave single longitudinal mode operation is achieved. The first order gratings were fabricated on the surface of indium tin oxide (ITO) on top of the laser ridge, which combines the benefits of simplified fabrication, easy scalability to wider ridges, and no regrowth or overgrowth. Under continuous-wave operation, the laser emits with a full FWHM of 5 pm, a SMSR of 29 dB and output power from a single facet as high as 80 mW. To the best of authors' knowledge, this is also the first demonstration of a DFB-LD on semipolar InGaN/GaN system.

How coronal alignment affects distal femoral anatomy: an MRI-based comparison of varus and valgus knees.

PURPOSE: In contemporary total knee arthroplasty (TKA), most often, the goal is to align the femoral component to the epicondylar axis (EA). The posterior condylar axis (PCA) is easier to define than the EA, and thus the relationship of PCA to the EA is then used instead to align the femoral component to the EA. However, the relationship of PCA to EA is not constant and has been reported to differ between varus and valgus knees and with increasing deformity. The aim of this large MRI-based study was to evaluate the relationship between PCA and EA with varying coronal deformity especially with increasing valgus deformity. METHODS: EA, PCA, AP (Whiteside's line) and the mechanical axis were obtained from 474 magnetic resonance imaging (MRI) scans used to create patient-specific instrumentation (PSI) for the Biomet Signature (Warsaw, NJ) system. RESULTS: The relationship of EA relative to the PCA showed considerable heterogeneity in both varus and valgus groups. In the valgus group, there was statistically greater external rotation (P < 0.05) of the EA from the PCA with a mean of 2.52° (range - 1.9° to 6°) compared to the varus group with a mean of 2.03° (range - 3.9° to 6.9°). This relationship did not significantly change with increasing severity of coronal malalignment. Externally rotating the femoral cutting guide by 3° from the PCA, 11% (42 of 382) of varus knees would lie outside of ± 3° from EA. In valgus knees, externally rotating the femoral cutting block by 3° or 5° from the PCA, 6.5% (6 of 92) and 33.7% (31 of 92) of knees, respectively, would lie outside of ± 3° from EA. CONCLUSION: The relationship of PCA to EA is heterogeneous and is not altered significantly with increasing valgus coronal deformity. External rotation beyond 3° from PCA in valgus knees may lead to significant femoral component malrotation in a large proportion cases.

Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans.

The PERIOD2 (PER2) gene is a core molecular component of the circadian clock and plays an important role in the generation and maintenance of daily rhythms. Rs35333999, a missense variant of PER2 common in European populations, has been shown to associate with later chronotype. Chronotype relates to the timing of biological and behavioral activities, including when we sleep, eat, and exercise, and later chronotype is associated with longer intrinsic circadian period (cycle length), a fundamental property of the circadian system. Thus, we tested whether this PER2 variant was associated with circadian period and found significant associations with longer intrinsic circadian period as measured under forced desynchrony protocols, the 'gold standard' for intrinsic circadian period assessment. Minor allele (T) carriers exhibited significantly longer circadian periods when determinations were based on either core body temperature or plasma melatonin measurements, as compared to non-carriers (by 12 and 11 min, respectively; accounting for ~7% of inter-individual variance). These findings provide a possible underlying biological mechanism for inter-individual differences in chronotype, and support the central role of PER2 in the human circadian timing system.

Chronic sleep restriction greatly magnifies performance decrements immediately after awakening.

