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ObjectiveThis study compared the benefits of cognitive-behavioral therapy for insomnia for sleep, mental health symptoms, and quality of life (QoL) in a sample of women veterans with and without probable post-traumatic stress disorder (PTSD) comorbid with insomnia disorder.MethodsSeventy-three women veterans (30 with probable PTSD) received a manual-based 5-week cognitive-behavioral therapy for insomnia treatment as part of a behavioral sleep intervention study. Measures were completed at baseline, post-treatment, and 3-month follow-up. Sleep measures included the Insomnia Severity Index, Pittsburgh Sleep Quality Index, sleep efficiency measured by actigraphy, and sleep efficiency and total sleep time measured by sleep diary. Mental health measures included the PTSD Checklist-5, nightmares per week, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7 scale. QoL was measured with the Short Form-12. Linear mixed models compared changes over time across groups. Independent t tests examined PTSD symptom changes in women veterans with probable PTSD.ResultsBoth groups demonstrated improvements across sleep (ps&nbsp

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Little is known about how human Y-Chromosome gene expression directly contributes to differences between XX (female) and XY (male) individuals in nonreproductive tissues. Here, we analyzed quantitative profiles of Y-Chromosome gene expression across 36 human tissues from hundreds of individuals. Although it is often said that Y-Chromosome genes are lowly expressed outside the testis, we report many instances of elevated Y-Chromosome gene expression in a nonreproductive tissue. A notable example is EIF1AY, which encodes eukaryotic translation initiation factor 1A Y-linked, together with its X-linked homolog EIF1AX. Evolutionary loss of a Y-linked microRNA target site enabled up-regulation of EIF1AY, but not of EIF1AX, in the heart. Consequently, this essential translation initiation factor is nearly twice as abundant in male as in female heart tissue at the protein level. Divergence between the X and Y Chromosomes in regulatory sequence can therefore lead to tissue-specific Y-Chromosome-driven sex biases in expression of critical, dosage-sensitive regulatory genes.

Insects, unlike vertebrates, are widely believed to lack male-biased sex steroid hormones

Objective/Background: Sleep problems are common in women and caregiving for an adult is a common role among women. However, the effects of caregiving on sleep and related daytime impairment are poorly understood among women veterans. This study compared stress-related sleep disturbances, insomnia symptoms, and sleep-related daytime impairment between women veterans who were caregivers and those who did not have a caregiving role. Participants: Of 12,225 women veterans who received care in one Veterans Administration Healthcare System, 1,457 completed data on a postal survey (mean age=51.7±15.9years). Two hundred forty three (17%) respondents (mean age 53.8±12.7years) were caregivers for an adult, predominantly for a parent, providing transportation. Methods: The survey included items that addressed insomnia symptoms, total sleep time, sleep-related daytime impairments, caregiving characteristics, self-rated health, pain, stress, body mass index, and demographic information. Results: In adjusted analyses, caregiver status did not directly predict sleep complaints alone. However, in multiple regression analyses, being a caregiver (odds ratio 1.7, p =.001) significantly predicted stress-related sleep disturbance, even after adjusting for age, pain, self-rated health, and other characteristics. Furthermore, being a caregiver (β=3.9, p =.031) significantly predicted more symptoms of sleep-related daytime impairment after adjusting for age, pain, self-rated health, and other factors. Conclusions: Compared to noncaregivers, women veterans who were caregivers for an adult were more likely to report stress causing poor sleep, and more daytime impairment due to poor sleep. These findings suggest the need to target stress and other factors when addressing sleep disturbance among women veterans who are caregivers.

STUDY OBJECTIVES: To estimate the prevalence of insomnia disorder among older veterans and to study relationships among age and self-rated health, with insomnia disorder, self-reported sleep duration and sleep efficiency. METHODS: A cross-sectional postal survey of community-dwelling older veterans (older than 60 years) seen at one VA Healthcare System in the prior 18 months was performed, which was constructed to align with the general diagnostic criteria for insomnia disorder (International Classification of Sleep Disorders, Second Edition [ICSD-2]). The survey also queried self-reported sleep duration, bedtime, and wake time, which were used to calculate sleep efficiency. The survey also asked about race/ethnicity and self-rated health (using the general health item from the Short Form-36). RESULTS: A completed survey was returned by 4,717 individuals (51.9% response rate; mean age 74.1 years). Of those, 2,249 (47.7%) met ICSD-2 diagnostic criteria for insomnia disorder. In logistic regression analyses, insomnia disorder was more likely among younger age categories (odds ratios [OR] 1.4–2.5) and in those with worse self-rated health (OR 2.1–14.4). Both total nocturnal sleep time and time in bed increased with older age (all P < .001), whereas sleep efficiency did not differ. Worse self-rated health was associated with shorter total nocturnal sleep time, more time in bed, and lower (worse) sleep efficiency. CONCLUSIONS: Results of the postal survey suggest that almost half of community-dwelling older veterans have insomnia disorder, which was more common in young-old and among those with worse self-rated health. Additional work is needed to address the high burden of insomnia among older adults, including those with poor health. CITATION: Ryden AM, Martin JL, Matsuwaka S, Fung CH, Dzierzewski JM, Song Y, Mitchell MN, Fiorentino L, Josephson KR, Jouldjian S, Alessi CA. Insomnia disorder among older veterans: results of a postal survey. J Clin Sleep Med. 2019;15(4):543–551.

Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.

Rationale: Data on the molecular mechanisms that regulate platelet–pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: To identify a hypoxia-sensitive, modifiable mediator of platelet–pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods: Network medicine was used to profile protein–protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography–mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet–endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models in vivo. Measurements and Main Results: The protein NEDD9 was identified in the hypoxia thrombosome network in silico. Compared with normoxia, hypoxia (0.2% O(2)) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)–dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9–P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors in vitro and from patients with CTEPH ex vivo. Compared with control mice, platelet–pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9(−/−) mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: The NEDD9–P-selectin protein–protein interaction is a modifiable target with which to inhibit platelet–pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.

