Left atrial appendage occlusion in patients suffering from advanced chronic kidney disease (stage 4 and 5). Long-term follow-up.

INTRODUCTION AND OBJECTIVES: Advanced chronic kidney disease (A-CKD) combined with atrial fibrillation increases the risk of both thrombogenic and bleeding events. Left atrial appendage occlusion (LAAO) may be an alternative to oral anticoagulation to prevent thromboembolic events. We aimed to evaluate the outcomes of LAAO in patients with A-CKD. METHODS: Comparison at long-term follow-up of patients diagnosed with and without A-CKD (eGFR<30 mL/min/1.73 m2 ) who underwent LAAO between 2009 and May 2022. RESULTS: Five hundred seventy-three patients were included. Eighty-one (14%) were diagnosed with A-CKD. There were no differences in sex, age, and cardiovascular risk factors, except for diabetes which was more frequent in patients with A-CKD. The control group had higher rates of stroke, both ischemic and hemorrhagic. There were no differences in the CHA2 DS2 -VASc score, although A-CKD patients had a higher bleeding risk according to the HASBLED scale. Global procedural success was 99.1%. At follow-up, there were no differences in stroke rate: at 1-year (HR: 1.22, IC-95%: 0.14-10.42, p = 0.861); at 5-years (HR: 0.60, IC-95%: 0.08-4.58, p = 0.594). Although bleeding events were higher in the A-CKD group, no differences were found in major bleeding (defined BARC ≥ 3) at 1-year (HR: 1.34, IC-95%: 0.63-2.88, p = 0.464) or at 5-years follow-up (HR: 1.30, IC-95%: 0.69-2.48, p = 0.434). Mortality rate at 5 years was higher in the A-CKD patients (HR: 1.84, IC-95%: 1.18-2.87, p = 0.012). CONCLUSIONS: LAAO is an effective and safe treatment in A-CKD patients to prevent ischemic events and bleeding. This strategy could be an alternative to oral anticoagulation in this high-risk group of patients.

Animal models of human insomnia.

Insomnia disorder (chronic sleep continuity disturbance) is a debilitating condition affecting 5%-10% of the adult population worldwide. To date, researchers have attempted to model insomnia in animals through breeding strategies that create pathologically short-sleeping individuals or with drugs and environmental contexts that directly impose sleeplessness. While these approaches have been invaluable for identifying insomnia susceptibility genes and mapping the neural networks that underpin sleep-wake regulation, they fail to capture concurrently several of the core clinical diagnostic features of insomnia disorder in humans, where sleep continuity disturbance is self-perpetuating, occurs despite adequate sleep opportunity, and is often not accompanied by significant changes in sleep duration or architecture. In the present review, we discuss these issues and then outline ways animal models can be used to develop approaches that are more ecologically valid in their recapitulation of chronic insomnia's natural aetiology and pathophysiology. Conditioning of self-generated sleep loss with these methods promises to create a better understanding of the neuroadaptations that maintain insomnia, including potentially within the infralimbic cortex, a substrate at the crossroads of threat habituation and sleep.

Further understanding the connection between Alzheimer's disease and Down syndrome.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.

Optimization of circadian responses with shorter and shorter millisecond flashes.

Recent work suggests that the circadian pacemaker responds optimally to millisecond flashes of light, not continuous light exposure as has been historically believed. It is unclear whether these responses are influenced by the physical characteristics of the pulsing. In the present study, Drosophila (n = 2199) were stimulated with 8, 16 or 120 ms flashes. For each duration, the energy content of the exposure was systematically varied by changing the pulse irradiance and the number of stimuli delivered over a fixed 15 min administration window (64 protocols surveyed in all). Results showed that per microjoule invested, 8 ms flashes were more effective at resetting the circadian activity rhythm than 16- and 120 ms flashes (i.e. left shift of the dose-response curve, as well as a higher estimated maximal response). These data suggest that the circadian pacemaker's photosensitivity declines within milliseconds of light contact. Further introduction of light beyond a floor of (at least) 8 ms leads to diminishing returns on phase-shifting.