STUDY OBJECTIVES: Sleep inertia, subjectively experienced as grogginess felt upon awakening, causes cognitive performance impairments that can require up to 1.5 hr to dissipate. It is unknown, however, how chronic sleep restriction (CSR) influences the magnitude and duration of sleep inertia-related performance deficits. METHODS: Twenty-six healthy participants were enrolled in one of two in-laboratory sleep restriction protocols (one 32 day randomized control and one 38 day protocol) that separated the influence of sleep and circadian effects on performance using different "day"-lengths (20 and 42.85 hr day-lengths, respectively). The sleep opportunity per 24 hr day was the equivalent of 5.6 hr for each CSR condition and 8 hr for the Control condition. Participant's performance and subjective sleepiness were assessed within ~2 min after electroencephalogram-verified awakening and every 10 min thereafter for 70 min to evaluate performance and subjective sleepiness during sleep inertia. RESULTS: Performance within 2 min of awakening was ~10% worse in CSR conditions compared with Control and remained impaired across the dissipation of sleep inertia in the CSR conditions when compared with Control. These impairments in performance during sleep inertia occurred after only chronic exposure to sleep restriction and were even worse after awakenings during the biological nighttime. Interestingly, despite differences in objective performance, there were no significant differences between groups in subjective levels of sleepiness during sleep inertia. CONCLUSIONS: CSR worsens sleep inertia, especially for awakenings during the biological night. These findings are important for individuals needing to perform tasks quickly upon awakening, particularly those who obtain less than 6 hr of sleep on a nightly basis. CLINICAL TRIAL: The study "Sleep Duration Required to Restore Performance During Chronic Sleep Restriction" was registered as a clinical trial (#NCT01581125) at clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT01581125?term=NCT01581125.&rank=1).

Zinc oxide clad limited area epitaxy semipolar III-nitride laser diodes.

We report continuous-wave (CW) blue semipolar (202¯1) III-nitride laser diodes (LDs) that incorporate limited area epitaxy (LAE) n-AlGaN bottom cladding with thin p-GaN and ZnO top cladding layers. LAE mitigates LD design limitations that arise from stress relaxation, while ZnO layers reduce epitaxial growth time and temperature. Numerical modeling indicates that ZnO reduces the internal loss and increases the differential efficiency of TCO clad LDs. Room temperature CW lasing was achieved at 445 nm for a ridge waveguide LD with a threshold current density of 10.4 kA/cm2, a threshold voltage of 5.8 V, and a differential resistance of 1.1 Ω.

Demonstration of enhanced continuous-wave operation of blue laser diodes on a semipolar 202¯1¯ GaN substrate using indium-tin-oxide/thin-p-GaN cladding layers.

The benefits of utilizing transparent conductive oxide on top of a thin p-GaN layer for continuous-wave (CW) operation of blue laser diodes (LDs) were investigated. A very low operating voltage of 5.35 V at 10 kA/cm2 was obtained for LDs with 250 nm thick p-GaN compared to 7.3 V for LDs with conventional 650 nm thick p-GaN. An improved thermal performance was also observed for the thin p-GaN samples resulting in a 40% increase in peak light output power and a 32% decrease in surface temperature. Finally, a tradeoff was demonstrated between low operating voltage and increased optical modal loss in the indium tin oxide (ITO) with thinner p-GaN. LDs lasing at 445 nm with 150 nm thick p-GaN had an excess modal loss while LDs with an optimal 250 nm thick p-GaN resulted in optical output power of 1.1 W per facet without facet coatings and a wall-plug efficiency of 15%.

Semipolar III-nitride laser diodes with zinc oxide cladding.

Incorporating transparent conducting oxide (TCO) top cladding layers into III-nitride laser diodes (LDs) improves device design by reducing the growth time and temperature of the p-type layers. We investigate using ZnO instead of ITO as the top cladding TCO of a semipolar (202¯1) III-nitride LD. Numerical modeling indicates that replacing ITO with ZnO reduces the internal loss in a TCO clad LD due to the lower optical absorption in ZnO. Lasing was achieved at 453 nm with a threshold current density of 8.6 kA/cm2 and a threshold voltage of 10.3 V in a semipolar (202¯1) III-nitride LD with ZnO top cladding.

Pharmacotherapies for sleep disturbances in dementia.