Rapid advances in biological and digital support systems are revolutionizing the population control of invasive disease vectors such as Aedes aegypti. Methods such as the sterile and incompatible insect techniques (SIT/IIT) rely on modified males to seek out and successfully mate with females, and in doing so outcompete the wild male population for mates. Currently, these interventions most frequently infer mating success through area-wide population surveillance and estimates of mating competitiveness are rare. Furthermore, little is known about male Ae. aegypti behaviour and biology in field settings. In preparation for a large, community scale IIT program, we undertook a series of mark- release-recapture experiments using rhodamine B to mark male Ae. aegypti sperm and measure mating interactions with females. We also developed a Spatial and Temporally Evolving Isotropic Kernel (STEIK) framework to assist researchers to estimate the movement of individuals through space and time. Results showed that ~40% of wild females captured daily were unmated, suggesting interventions will need to release males multiple times per week to be effective at suppressing Ae. aegypti populations. Males moved rapidly through the landscape, particularly when released during the night. Although males moved further than what is typically observed in females of the species, survival was considerably lower. These unique insights improve our understanding of mating interactions in wild Ae. aegypti populations and lay the foundation for robust suppression strategies in the future., Author summary Incompatible insect techniques for controlling populations of the dengue vector, Aedes aegypti, utilize the mating biology of adult male mosquitoes to achieve suppression through a sterilization process. As the study of Ae. aegypti control has typically focused on adult female mosquitoes, knowledge on male movement, survival and mating interactions in the field is lacking. Here we undertook several mark-release-recapture experiments on adult male Ae. aegypti in Innisfail, Australia, and measured important biological parameters. For the first time in large field experiments, we employed rhodamine B as a marker that when fed to adult males, identified both marked males and the wild females they mated with. We observed males moving further through the landscape, but surviving for a shorter period, than previous measurements undertaken on females in a field setting. A high proportion (~40%) of unmated females suggests individuals are constantly available for mating. As such, sterile male strategies may need to release at regular intervals to achieve effective population suppression. The unique insights provided by this study will assist in designing future sterile male field interventions.

STUDY OBJECTIVES: Person-centered obstructive sleep apnea (OSA) care is a collaborative approach that is respectful of an individual’s health priorities. Informed decision-making is essential to person-centered care, especially as patients age. In a feasibility study, we evaluated the effects of a new decision aid (Decide2Rest) on OSA treatment decision-making in older adults. METHODS: Patients (aged ≥ 60 years) with newly diagnosed OSA were recruited from two health care systems and randomized either to Decide2Rest or to a control program. Postintervention outcomes included 1) Decisional Conflict Scale (0–100, where 0 = low and 100 = high conflict), which measures perceptions of uncertainty, whether decisions reflect what matters most to patients, and whether patients feel supported in decision-making; 2) Preparation for Decision-Making scale (0–100, where 0 = least and 100 most prepared); and 3) OSA knowledge (0–100, where 0 = poor and 100 = outstanding). Multivariable linear regression models examined relationships between Decide2Rest and outcomes (Decisional Conflict Scale, Preparation for Decision-Making, OSA knowledge). RESULTS: Seventy-three patients were randomized to Decide2Rest (n = 36; mean age, 69 years; 72% male) vs control (n = 37; mean age, 69 years; 70% male). Results from the regressions, controlling for study site, indicate that the Decide2Rest program resulted in less decisional conflict (20.5 vs 32.7 on the Decisional Conflict Scale; P = .014), more preparedness for decision-making (87.8 vs 66.2 on the Preparation for Decision-Making scale; P < .001), and greater OSA knowledge (75.1 vs 65.3 OSA knowledge score; P = .04) scores than in the control group. CONCLUSIONS: The Decide2Rest program promotes person-centered OSA decision-making for older patients with newly diagnosed OSA. Future studies are needed to optimize implementation of the program. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Name: Improving Older Adults’ Decision-Making for OSAT (eDecide2Rest); URL: https://clinicaltrials.gov/ct2/show/NCT03138993; Identifier: NCT03138993. CITATION: Fung CH, Martin JL, Liang LJ, et al. Efficacy of a patient decision aid for improving person-centered decision-making by older adults with obstructive sleep apnea. J Clin Sleep Med. 2021;17(2):121–128.

(1) describe imaging features of CIA, (2) compare dilation rate and wall thickening of aortic aneurysms in patients with CIA versus those with giant cell arteritis/aortitis (GCA), (3) present clinical outcomes of CIA patients. Retrospective search of electronic records from 2004 to 2018 yielded 71 patients, 52 of whom were female, with a mean age of 67.5 ± 9.0 years old, with a new clinical diagnosis of cranial or extracranial GCA (GCA group), and giant cell aortitis revealed by the aortic biopsy (CIA group). Comparisons between groups were conducted using the Wilcoxon rank-sum and Fisher's exact tests. Survival from the date of initial diagnosis to the end of data collection was compared between the two groups through a log-rank test. CIA patients (n = 23; 32%) presented with cardiovascular symptoms, and none had systemic inflammatory symptoms. Inflammatory markers were significantly higher among GCA patients than among CIA patients (p0.0001). The CIA group demonstrated thoracic aortic aneurysms without wall thickening. None of the GCA patients (n = 48; 68%) had aneurysmal dilation in the aorta at the time of diagnosis. None of the four CIA patients had FDG uptake in the aorta, while nine out of 13 GCA patients had FDG uptake in the vessels. There was no statistically significant difference in the survival between the two groups (p = 0.12). CIA patients presented with cardiovascular symptoms and was characterized by aneurysm of the aorta without the involvement of the infrarenal aortic segment. The role of FDG-PET/CT in CIA is less certain, though none of the patients in this cohort had FDG uptake in the vessels.