Circadian Responses to Fragmented Light: Research Synopsis in Humans.

Light is the chief signal used by the human circadian pacemaker to maintain precise biological timekeeping. Though it has been historically assumed that light resets the pacemaker's rhythm in a dose-dependent fashion, a number of studies report enhanced circadian photosensitivity to the initial moments of light exposure, such that there are quickly diminishing returns on phase-shifting the longer the light is shown. In the current review, we summarize findings from a family of experiments conducted over two decades in the research wing of the Brigham and Women's Hospital that examined the human pacemaker's responses to standardized changes in light patterns generated from an overhead fluorescent ballast. Across several hundred days of laboratory recording, the research group observed phase-shifts in the body temperature and melatonin rhythms that scaled with illuminance. However, as suspected, phase resetting was optimized when exposure occurred as a series of minute-long episodes separated by periods of intervening darkness. These observations set the stage for a more recent program of study at Stanford University that evaluated whether the human pacemaker was capable of integrating fragmented bursts of light in much the same way it perceived steady luminance. The results here suggest that ultra-short durations of light-lasting just 1-2 seconds in total-can elicit pacemaker responses rivaling those created by continuous hour-long stimulation if those few seconds of light are evenly distributed across the hour as discreet 2-millisecond pulses. We conclude our review with a brief discussion of these findings and their potential application in future phototherapy techniques.

The circadian activity rhythm is reset by nanowatt pulses of ultraviolet light.

The circadian pacemaker synchronizes to the Earth's rotation by tracking step-by-step changes in illumination that occur as the sun passes the horizon. While twilight progressions of irradiance and colour are considered important stimuli in this process, comparably less thought has been given to the possibility that ultraviolet A (UVA) radiation might actually play a more formative role given its evolutionary significance in shaping 24 h timekeeping. Here, we show that Drosophila activity rhythms can be phase-shifted by UVA light at an energy range seated well below that of the visible spectrum. Because the energy threshold for this resetting matches the incident amount of UVA on the human retina at twilight, our results suggest that UVA light has the potential to function as a similar time cue in people.

Precision Light for the Treatment of Psychiatric Disorders.

Circadian timekeeping can be reset by brief flashes of light using stimulation protocols thousands of times shorter than those previously assumed to be necessary for traditional phototherapy. These observations point to a future where flexible architectures of nanosecond-, microsecond-, and millisecond-scale light pulses are compiled to reprogram the brain's internal clock when it has been altered by psychiatric illness or advanced age. In the current review, we present a chronology of seminal experiments that established the synchronizing influence of light on the human circadian system and the efficacy of prolonged bright-light exposure for reducing symptoms associated with seasonal affective disorder. We conclude with a discussion of the different ways that precision flashes could be parlayed during sleep to effect neuroadaptive changes in brain function. This article is a contribution to a special issue on Circadian Rhythms in Regulation of Brain Processes and Role in Psychiatric Disorders curated by editors Shimon Amir, Karen Gamble, Oliver Stork, and Harry Pantazopoulos.

Tillage and Fertilizer Management Effects on Phosphorus Runoff from Minimal Slope Fields.

Phosphorus fertilization can increase P losses in surface runoff, but limited information is available for fields with <2% slopes in the US Midwest. Our objectives were to determine the effects of tillage-fertilizer placement (no-till-broadcast, strip till-broadcast; or strip till-deep placement, -15-cm subsurface band) and fertilizer rate applied in the fall (0, 52, or 90 kg PO ha yr) on runoff P concentrations and loads in fields with <2% slopes near Pesotum, IL, during fall and spring simulation runoff events, and to measure corn ( L.) and soybean [ (L.) Merr.] grain yield. Across four simulated runoff events, deep placement reduced dissolved reactive P (DRP) loads by 69 to 72% compared with the broadcast treatments. A tillage-fertilizer placement × P rate interaction showed that DRP and total P (TP) concentrations remained low when P was deep placed, regardless of P rate, whereas concentrations increased with increasing P rate for the broadcast treatments, but no differences existed for bioavailable P (BAP) (α = 0.05). At one site, rainfall simulation in the spring versus fall increased runoff volumes but sharply decreased BAP concentrations. During fall runoff simulations, deep placement reduced TP loads, and greater TP loads occurred with the 90- than the 52-kg PO ha yr rate. Similarly, when P was broadcast in the fall, DRP and TP concentrations were greater than deep-placed P, but no treatment differences occurred in the spring. Deep banding P and K did not reduce crop yield but reduced runoff losses of P from flat fields compared with broadcast P applications, particularly at high rates of P application.