BACKGROUND: Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia, and are associated with significant caregiver distress, increased healthcare costs, and institutionalisation. Drug treatment is often sought to alleviate these problems, but there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this vulnerable population. OBJECTIVES: To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with dementia, through identification and analysis of all relevant randomised controlled trials (RCTs). SEARCH METHODS: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, in March 2013 and again in March 2016, using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, rest-activity, sundowning. SELECTION CRITERIA: We included RCTs that compared a drug with placebo, and that had the primary aim of improving sleep in people with dementia who had an identified sleep disturbance at baseline. Trials could also include non-pharmacological interventions, as long as both drug and placebo groups had the same exposure to them. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on study design, risk of bias, and results from the included study reports. We obtained additional information from study authors where necessary. We used the mean difference as the measure of treatment effect, and where possible, synthesized results using a fixed-effect model. MAIN RESULTS: We found six RCTs eligible for inclusion for three drugs: melatonin (222 participants, four studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), trazodone (30 participants, one study), and ramelteon (74 participants, one study, no peer-reviewed publication, limited information available).The participants in the trazodone study and almost all participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. All primary sleep outcomes were measured using actigraphy. In one study of melatonin, drug treatment was combined with morning bright light therapy. Only two studies made a systematic assessment of adverse effects. Overall, the evidence was at low risk of bias, although there were areas of incomplete reporting, some problems with participant attrition, related largely to poor tolerance of actigraphy and technical difficulties, and a high risk of selective reporting in one trial that contributed very few participants. The risk of bias in the ramelteon study was unclear due to incomplete reporting.We found no evidence that melatonin, at doses up to 10 mg, improved any major sleep outcome over 8 to 10 weeks in patients with AD who were identified as having a sleep disturbance. We were able to synthesize data for two of our primary sleep outcomes: total nocturnal sleep time (mean difference (MD) 10.68 minutes, 95% CI -16.22 to 37.59; N = 184; two studies), and the ratio of daytime sleep to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; N = 184; two studies). From single studies, we found no difference between melatonin and placebo groups for sleep efficiency, time awake after sleep onset, or number of night-time awakenings. From two studies, we found no effect of melatonin on cognition or performance of activities of daily living (ADL). No serious adverse effects of melatonin were reported in the included studies. We considered this evidence to be of low quality.There was low-quality evidence that trazodone 50 mg given at night for two weeks improved total nocturnal sleep time (MD 42.46 minutes, 95% CI 0.9 to 84.0; N = 30; one study), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; N = 30; one study) in patients with moderate-to-severe AD, but it did not affect the amount of time spent awake after sleep onset (MD -20.41, 95% CI -60.4 to 19.6; N = 30; one study), or the number of nocturnal awakenings (MD -3.71, 95% CI -8.2 to 0.8; N = 30; one study). No effect was seen on daytime sleep, cognition, or ADL. No serious adverse effects of trazodone were reported.Results from a phase 2 trial investigating ramelteon 8 mg administered at night were available in summary form in a sponsor's synopsis. Because the data were from a single, small study and reporting was incomplete, we considered this evidence to be of low quality in general terms. Ramelteon had no effect on total nocturnal sleep time at one week (primary outcome) or eight weeks (end of treatment) in patients with mild-to-moderate AD. The synopsis reported few significant differences from placebo for any sleep, behavioural, or cognitive outcomes; none were likely to be of clinical significance. There were no serious adverse effects from ramelteon. AUTHORS' CONCLUSIONS: We discovered a distinct lack of evidence to help guide drug treatment of sleep problems in dementia. In particular, we found no RCTs of many drugs that are widely prescribed for sleep problems in dementia, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks associated with these common treatments. From the studies we identified for this review, we found no evidence that melatonin (up to 10mg) helped sleep problems in patients with moderate to severe dementia due to AD. There was some evidence to support the use of a low dose (50 mg) of trazodone, although a larger trial is needed to allow a more definitive conclusion to be reached on the balance of risks and benefits. There was no evidence of any effect of ramelteon on sleep in patients with mild to moderate dementia due to AD. This is an area with a high need for pragmatic trials, particularly of those drugs that are in common clinical use for sleep problems in dementia. Systematic assessment of adverse effects is essential.

Prediction of Vigilant Attention and Cognitive Performance Using Self-Reported Alertness, Circadian Phase, Hours since Awakening, and Accumulated Sleep Loss.