Objectives: To investigate and compare post-traumatic stress (PTS), depression and anxiety in women and their partners over a 9-month period following miscarriage or ectopic pregnancy.Methods: This was a prospective cohort study. Consecutive women and their partners were approached in the early pregnancy units of three hospitals in central London. At 1, 3 and 9 months after early pregnancy loss, recruits were e-mailed links to surveys containing the Hospital Anxiety and Depression Scale and the Post-traumatic Stress Diagnostic Scale. The proportion of participants meeting the screening criteria for moderate or severe anxiety or depression and PTS was assessed. Mixed-effects logistic regression was used to analyze differences between women and their partners and their evolution over time.Results: In total, 386 partners were approached after the woman in whom the early pregnancy loss had been diagnosed consented to participate, and 192 couples were recruited. All partners were male. Response rates were 60%, 48% and 39% for partners and 78%, 70% and 59% for women, at 1, 3 and 9 months, respectively. Of the partners, 7% met the criteria for PTS at 1 month, 8% at 3 months and 4% at 9 months, compared with 34%, 26% and 21% of women, respectively. Partners also experienced lower rates of moderate/severe anxiety (6% vs 30% at 1 month, 9% vs 25% at 3 months and 6% vs 22% at 9 months) and moderate/severe depression (2% vs 10% at 1 month, 5% vs 8% at 3 months and 1% vs 7% at 9 months). The odds ratios for psychological morbidity in partners vs women after 1 month were 0.02 (95% CI, 0.004-0.12) for PTS, 0.05 (95% CI, 0.01-0.19) for moderate/severe anxiety and 0.15 (95% CI, 0.02-0.96) for moderate/severe depression. Morbidity for each outcome decreased modestly over time, without strong evidence of a different evolution between women and their partners.Conclusions: Some partners report clinically relevant levels of PTS, anxiety and depression after pregnancy loss, though to a far lesser extent than women physically experiencing the loss. (C) 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Study ObjectivesCognitive behavioral therapy for insomnia (CBTI) for comorbid insomnia and obstructive sleep apnea (OSA) has had mixed results. We integrated CBTI with a positive airway pressure (PAP) adherence program and tested effects on sleep and PAP use.Methods125 veterans (mean age 63.2, 96% men, 39% non-Hispanic white, 26% black/African American, 18% Hispanic/Latino) with comorbid insomnia and newly-diagnosed OSA (apnea-hypopnea index ≥ 15) were randomized to 5-weekly sessions integrating CBTI with a PAP adherence program provided by a “sleep coach” (with behavioral sleep medicine supervision), or 5-weekly sleep education control sessions. Participants and assessment staff were blinded to group assignment. Outcomes (baseline, 3 and 6 months) included Pittsburgh Sleep Quality Index (PSQI), 7-day sleep diary (sleep onset latency [SOL-D], wake after sleep onset [WASO-D], sleep efficiency [SE-D]), 7-day actigraphy (SE-A), and objective PAP use (hours/night and nights ≥ 4 h). Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10) were also collected.ResultsCompared to controls, intervention participants showed greater improvement (baseline to 3 and 6 months, respectively) in PSQI (−3.2 and −1.7), SOL-D (−16.2 and −15.5 minutes), SE-D (10.5% and 8.5%), SE-A (4.4% and 2.6%) and more 90-day PAP use (1.3 and 0.9 more hours/night, 17.4 and 11.3 more nights PAP ≥ 4 h). 90-day PAP use at 3 months was 3.2 and 1.9 h/night in intervention versus controls. Intervention participants also had greater improvements in ISI, ESS, and FOSQ-10 (all p < 0.05).ConclusionsAn intervention integrating CBTI with a PAP adherence program delivered by a supervised sleep coach improved sleep and PAP use in adults with comorbid insomnia and OSA.Trial RegistrationClinicalTrials.govStudy name: Novel Treatment of Comorbid Insomnia and Sleep Apnea in Older VeteransURL: https://clinicaltrials.gov/ct2/results?cond=&term=NCT02027558&cntry=&state=&city=&dist=Registration: NCT02027558

Background The HeartWare HVAD (Medtronic, Minneapolis, MN) is a continuous-flow left ventricular assist device (LVAD) approved by the FDA in 2012 as a bridge to transplant in patients with end-stage left ventricular heart failure. The current inflow cannula has a smooth outer surface near the inflow edge and a sintered collar of titanium microspheres near the pump. A previous case series of HVAD patients bridged to transplant revealed thrombus on the outer surface of the inflow cannula in 8 of 8 patients, predominantly at the smooth-sintered interface, that was associated with a clinical stroke rate of 12.5%. Design Cases of HVAD devices removed at the time of heart transplant were identified in the surgical pathology database. The gross and microscopic findings were reviewed along with clinical data. Results A total of 22 patients with 24 HVAD implants diagnosed with dilated cardiomyopathy (13 patients), ischemic heart disease (4 patients), lymphocytic myocarditis (2 patients), hypertrophic cardiomyopathy (2 patients), and congenital valvular disease (1 patient) were included. Two patients received two HVADs to provide biventricular support. All patients received post-implantation anti-coagulation with an INR goal of 2 to 3. Gross pathologic examination revealed thrombi on the outer aspect of the HVAD inflow cannula in 23 of 24 devices (96%). The inflow cannula of the one device that did not develop thrombus was positioned such that the smooth-sintered interface was buried in the ventricular myocardium and not in contact with blood in the ventricular chamber. Complications during the period of device support included 9 thromboembolic events (41%) including 6 ischemic strokes (27%), 2 intracoronary thromboembolic events and 1 splenic infarct. Patients suffered strokes 4 to 174 days (mean 82) after HVAD placement and had thrombus on the inflow cannula ranging in size from 0.1–2.5 cm (axial), 0.4–4.5 cm (circumferential) and 0.1–0.5 cm (thickness). Histologic evaluation revealed bland, partially organized thrombi without evidence of infection. Other complications included driveline infections (9%), non-driveline related bacteremia (9%) and hemorrhage (5%). Conclusions We report here an extension of our original study to a total of 22 patients with 24 HVAD implants who were all successfully bridged to transplant. We validate the very high prevalence of thrombus around the HVAD inflow cannula, associated with a clinical thromboembolic event in over a third of the patients, the majority of which were strokes. The nidus for thrombus formation appears to be the smooth-sintered interface of the HVAD inflow cannula.

The reproductive fitness of the Anopheles gambiae mosquito represents a promising target to prevent malaria transmission. The ecdysteroid hormone 20-hydroxyecdysone (20E), transferred from male to female during copulation, is key to An. gambiae reproductive success as it licenses females to oviposit eggs developed after blood feeding. Here we show that 20E-triggered oviposition in these mosquitoes is regulated by the stress- and immune-responsive c-Jun N-terminal kinase (JNK). The heads of mated females exhibit a transcriptional signature reminiscent of a JNK-dependent wounding response while mating — or injection of virgins with exogenous 20E — selectively activates JNK in the same tissue. RNAi-mediated depletion of JNK pathway components inhibits oviposition in mated females, whereas JNK activation by silencing the JNK phosphatase puckered induces egg laying in virgins. Together, these data identify JNK as a potential conduit linking stress responses and reproductive success in the most important vector of malaria.

BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.MethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.ResultsNo variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in highrisk populations and the general community.

Objective To evaluate the prevalence of monoclonal gammopathy (MG) in patients with wild-type transthyretin amyloidosis (ATTRwt) (formerly known as senile amyloidosis). Patients and Methods We retrospectively analyzed the serum protein electrophoresis and serum immunofixation results, free light chain (FLC) levels, and renal function of 113 consecutive patients with ATTRwt seen at the Brigham and Women's Hospital's Cardiac Amyloidosis Program between February 21, 2006, and November 9, 2016. Monoclonal gammopathy was defined as a monoclonal protein present in the serum. Light chain MG was defined as an abnormal serum FLC κ/λ ratio with an elevated FLC level in the absence of a monoclonal protein. In patients with renal dysfunction, the renal FLC reference range was used. Results The mean age of the population was 75 years, 3 of the 113 patients (3%) were female, and 110 (97%) were white. Monoclonal gammopathy was present in 26 patients (23%), 24 of whom had monoclonal protein present and 2 others who met criteria for light chain MG. Most clones (12 of 20 [60%]) were λ restricted. Another 7 patients had an abnormal FLC κ/λ ratio in the setting of renal dysfunction. Conclusion In this study, MG was present in 23% of patients with ATTRwt. The finding of MG or an abnormal FLC κ/λ ratio in an elderly man may cause diagnostic confusion during subtyping of amyloidosis. A high degree of clinical suspicion for ATTRwt and precise tissue typing using mass spectrometry may overcome such diagnostic challenges.

ObjectivesTo examine relationships between cognitive expectancies about sleep and hypnotics and use of medications commonly used for insomnia (hypnotics).MethodsWe analyzed baseline data from older veterans who met diagnostic criteria for insomnia and were enrolled in a trial comparing CBTI delivered by a supervised, sleep educator to an attention control condition (N=159; 97% male, mean age 72years). We classified individuals as hypnotic users (N=23) vs. non-users (N=135) based upon medication diaries. Associations between hypnotic status and Dysfunctional Beliefs and Attitudes about Sleep-16 (DBAS) total score (0-10, higher=worse) and two DBAS medication item scores (Item 1: "…better off taking a sleeping pill rather than having a poor night's sleep;" Item 2: "Medication… probably the only solution to sleeplessness"; 0-10, higher=worse) were examined in logistic regression models.ResultsHigher scores on the DBAS medication items (both odds ratios=1.3; p-values < .001) were significantly associated with hypnotic use. DBAS-16 total score was not associated with hypnotic use.ConclusionCognitive expectancy (dysfunctional beliefs) about hypnotics was associated with hypnotic use in older adults with chronic insomnia disorder.Clinical implicationsStrategies that specifically target dysfunctional beliefs about hypnotics are needed and may impact hypnotic use in older adults.

Background Adult patients with Down syndrome (DS) are at higher risk of developing Alzheimer-type dementia and epilepsy. The relationship between developing dementia and the risk of developing seizures in DS is poorly characterized to date. In addition, treatment response and medication tolerability have not been rigorously studied. Methods We identified 220 patients with a diagnosis of DS and dementia. Those without a history of developing seizures (DD) were compared to patients with new-onset seizures (DD + S) after the age of 35. Electronic records were reviewed for demographics, seizure characteristics, cognitive status, and psychiatric comorbidities. Results Of the patients included for analysis, twenty-six out of 60 patients had new-onset seizures or developed seizures during the follow-up period (the DD + S group) with a median onset of 2.0 years after the dementia diagnosis. Generalized tonic–clonic seizures were the most common seizure type (61.5% of DD + S). Sixteen (61.5%) patients were reported to have myoclonus. Levetiracetam was the most commonly used initial medication, with the majority (73%) of patients treated achieving partial or complete seizure control. The DD + S patients tended to have a similar burden of new-onset neuropsychiatric symptoms compared to the DD group. Discussion New-onset epilepsy seems to occur early in the course of dementia in DS patients. Patients generally respond to treatment. A great burden of neuropsychiatric symptoms is seen. Future studies need to explore the relationship between β-amyloid accumulation and epileptiform activity and attend to the care and needs of DS patients with dementia and seizures.

Background\ud Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency.\ud \ud Methods\ud In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544.\ud \ud Findings\ud Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0–20] in the CBT plus standardised medical care group vs 7 seizures [1–35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56–1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference −0·53 [95% CI −0·97 to −0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference −4·12 [95% CI −6·35 to −1·89]; p

Background Long-term outcomes after face transplantation are rarely reported in the scientific literature. Here we present outcome data of a partial face allograft recipient 10 years after transplantation. Methods Medical records were reviewed for functional and psychosocial outcomes as well as complications. Histopathologic analyses of autopsy tissues and characterization of skin immune cells were performed. Results The patient retained long-term motor and sensory function, though with a noticeable drop in sensory function after year 5. Social reintegration of the patient was marked by reconnection with his family and participation in public social activities. Immunosuppressive therapy consisted of tacrolimus (target levels 6–8 ng/mL after the first year), mycophenolate, and prednisone, while steroids were completely weaned between years 1 and 7. One acute cellular rejection episode of grade II or higher occurred on average per year and led to chronic skin changes (papillary dermal sclerosis with superficial hyalinization, epidermal thinning with loss of rete ridges, perieccrine fibrosis), but the allograft vessels, muscles, adipose tissue, and bone were spared. Allograft skin was characterized by increased number of CD4+ TNF-α/IL17A producing T-cells as compared with native skin. Long-term kidney function was maintained at 60 mL/min estimated glomerular filtration rate. Unfortunately, the preexisting hepatitis C virus infection with liver cirrhosis was resistant to 3 treatments with new direct-acting antivirals and eventually hepatocellular carcinoma developed, causing the patient’s death 10 years after transplantation. Conclusion This report suggests that face transplants can maintain their function for at least 10 years. Chronic skin changes can occur independently of allograft vasculopathy.