The medial temporal memory system in Down syndrome: Translating animal models of hippocampal compromise.

Recent studies have highlighted the dentate gyrus as a region of increased vulnerability in mouse models of Down syndrome (DS). It is unclear to what extent these findings are reflected in the memory profile of people with the condition. We developed a series of novel tasks to probe distinct medial temporal functions in children and young adults with DS, including object, spatial, and temporal order memory. Relative to mental age-matched controls (n = 45), individuals with DS (n = 28) were unimpaired on subtests involving short-term object or configural recall that was divorced from spatial or temporal contexts. By contrast, the DS group had difficulty recalling spatial locations when contextual information was salient and recalling the order in which objects were serially presented. Results are consistent with dysfunction of spatial and temporal contextual pattern separation abilities in individuals with DS, mediated by the hippocampus, including the dentate gyrus. Amidst increasing calls to bridge human and animal work, the memory profile demonstrated here in humans with DS is strikingly similar to that of the Ts65Dn mouse model of DS. The study highlights the trisynaptic circuit as a potentially fruitful intervention target to mitigate cognitive impairments associated with DS.

Spontaneous alternation: A potential gateway to spatial working memory in Drosophila.

Despite their ubiquity in biomedical research, Drosophila have yet to be widely employed as model organisms in psychology. Many complex human-like behaviors are observed in Drosophila, which exhibit elaborate displays of inter-male aggression and female courtship, self-medication with alcohol in response to stress, and even cultural transmission of social information. Here, we asked whether Drosophila can demonstrate behavioral indices of spatial working memory in a Y-maze, a classic test of memory function and novelty-seeking in rodents. Our data show that Drosophila, like rodents, alternate their visits among the three arms of a Y-maze and spontaneously favor entry into arms they have explored less recently versus ones they have just seen. These findings suggest that Drosophila possess some of the information-seeking and working memory facilities mammals depend on to navigate through space and might be relevant models for understanding human psychological phenomena such as curiosity.

Revealing the Diversity of Introduced Coffea canephora Germplasm in Ecuador: Towards a National Strategy to Improve Robusta.

Genetic resources of Coffea canephora have been introduced in several tropical countries with potential for crop development. In Ecuador, the species has been cultivated since the mid-20th century. However, little is known about the diversity and genetic structure of introduced germplasm. This paper provides an overview of the genetic and phenotypic diversity of C. canephora in Ecuador and some proposals for implementing a breeding program. Twelve SSR markers were used to analyze 1491 plants of C. canephora grown in different living collections in Ecuador, compared to 29 genotypes representing the main genetic and geographic diversity groups identified within the species. Results indicated that most of the genotypes introduced are of Congolese origin, with accessions from both main subgroups, SG1 and SG2. Some genotypes were classed as hybrids between both subgroups. Substantial phenotypic diversity was also found, and correlations were observed with genetic diversity. Ecuadorian Robusta coffee displays wide genetic diversity and we propose some ways of improving Robusta in Ecuador. A breeding program could be based on three operations: the choice of elite clones, the introduction of new material from other countries (Ivory Coast, Uganda), and the creation of new hybrid material using genotypes from the different diversity groups.

Corn Nitrogen Management Influences Nitrous Oxide Emissions in Drained and Undrained Soils.