Sleep restriction causes impaired cognitive performance that can result in adverse consequences in many occupational settings. Individuals may rely on self-perceived alertness to decide if they are able to adequately perform a task. It is therefore important to determine the relationship between an individual's self-assessed alertness and their objective performance, and how this relationship depends on circadian phase, hours since awakening, and cumulative lost hours of sleep. Healthy young adults (aged 18-34) completed an inpatient schedule that included forced desynchrony of sleep/wake and circadian rhythms with twelve 42.85-hour "days" and either a 1:2 (n = 8) or 1:3.3 (n = 9) ratio of sleep-opportunity:enforced-wakefulness. We investigated whether subjective alertness (visual analog scale), circadian phase (melatonin), hours since awakening, and cumulative sleep loss could predict objective performance on the Psychomotor Vigilance Task (PVT), an Addition/Calculation Test (ADD) and the Digit Symbol Substitution Test (DSST). Mathematical models that allowed nonlinear interactions between explanatory variables were evaluated using the Akaike Information Criterion (AIC). Subjective alertness was the single best predictor of PVT, ADD, and DSST performance. Subjective alertness alone, however, was not an accurate predictor of PVT performance. The best AIC scores for PVT and DSST were achieved when all explanatory variables were included in the model. The best AIC score for ADD was achieved with circadian phase and subjective alertness variables. We conclude that subjective alertness alone is a weak predictor of objective vigilant or cognitive performance. Predictions can, however, be improved by knowing an individual's circadian phase, current wake duration, and cumulative sleep loss.

Pharmacotherapies for sleep disturbances in Alzheimer's disease.

BACKGROUND: Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering and daytime sleepiness are common clinical problems in dementia due to Alzheimer's disease (AD), and are associated with significant caregiver distress, increased healthcare costs and institutionalisation. Drug treatment is often sought to alleviate these problems, but there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this vulnerable population. OBJECTIVES: To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with Alzheimer's disease through identification and analysis of all relevant randomized controlled trials (RCTs). SEARCH METHODS: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 31 March 2013 using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, "rest-activity", sundowning. SELECTION CRITERIA: We included RCTs that compared a drug with placebo and that had the primary aim of improving sleep in people with Alzheimer's disease who had an identified sleep disturbance at baseline. Trials could also include non-pharmacological interventions as long as both drug and placebo groups had the same exposure to them. DATA COLLECTION AND ANALYSIS: Two authors working independently extracted data on study design, risk of bias and results from the included study reports. Additional information was obtained from study authors where necessary. We used the mean difference as the measure of treatment effect and, where possible, synthesized results using a fixed-effect model. MAIN RESULTS: We found RCTs eligible for inclusion for three drugs: melatonin (209 participants, three studies, but only two yielded data suitable for meta-analysis), trazodone (30 participants, one study) and ramelteon (74 participants, one study, no peer-reviewed publication, very limited information available).The melatonin and trazodone studies were of people with moderate-to-severe AD; the ramelteon study was of people with mild-to-moderate AD. In all studies participants had a variety of common sleep problems. All primary sleep outcomes were measured using actigraphy. In one study of melatonin, drug treatment was combined with morning bright light therapy. Only two studies made a systematic assessment of adverse effects. Overall, the published studies were at low risk of bias, although there were areas of incomplete reporting and some problems with participant attrition, related largely to poor tolerance of actigraphy and technical difficulties. The risk of bias in the ramelteon study was unclear due to incomplete reporting.We found no evidence that melatonin, either immediate- or slow-release, improved any major sleep outcome in patients with AD. We were able to synthesize data for two sleep outcomes: total nocturnal sleep time (MD 10.68 minutes, 95% CI -16.22 to 37.59, two studies), and the ratio of daytime sleep to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03, two studies). Other outcomes were reported in single studies. We found no difference between intervention and control groups for sleep efficiency, time awake after sleep onset or number of night-time awakenings, nor in cognition or performance of activities of daily living (ADLs). No serious adverse effects of melatonin were reported in the included studies.Trazodone 50 mg administered at night for two weeks significantly improved total nocturnal sleep time (MD 42.46 minutes, 95% CI 0.9 to 84.0, one study) and sleep efficiency (MD 8.53, 95% CI 1.9 to 15.1, one study), but there was no clear evidence of any effect on the amount of time spent awake after sleep onset (MD -20.41, 95% CI -60.4 to 19.6, one study) or the number of nocturnal awakenings (MD -3.71, 95% CI -8.2 to 0.8, one study). No effect was seen on daytime sleep, nor on cognition or ADLs. No serious adverse effects were reported.Results from a phase 2 trial investigating ramelteon 8 mg administered at night were available in summary form in a sponsor's synopsis. Ramelteon had no effect on total nocturnal sleep time at one week (primary outcome) or eight weeks (end of treatment). The synopsis reported few significant differences from placebo for any sleep, behavioural or cognitive outcomes; none were likely to be of clinical significance. There were no serious adverse effects of ramelteon. AUTHORS' CONCLUSIONS: We discovered a distinct lack of evidence to help guide drug treatment of sleep problems in AD. In particular, we found no RCTs of many drugs that are widely prescribed for sleep problems in AD, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks associated with these common treatments. From the studies we identified for this review, we found no evidence that melatonin is beneficial to AD patients with moderate to severe dementia and sleep problems. There is some evidence to support the use of a low dose (50 mg) of trazodone, although a larger trial is needed to allow a more definitive conclusion to be reached on the balance of risks and benefits. There was no evidence of any effect of ramelteon on sleep in patients with mild to moderate dementia due to AD. This is an area with a high need for pragmatic trials, particularly of those drugs that are in common clinical use for sleep problems in AD. Systematic assessment of adverse effects is essential.