Sex differences abound in human health and disease, as they do in other mammals used as models. The extent to which sex differences are conserved at the molecular level across species and tissues is unknown. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased expression-findings that, combined with genomic analyses of human height, explain ∼12% of the difference in height between females and males. We surmise that conserved sex biases in expression of genes otherwise operating equivalently in females and males contribute to sex differences in traits. However, most sex-biased expression arose during the mammalian radiation, which suggests that careful attention to interspecies divergence is needed when modeling human sex differences., National Institutes of Health (U.S.) (Grant R01HG007852), National Institutes of Health (U.S.) (Grant U01HG007857)

Background and Objectives: The formation of a fistula between the gastrointestinal tract and cardiovascular system is a rare but devastating condition. Although clinical diagnosis is suspected, autopsy confirmation is rarely obtained. Advancement in the treatment of esophageal cancer could result in an increased risk of enterovascular fistula formation. We describe autopsy-proven series of enterovascular fistulas with particular focus on this complication developing as a consequence of esophageal cancer therapy. Methods: Cases of enterovascular fistulas were retrospectively identified in the institutional autopsy case records (1994-2017). Relevant clinical information and pathologic findings were reviewed. Results: Nine cases were identified. Seven out of 9 were related to malignancy, with 6/9 occurring in the setting of treated esophageal carcinoma. This esophageal cancer group was a unique set of patients (age median: 71 years) with male predominance (M:F-5:1) presenting with hematemesis as the main symptom. All patients had advanced disease at diagnosis and the complication generally occurred late after treatment (mean interval: 1.7 years). The fistula site was between the esophagus and variety of vascular structures. The most common etiology was tumor invasion (4/6). The diagnosis of enterovascular fistula was made postmortem in all cases. Conclusions: The development of enterovascular fistulas is a late complication of treated esophageal cancer. Tumor invasion, infection, and radiation response are the leading etiologies. Early recognition and aggressive treatment may salvage this highly morbid complication.

Leaflet thrombosis is currently one of the greatest concerns related to transcatheter aortic valve replacement (TAVR). Symptomatic valve thrombosis is a rare occurrence, but reduced leaflet motion, diagnosed by computed tomography, seems to be a more common finding [(1)][1]. We screened our

Purpose Female veterans are at high risk for sleep problems, and there is a need to provide effective treatment for this population who experience insomnia. This study’s primary goal was to compare the acceptability of medication versus nonmedication treatments for insomnia among female veterans. In addition, we examined the role of patient age, severity of sleep disturbance, and psychiatric symptoms on acceptability of each treatment approach and on the differences in acceptability between these approaches. Methods A large nationwide postal survey was sent to a random sample of 4000 female veterans who had received health care at a Veterans Administration (VA) facility in the previous 6 months (May 29, 2012–November 28, 2012). A total of 1559 completed surveys were returned. Survey items used for the current analyses included: demographic characteristics, sleep quality, psychiatric symptoms, military service experience, and acceptability of medication and nonmedication treatments for insomnia. For analysis, only ratings of “very acceptable” were used to indicate an interest in the treatment approach (vs ratings of “not at all acceptable,” “a little acceptable,” “somewhat acceptable,” and “no opinion/don׳t know”). Findings In the final sample of 1538 women with complete data, 57.7% rated nonmedication treatment as very acceptable while only 33.5% rated medication treatment as very acceptable. This difference was statistically significant for the group as a whole and when examining subgroups of patients based on age, sleep quality, psychiatric symptoms, and military experience. The percentage of respondents rating medication treatment as very acceptable was higher for women who were younger, had more severe sleep disturbances, had more psychiatric symptoms, who were not combat exposed, and who had experienced military sexual trauma. By contrast, the percentage of respondents rating nonmedication treatment as very acceptable differed only by age (younger women were more likely to find nonmedication treatment acceptable) and difficulty falling asleep. Implications Female veterans are more likely to find nonmedication insomnia treatment acceptable compared with medication treatment. Thus, it is important to match these patients with effective behavioral interventions such as cognitive behavioral therapy for insomnia. Efforts to educate providers about these preferences and about the efficacy of cognitive behavioral therapy for insomnia may serve to connect female veterans who have insomnia to the treatment they prefer. These findings also suggest that older female veterans may be less likely to find either approach as acceptable as their younger counterparts.

Pericardial effusion can cause cardiac tamponade physiology with resultant cardiogenic shock and death. Myelofibrosis, the replacement of marrow cavity by fibrous connective tissue, is a secondary complication of a group of disorders known as myeloproliferative neoplasms, which are clonal processes characterized by abnormal proliferative growth of one or more hematopoietic lineages. One consequence of myelofibrosis is the development of hematopoiesis at other anatomic sites, most commonly the spleen and liver, a phenomenon known as extramedullary hematopoiesis (EMH). Herein we report a case of a man who died from pericardial tamponade due to a subacute pericardial effusion secondary to EMH in the pericardium in the setting of myelofibrosis. This case highlights an unusual etiology for pericardial effusion and tamponade that should be considered in cases of myelofibrosis and stimulates a discussion regarding the mechanisms and anatomic distribution of EMH.

Objectives To test a new cognitive behavioral therapy for insomnia (CBT-I) program designed for use by nonclinicians. Design Randomized controlled trial. Setting Department of Veterans Affairs healthcare system. Participants Community-dwelling veterans aged 60 and older who met diagnostic criteria for insomnia of 3 months duration or longer (N = 159). Intervention Nonclinician “sleep coaches” delivered a five-session manual-based CBT-I program including stimulus control, sleep restriction, sleep hygiene, and cognitive therapy (individually or in small groups), with weekly telephone behavioral sleep medicine supervision. Controls received five sessions of general sleep education. Measurements Primary outcomes, including self-reported (7-day sleep diary) sleep onset latency (SOL-D), wake after sleep onset (WASO-D), total wake time (TWT-D), and sleep efficiency (SE-D); Pittsburgh Sleep Quality Index (PSQI); and objective sleep efficiency (7-day wrist actigraphy, SE-A) were measured at baseline, at the posttreatment assessment, and at 6- and 12-month follow-up. Additional measures included the Insomnia Severity Index (ISI), depressive symptoms (Patient Health Questionnaire-9 (PHQ-9)), and quality of life (Medical Outcomes Study 12-item Short-form Survey version 2 (SF-12v2)). Results Intervention subjects had greater improvement than controls between the baseline and posttreatment assessments, the baseline and 6-month assessments, and the baseline and 12-month assessments in SOL-D (−23.4, −15.8, and −17.3 minutes, respectively), TWT-D (−68.4, −37.0, and −30.9 minutes, respectively), SE-D (10.5%, 6.7%, and 5.4%, respectively), PSQI (−3.4, −2.4, and −2.1 in total score, respectively), and ISI (−4.5, −3.9, and −2.8 in total score, respectively) (all P < .05). There were no significant differences in SE-A, PHQ-9, or SF-12v2. Conclusion Manual-based CBT-I delivered by nonclinician sleep coaches improves sleep in older adults with chronic insomnia.