To date, no studies have evaluated nitrous oxide (NO) emissions of a single versus a split-nitrogen (N) fertilizer application under different soil drainage conditions for corn ( L.). The objective of this study was to quantify season-long cumulative NO emissions, N use efficiency, and soil N dynamics when corn received a recommended N rate as single or split-N application in Minnesota soils with and without tile drainage over two growing seasons. Preplant urea was broadcast incorporated, and in-season split-N was broadcast as urea plus urease inhibitor. Tile drainage reduced NO emissions during periods of excess moisture but did not affect grain yield or other agronomic parameters. Conversely, when precipitation was adequate and well distributed, tile drainage did not affect NO emissions, but it did enhance grain yield. Averaged across years, the undrained soil emitted 1.8 times more NO than the drained soil (2.36 vs. 1.29 kg N ha). Compared with the Zero-N control, the Single Preplant and Split N applications emitted 2.1 and 1.6 times more NO, produced 1.4 and 1.3 times greater grain yield, and resulted in 1.5 and 1.4 times more residual soil total inorganic N, respectively. Per unit of grain yield, the Split application emitted similar amounts of NO as the Zero-N control. Averaged across years and drainage, the Split application emitted 26% less NO than the Single Preplant application (1.84 vs. 2.48 kg N ha; < 0.001) with no grain yield differences. These results highlight that soil drainage can reduce NO emissions and that a split N application may be a feasible way to achieve NO reduction while enhancing grain yield.

Nitrogen Management for Corn and Groundwater Quality in Upper Midwest Irrigated Sands.

Groundwater contamination from NO-N leaching in corn ( L.) production with coarse-textured soils poses an environmental concern. Our objectives were to evaluate NO-N leaching in continuous corn (CC), corn after soybean ( L.) (CSb), and soybean after corn (SbC) in irrigated sandy soils in Minnesota related to (i) N rate using best management practices of split-N application, (ii) a split-N application and single preplant applications of enhanced-efficiency fertilizers (EEF), and (iii) residual N treatment in SbC. Urea (0-315 kg N ha in 45-kg increments) was broadcast as a split application (half at preplant and half at the V4 development stage) and polymer-coated urea (ESN), ESN/urea, and SuperU at preplant at a rate of 180 kg N ha on an Arvilla sandy loam soil. In May and June, 75% of the total drainage and 73% of the total NO-N leached occurred. At the economic optimum N rate (EONR), season-long NO-N leaching rates were 86 and 106 kg NO-N ha for CC and CSb, respectively. In CC, reducing the EONR by 20% reduced grain yield by 4% and NO-N leached by 9%, and a 25% reduction in EONR resulted in an additional 2% reduction for both, whereas no significant reductions occurred for CSb. Similar NO-N leaching occurred with EEFs and the split-N application. After 4 yr of no N application, we measured 9 to 20 mg NO-N L and leaching of 21 to 51 kg NO-N ha, highlighting the difficulty of meeting drinking water quality standards in corn cropping systems.

Assessing cognitive improvement in people with Down syndrome: important considerations for drug-efficacy trials.

Experimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized.

Nitrous oxide emissions from anhydrous ammonia, urea, and polymer-coated urea in illinois cornfields.

The use of alternative N sources relative to conventional ones could mitigate soil-surface NO emissions. Our objective was to evaluate the effect of anhydrous ammonia (AA), urea, and polymer-coated urea (ESN) on NO emissions for continuous corn ( L.) production. Corn received 110 kg N ha in 2009 and 180 kg N ha in 2010 and 2011. Soil NO fluxes were measured one to three times per week early in the growing season and less frequently later, using vented non-steady state closed chambers and a gas chromatograph. Regardless of N source, NO emissions were largest immediately after substantial (>20 mm) rains, dropping to background levels thereafter. Averaged across N sources, 2.85% of the applied N was lost as NO. Emission differences for treatments only occurred in 2010, the year with maximum NO production. In the 2010 growing season, cumulative emissions (in kg NO-N ha) were lowest for the check (2.21), followed by ESN (9.77), and ESN was lower than urea (14.07) and AA (16.89). Emissions in 2010 based on unit of corn yield produced followed a similar pattern, and NO emissions calculated as percent of applied N showed that AA losses were 1.9 times greater than ESN. Across years, relative to AA, ESN reduced NO emissions, emissions per unit of corn yield, and emissions per unit of N applied, whereas urea produced intermediate values. The study indicates that, under high N loss potential (wet and warm conditions), ESN could reduce NO emissions more that urea and AA.