Structure and permeability of ion-channels by integrated AFM and waveguide TIRF microscopy.

Membrane ion channels regulate key cellular functions and their activity is dependent on their 3D structure. Atomic force microscopy (AFM) images 3D structure of membrane channels placed on a solid substrate. Solid substrate prevents molecular transport through ion channels thus hindering any direct structure-function relationship analysis. Here we designed a ~70 nm nanopore to suspend a membrane, allowing fluidic access to both sides. We used these nanopores with AFM and total internal reflection fluorescence microscopy (TIRFM) for high resolution imaging and molecular transport measurement. Significantly, membranes over the nanopore were stable for repeated AFM imaging. We studied structure-activity relationship of gap junction hemichannels reconstituted in lipid bilayers. Individual hemichannels in the membrane overlying the nanopore were resolved and transport of hemichannel-permeant LY dye was visualized when the hemichannel was opened by lowering calcium in the medium. This integrated technique will allow direct structure-permeability relationship of many ion channels and receptors.

Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2.

CONTEXT: Loss of prokineticin 2 (PROK2) signaling in mice disrupts circadian rhythms, but the role of PROK2 signaling in the regulation of circadian rhythms in humans is undetermined. OBJECTIVE: The aim of the study was to examine the circadian rhythms of humans with a complete loss-of-function PROK2 mutation using an inpatient constant routine (CR) protocol. DESIGN AND SETTING: We conducted a case study in an academic medical center. SUBJECTS AND METHODS: Two siblings (one male and one female, ages 67 and 62 y, respectively) with isolated GnRH deficiency (IGD) due to a biallelic loss-of-function PROK2 mutation were studied using an inpatient CR protocol. Historical data from inpatient CR protocols conducted in healthy controls (ages 65-81 y) were used for comparison. MAIN OUTCOME MEASURES: We measured circadian phase markers (melatonin, cortisol, and core body temperature) and neurobehavioral performance (psychomotor vigilance task [PVT] and subjective alertness scale). RESULTS: Circadian waveforms of melatonin and cortisol did not differ between the IGD participants with PROK2 mutation and controls. In both IGD participants, neurobehavioral testing with PVT showed disproportionate worsening of PVT lapses and median reaction time in the second half of the CR. CONCLUSIONS: Humans with loss of PROK2 signaling lack abnormalities in circadian phase markers, indicating intact central circadian pacemaker activity in these patients. These results suggest that PROK2 signaling in humans is not required for central circadian pacemaker function. However, impaired PVT in the PROK2-null participants despite preserved endocrine rhythms suggests that PROK2 may transmit circadian timing information to some neurobehavioral neural networks.

High performance, LED powered, waveguide based total internal reflection microscopy.

Total internal reflection fluorescence (TIRF) microscopy is a rapidly expanding optical technique with excellent surface sensitivity and limited background fluorescence. Commercially available TIRF systems are either objective based that employ expensive special high numerical aperture (NA) objectives or prism based that restrict integrating other modalities of investigation for structure-function analysis. Both techniques result in uneven illumination of the field of view and require training and experience in optics. Here we describe a novel, inexpensive, LED powered, waveguide based TIRF system that could be used as an add-on module to any standard fluorescence microscope even with low NA objectives. This system requires no alignment, illuminates the entire field evenly, and allows switching between epifluorescence/TIRF/bright field modes without adjustments or objective replacements. The simple design allows integration with other imaging systems, including atomic force microscopy (AFM), for probing complex biological systems at their native nanoscale regimes.