Ketamine is a rapidly acting antidepressant in patients with treatment-resistant depression (TRD). Although the mechanisms underlying these effects are not fully established, inquiry to date has focused on the triggering of synaptogenesis transduction pathways via glutamatergic mechanisms. Preclinical data suggest that blockade of metabotropic glutamate (mGlu2/3) receptors shares many overlapping features and mechanisms with ketamine and may also provide rapid efficacy for TRD patients. Central dopamine circuitry is recognized as an end target for mood regulation and hedonic valuation and yet has been largely neglected in mechanistic studies of antidepressant-relevant effects of ketamine. Herein, we evaluated the changes in dopaminergic neurotransmission after acute administration of ketamine and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid ] in preclinical models using electrophysiologic, neurochemical, and behavioral endpoints. When given acutely, both ketamine and LY341495, but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increased the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), increased extracellular levels of dopamine in the nucleus accumbens and prefrontal cortex, and enhanced the locomotor stimulatory effects of the dopamine D2/3 receptor agonist quinpirole. Further, both ketamine and LY341495 reduced immobility time in the tail-suspension assay in CD1 mice, which are relatively resistant to SSRI antidepressants. Both the VTA neuronal activation and the antidepressant phenotype induced by ketamine and LY341495 were attenuated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo- (9CI)-benzo[f]quinoxaline-7-sulfonamide, indicating AMPA-dependent effects. These findings provide another overlapping mechanism of action of ketamine and mGlu2/3 receptor antagonism that differentiates them from conventional antidepressants and thus support the potential rapidly acting antidepressant actions of mGlu2/3 receptor antagonism in patients.

The purpose of this article is to examine two evidence-based models of case management for people with co-occurring disorders and histories of chronic homelessness and to better understand their roles in permanent supported housing. Critical Time Intervention and Assertive Community Treatment are examined in terms of key elements, how they assist in ending homelessness, as well as the role they play in an individual's recovery from co-occurring disorders.Participants in two supported housing programs were interviewed at baseline and 6 months. One program used Critical Time Intervention (n = 144) and the other used Assertive Community Treatment (n = 90). Staff in both programs were interviewed about their experiences and fidelity assessments were conducted for each program.Both programs operated at high levels of fidelity. Despite similar criteria for participation, there were significant differences between groups. Critical Time Intervention participants were older, were more likely to be male, were more likely to be homeless, and reported greater psychiatric symptoms and higher levels of substance use (all p's.001). Separate outcome analyses suggested that each program was successful in supporting people to transition from homelessness to stable housing; 88.6% of Assertive Community Treatment participants were homeless at baseline, while at 6 months 30% were homeless (p.001), and 91.3% of those in the Critical Time Intervention were homeless at baseline, while 44.3% were homeless at 6 months (p.001). Participants in the Critical Time Intervention program also showed significant decreases in alcohol use, drug use, and psychiatric symptoms (all p's.01). The preliminary results suggest that each case management model is helpful in assisting people with complex behavioral health needs and chronic homelessness to move to stable housing.Permanent supported housing seems to be an effective way to end homelessness among people with co-occurring disorders. Further research is needed to determine which case management models work most effectively with supported housing to help policy makers and program directors make informed decisions in developing these programs.

Anopheles mosquitoes have transmitted Plasmodium parasites for millions of years, yet it remains unclear whether they suffer fitness costs to infection. Here we report that the fecundity of virgin and mated females of two important vectors—Anopheles gambiae and Anopheles stephensi—is not affected by infection with Plasmodium falciparum, demonstrating that these human malaria parasites do not inflict this reproductive cost on their natural mosquito hosts. Additionally, parasite development is not impacted by mating status. However, in field studies using different P. falciparum isolates in Anopheles coluzzii, we find that Mating-Induced Stimulator of Oogenesis (MISO), a female reproductive gene strongly induced after mating by the sexual transfer of the steroid hormone 20-hydroxyecdysone (20E), protects females from incurring fecundity costs to infection. MISO-silenced females produce fewer eggs as they become increasingly infected with P. falciparum, while parasite development is not impacted by this gene silencing. Interestingly, previous work had shown that sexual transfer of 20E has specifically evolved in Cellia species of the Anopheles genus, driving the co-adaptation of MISO. Our data therefore suggest that evolution of male-female sexual interactions may have promoted Anopheles tolerance to P. falciparum infection in the Cellia subgenus, which comprises the most important malaria vectors., Author summary Plasmodium falciparum, the deadliest form of human malaria, is transmitted when female Anopheles mosquitoes bite people and take a blood meal in order to develop eggs. To date, it is still poorly understood whether Anopheles mosquitoes that get infected with P. falciparum suffer fitness costs. Here, we find that the number of eggs produced by Anopheles gambiae and Anopheles stephensi females is not affected by P. falciparum infection, and that the mating status of the mosquitoes does not impact the parasite. However, in field experiments infecting a related species, Anopheles coluzzii, with P. falciparum using blood from donors in Burkina Faso, we find that interfering with the expression of a gene normally triggered by the sexual transfer of the steroid hormone 20-hydroxyecdysone induces increasing costs to egg development as females become more infected with P. falciparum, with no impacts on the parasite. The results of our study suggest that pathways triggered by mating may help Anopheles prevent reproductive costs associated with P. falciparum infection, providing new insights into evolutionary strategies adopted by anophelines in the face of a longstanding association with Plasmodium parasites.