Nitrous oxide emissions from soybean in response to drained and undrained soils and previous corn nitrogen management.

While corn (Zea mays L.)-soybean (Glycine max. Merr. L) is a predominant rotation system in the US Midwest the residual effect of nitrogen (N) fertilization to corn on the following year's soybean and N2O emissions under different soil drainage conditions has not been studied. Our objective was to quantify agronomic parameters and season-long N2O emissions from soybean as affected by N management (0-N and optimum N rate of 135 kg N ha-1 as single or split application) during the previous corn crop under drained and undrained systems. Urea was applied to corn, and residual N effects were measured on soybean the following year in a poorly drained soil with and without subsurface tile drainage. Drainage reduced N2O emissions in one of three growing seasons but had no effect on soybean yield or N removal in grain. Nitrogen management in the previous corn crop had no effect on soybean grain yield, N removal, or N2O emissions during the soybean phase. Even though soybean symbiotically fixes N and removes more N in grain than corn, N2O emissions were more than two times greater during the corn phase (mean = 1.83 kg N ha-1) due to N fertilization than during the soybean phase (mean = 0.80 kg N ha-1). Also, N2O emissions in the corn years were increased possibly due to decomposition of the previous year's soybean crop residue compared to corn residue decomposition in the soybean years. Tile drainage, especially where wet soil conditions are prevalent, is a viable option to mitigate agricultural N2O emissions.

Risk for Suicide and Homicide Peaks at Night: Findings From the National Violent Death Reporting System, 35 States, 2003-2017.

Objective: The Mind after Midnight hypothesis proposes that nocturnal wakefulness increases the risk for dysregulated behaviors. Prior studies highlight a greater risk for suicide at night after adjusting for population wakefulness. How this risk varies hour to hour, differs across subgroups, or applies to other behaviors is unknown.Methods: Data on 78,647 suicides and 50,526 homicides from the National Violent Death Reporting System were combined with population wakefulness data for 2003-2017 from the American Time Use Survey. Hourly incident risk ratios (IRRs) were estimated after adjusting for population wakefulness. Two-way analysis of variances identified significant time-by-subgroup interactions that were quantified in post hoc analyses.Results: Suicide counts peaked at 12:00 PM, while homicide counts peaked at 10:00- 11:00 PM. Adjusting for demographics and population wakefulness revealed a 5-fold greater risk for suicide at 3:00 AM (aIRR: 5.20 [4.74-5.70]) and an 8-fold greater risk for homicide at 2:00 AM (aIRR: 8.04 [6.35-10.2]). Hourly risk for suicide varied by age, ethnicity, blood alcohol level, and current partner conflict. Hourly risk for homicide varied by sex and blood alcohol level.Conclusions: Risk for suicide and homicide is greater at night than expected based on the number of people awake at that time. Nighttime risk was greater among young adults and those intoxicated with alcohol, but not among those with a history of suicidal ideation or attempts. Further research should evaluate mechanisms of risk and confirm these findings at an individual level.

Empirical clustering to identify individuals for whom insomnia is more closely related to suicidal ideation.