Background Sudden cardiac death ( SCD ) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex‐ and coronary artery disease–stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval–associated single‐nucleotide polymorphism, rs12143842 (in the NOS 1 AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non‐ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate ( P =0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [U19AI110818]; USDA [2017-05741]; NIH Intramural Research Program; National Library of Medicine; National Human Genome Research Institute; NSF [PHY-1427654]; NIH [R01AI101112, R35GM118336, R21AI121853, R01AI123338, T32GM007739, NIH/NCATS UL1TR000043, DP2OD008540, U01AI088647, 1R01AI121211, D43TW001130-08, U01HL130010, UM1HG009375, 5K22AI113060, 1R21AI123937, R00DC012069]; Defence Advanced Research Project Agency [HR0011-17-2-0047]; Jane Coffin Childs Memorial Fund; Center for Theoretical Biological Physics postdoctoral fellowship; Robertson Foundation; McNair Foundation; Welch Foundation [Q-1866]; French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID]; Agence Nationale de la Recherche [ANR-17-ERC2-0016-01]; European Union [734584]; Pew and Searle Scholars Programs; Klingenstein-Simons Fellowship in the Neurosciences; Verily Life Sciences We thank R. Andino; S. Emrich and D. Lawson (Vectorbase); A. A. James, M. Kunitomi, C. Nusbaum, D. Severson, N. Whiteman; T. Dickinson, M. Hartley and B. Rice (Dovetail Genomics) for early participation in the AGWG; C. Bargmann, D. Botstein, E. Jarvis and E. Lander for encouragement and facilitation. N. Keivanfar, D. Jaffe and D. M. Church (10X Genomics) prepared DNA for structural-variant analysis. We thank A. Harmon of the New York Times and acknowledge generous pro bono data and analysis from our corporate collaborators. This research was supported in part by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant number U19AI110818 to the Broad Institute (S.N.R. and D.E.N.); USDA 2017-05741 (E.L.A.); NSF PHY-1427654 Center for Theoretical Biological Physics (E.L.A.); NIH Intramural Research Program, National Library of Medicine and National Human Genome Research Institute (A.M.P. and S.K.) and the following extramural NIH grants: R01AI101112 (J.R.P.), R35GM118336 (R.S.M. and W.J.G.), R21AI121853 (M.V.S., I.V.S. and A. S.), R01AI123338 (Z.T.), T32GM007739 (M.H.), NIH/NCATS UL1TR000043 (Rockefeller University), DP2OD008540 (E.L.A.), U01AI088647, 1R01AI121211 (W.C.B. IV), Fogarty Training Grant D43TW001130-08, U01HL130010 (E.L.A.), UM1HG009375 (E.L.A), 5K22AI113060 (O.S.A.), 1R21AI123937 (O.S.A.), and R00DC012069 (C.S.M.); Defence Advanced Research Project Agency: HR0011-17-2-0047 (O.S.A.). Other support was provided by Jane Coffin Childs Memorial Fund (B.J.M.), Center for Theoretical Biological Physics postdoctoral fellowship (O.D.), Robertson Foundation (L.Z.), and McNair & Welch (Q-1866) Foundations (E.L.A.), French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (grant ANR-10-LABX-62-IBEID to L.L.), Agence Nationale de la Recherche grant ANR-17-ERC2-0016-01 (L.L.), European Union's Horizon 2020 research and innovation program under ZikaPLAN grant agreement no. 734584 (L.L.), Pew and Searle Scholars Programs (C.S.M.), Klingenstein-Simons Fellowship in the Neurosciences (C.S.M.). A.M.W., B.J.W., J.E.C. and S.N.M. were supported by Verily Life Sciences. L.B.V. is an investigator of the Howard Hughes Medical Institute.

Objective/backgroundTo identify caregiving-related sleep problems and their relationship to mental health and daytime function in female Veterans.ParticipantsFemale Veterans (N = 1,477) from cross-sectional, nationwide, postal survey data.MethodsThe survey respondent characteristics included demographics, comorbidity, physical activity, health, use of sleep medications, and history of sleep apnea. They self-identified caregiving- related sleep problems (i.e., those who had trouble sleeping because of caring for a sick adult, an infant/child, or other respondents). Patient Health Questionnaire (PHQ-4) was used to assess mental health, and daytime function was measured using 11 items of International Classification of Sleep Disorders-2 (ICSD-2).ResultsFemale Veterans with self-identified sleep problems due to caring for a sick adult (n = 59) experienced significantly more symptoms of depression and anxiety (p < 0.001) and impairment in daytime function (e.g., fatigue, daytime sleepiness, loss of concentration, p < 0.001) than those with self-identified sleep problems due to caring for an infant or child (n = 95) or all other respondents (n = 1,323) after controlling for the respondent characteristics.ConclusionsHealthcare providers should pay attention to assessing sleep characteristics of female Veterans with caregiving responsibilities, particularly those caregiving for a sick adult.

Home-based primary care (HBPC) is a comprehensive, interdisciplinary program to meet the medical needs of community-dwelling populations needing long-term care (LTC). The U.S. Department of Veterans Affairs (VA) expanded its HBPC program to underserved rural communities, including American Indian reservations, providing a "natural laboratory" to study change in access to VA LTC benefits and utilization outcomes for rural populations that typically face challenges in accessing LTC medical support.Pretest-Posttest quasi-experimental approach with interrupted time-series design using linked VA, Medicare, and Indian Health Service (IHS) records.American Indian reservations and non-Indian communities in rural HBPC catchment areas.376 veterans (88 IHS beneficiaries, 288 non-IHS beneficiaries) with a HBPC length of stay of 12 months or longer.Baseline demographic and health characteristics, activities of daily living (ADL), previous VA enrollment, and hospital admissions and emergency department (ED) visits as a function of time, accounting for IHS beneficiary and functional statuses.For HBPC users, VA enrollment increased by 22%. At baseline, 30% of IHS and non-IHS beneficiaries had 2 or more ADLs impairments; IHS populations were younger (P .001) and had more diagnosed chronic diseases (P = .007). Overall, hospital admissions decreased by 0.10 (95% confidence interval (CI) = -0.14 to -0.05) and ED visits decreased by 0.13 (95% CI = -0.19 to -0.07) in the 90 days after HBPC admission (Ps .001) and these decreases were maintained over 1 year follow-up. Before HBPC, probability of hospital admission was 12% lower for IHS than non-IHS beneficiaries (P = .02).Introducing HBPC to rural areas increased access to LTC and enrollment for healthcare benefits, with equitable outcomes in IHS and non-IHS populations.