BACKGROUND: Although the effect sizes are modest, insomnia is consistently associated with suicidal thoughts and behaviors. Subgroup analyses can efficiently identify for whom insomnia is most relevant to suicidal ideation. To improve clinical case identification, the present study sought to identify subclusters of lifetime suicidal ideators for whom insomnia was most closely related to current suicidal ideation. METHODS: Data on N = 4750 lifetime suicidal ideators were extracted from the Military Suicide Research Consortium's Common Data Elements. Data on sociodemographic characteristics, severity and history of suicidal thoughts and behaviors, and related clinical characteristics were clustered by unsupervised machine learning algorithms. Robust Poisson regression estimated cluster by insomnia associations with current suicidal ideation. RESULTS: Three clusters were identified: a modest symptom severity cluster (N = 1757, 37.0 %), an elevated severity cluster (N = 1444 30.4 %), and a high severity cluster (N = 1549 32.6 %). In Cluster 1, insomnia was associated with current suicidal ideation (PRR 1.29 [1.13-1.46]) and remained significant after adjusting for sociodemographic and clinical covariates. In Cluster 2, insomnia was associated with current suicidal ideation (PRR 1.14 [1.01-1.30]), but not after adjusting for sociodemographic and clinical covariates. In Cluster 3, insomnia was associated with current suicidal ideation (PRR 1.12 [1.03-1.21]) and remained significant after adjusting for sociodemographic covariates, but not clinical covariates. LIMITATIONS: Cross-sectional design, lack of diagnostic data, non-representative sample. CONCLUSION: Insomnia appears more closely related to current suicidal ideation among modest severity individuals than other subgroups. Future work should use prospective designs and more comprehensive risk factor measures to confirm these findings.

Social Jetlag and Other Aspects of Sleep Are Linked to Non-Suicidal Self-Injury Among College Students.

INTRODUCTION: Disrupted sleep is associated with non-suicidal self-injury (NSSI) in young adults, but many specific features of sleep continuity and timing have yet to be examined. Additionally, the psychological mechanisms linking sleep to NSSI are unclear. The present study evaluated 14 sleep variables as classifiers of lifetime or recent NSSI and examined potential confounding and mediating factors. METHODS: A sample of 885 college students provided measures of sleep continuity (e.g., duration, timing, fragmentation), nightmares, insomnia, and perceived sleep control. Lifetime and past 3-month NSSI were measured using a self-report version of the Columbia Suicide Severity Ratings Scale. Bidirectional stepwise regression identified significant sleep classifiers and subsequent models examined their associations with NSSI after adjusting for covariates and through potential psychological mediators. RESULTS: Only absolute social jetlag was associated with recent NSSI, even after adjusting for covariates, such that each additional hour difference between weekday and weekend sleep schedules was associated with a 17% greater risk of recent NSSI. Nightmares, weekend sleep efficiency, and perceived sleep control were associated with lifetime NSSI, although only weekend sleep efficiency remained associated after adjusting for covariates. Bootstrap mediations identified negative urgency as a partial mediator for recent and lifetime NSSI, and lack of premeditation and perceived burdensomeness as partial mediators for lifetime NSSI. CONCLUSIONS: The timing and consistency of young adults' sleep schedules may be of greater importance to NSSI among college students than insomnia or insufficient sleep. Future studies of sleep and NSSI should include these measures as potential risk factors. HIGHLIGHTSDifferences between weekday/weekend sleep timing are linked to recent NSSI.Negative urgency partially mediates poor sleep on recent and lifetime NSSI.Sleep shares a multifaceted relationship with NSSI risk in college students.

Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome.

Trisomy 21 and mutations in the Sonic hedgehog (SHH) signaling pathway cause overlapping and pleiotropic phenotypes including cerebellar hypoplasia, craniofacial abnormalities, congenital heart defects and Hirschsprung disease. Trisomic cells derived from individuals with Down syndrome possess deficits in SHH signaling, suggesting that overexpression of human chromosome 21 genes may contribute to SHH-associated phenotypes by disrupting normal SHH signaling during development. However, chromosome 21 does not encode any known components of the canonical SHH pathway. Here, we sought to identify chromosome 21 genes that modulate SHH signaling by overexpressing 163 chromosome 21 cDNAs in a series of SHH-responsive mouse cell lines. We confirmed overexpression of trisomic candidate genes using RNA sequencing in the cerebella of Ts65Dn and TcMAC21 mice, model systems for Down syndrome. Our findings indicate that some human chromosome 21 genes, including DYRK1A, upregulate SHH signaling, whereas others, such as HMGN1, inhibit SHH signaling. Individual overexpression of four genes (B3GALT5, ETS2, HMGN1 and MIS18A) inhibits the SHH-dependent proliferation of primary granule cell precursors. Our study prioritizes dosage-sensitive chromosome 21 genes for future mechanistic studies. Identification of the genes that modulate SHH signaling may suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.