STUDY OBJECTIVES: Sleep quality is poor among patients with chronic obstructive pulmonary disease (COPD), and studies show that sleep disturbance is associated with low overall quality of life in this population. We evaluated the impact of patient-reported sleep quality and sleep apnea risk on disease-specific and overall quality of life within patients with COPD enrolled in the SPIROMICS study, after accounting for demographics and COPD disease severity. METHODS: Baseline data from 1341 participants [892 mild/moderate COPD (FEV(1) ≥ 50% predicted); 449 severe COPD (FEV(1) < 50%)] were used to perform three nested (blocks) regression models to predict quality of life (Short Form-12 mental and physical components and St. George’s Respiratory Questionnaire). Dependent measures used for the nested regressions included the following: Block1: demographics and smoking history; Block 2: disease severity (forced expiratory volume 1 s; 6 min walk test); Block 3: risk for obstructive sleep apnea (OSA; Berlin questionnaire); and Block 4: sleep quality (Pittsburgh Sleep Quality Index [PSQI]). RESULTS: Over half of participants with COPD reported poor sleep quality (Mean PSQI 6.4 ± 3.9; 50% with high risk score on the Berlin questionnaire). In all three nested regression models, sleep quality (Block 4) was a significant predictor of poor quality of life, over and above variables included in blocks 1–3. CONCLUSIONS: Poor sleep quality represents a potentially modifiable risk factor for poor quality of life in patients with COPD, over and above demographics and smoking history, disease severity, and risk for OSA. Improving sleep quality may be an important target for clinical interventions. CLINICAL TRIAL: SPIROMICS CLINICAL TRIAL URL: http://www2.cscc.unc.edu/spiromics/ CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01969344

OBJECTIVES:This study compared subjective (questionnaire) and objective (actigraphy) sleep assessments, and examined agreement between these methods, in vulnerable older adults participating in a Veterans Administration Adult Day Health Care (ADHC) program. METHODS:59 ADHC participants (95% male, mean age=78years) completed sleep questionnaires and 72 continuous hours of wrist actigraphy. Linear regression was used to examine agreement between methods and explore discrepancies in subjective/objective measures. RESULTS:Disturbed sleep was common, yet there was no agreement between subjective and objective sleep assessment methods. Compared with objective measures, one-half of participants reported worse sleep efficiency (SE) on questionnaires while one-quarter over-estimated SE. Participants reporting worse pain had a greater discrepancy between subjective and objective SE. CONCLUSIONS:Vulnerable older adults demonstrated unique patterns of reporting sleep quality when comparing subjective and objective methods. Additional research is needed to better understand how vulnerable older adults evaluate sleep problems. CLINICAL IMPLICATIONS:Objective and subjective sleep measures may represent unique and equally important constructs in this population. Clinicians should consider utilizing both objective and subjective sleep measures to identify individuals who may benefit from behavioral sleep treatments, and future research is needed to develop and validate appropriate sleep assessments for vulnerable older adults.

Deep brain stimulation (DBS) of the fornix has gained interest as a potential therapy for advanced treatment-resistant dementia, yet the mechanism of action remains widely unknown. Previously, we have reported beneficial memory effects of fornix DBS in a scopolamine induced rat model of dementia, which is dependent on various brain structures including hippocampus. To elucidate mechanisms of action of fornix DBS with regard to memory restoration, we performed c-Fos immunohistochemistry in the hippocampus. We found that fornix DBS induced a selective activation of cells in the CA1 and CA3 subfields of the dorsal hippocampus. In addition, hippocampal neurotransmitter levels were measured using microdialysis before, during and after 60 min of fornix DBS in a next experiment. We observed a substantial increase in the levels of extracellular hippocampal acetylcholine, which peaked 20 min after stimulus onset. Interestingly, hippocampal glutamate levels did not change compared to baseline. Therefore, our findings provide first experimental evidence that fornix DBS activates the hippocampus and induces the release of acetylcholine in this region. Publisher PDF

Objective The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE). Methods This randomized, double-blind, single-dose, dose-escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004–5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5–60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1. Results Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose-proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657. Conclusion Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE.

Mating plugs promote malaria parasites Males of some of the malaria-transmitting mosquitoes “plug” females after copulation to stop interloping males from mating. The mating plug also delivers a steroid hormone into the female uterus. This hormone pulse promotes egg production and stimulates egg laying. It also curbs the mosquitoes' immune responses, which allows parasites such as malaria to develop unhindered. Mitchell et al. discovered that plugs are a recent evolutionary acquisition (see the Perspective by Alonzo). South American anopheline mosquitoes lack these plugs altogether, whereas African and Indian species have complex plugs replete with hormones. It is unlikely to be a coincidence that the most elaborate mosquito plugs are also found in regions where malaria transmission rates are highest. Science , this issue p. 985 ; see also p. 948

Background Recent interest in male-based sterile insect technique (SIT) and incompatible insect technique (IIT) to control Aedes aegypti and Aedes albopictus populations has revealed the need for an economical, rapid diagnostic tool for determining dispersion and mating success of sterilized males in the wild. Previous reports from other insects indicated rhodamine B, a thiol-reactive fluorescent dye, administered via sugar-feeding can be used to stain the body tissue and seminal fluid of insects. Here, we report on the adaptation of this technique for male Ae. aegypti to allow for rapid assessment of competitiveness (mating success) during field releases. Methodology/Principle findings Marking was achieved by feeding males on 0.1, 0.2, 0.4 or 0.8% rhodamine B (w/v) in 50% honey solutions during free flight. All concentrations produced >95% transfer to females and successful body marking after 4 days of feeding, with 0.4 and 0.8% solutions producing the longest-lasting body marking. Importantly, rhodamine B marking had no effect on male mating competitiveness and proof-of-principle field releases demonstrated successful transfer of marked seminal fluid to females under field conditions and recapture of marked males. Conclusions/Significance These results reveal rhodamine B to be a potentially useful evaluation method for male-based SIT/IIT control strategies as well as a viable body marking technique for male-based mark-release-recapture experiments without the negative side-effects of traditional marking methods. As a standalone method for use in mating competitiveness assays, rhodamine B marking is less expensive than PCR (e.g. paternity analysis) and stable isotope semen labelling methods and less time-consuming than female fertility assays used to assess competitiveness of sterilised males., Author summary The recent resurgence in male-based “rear and release” strategies (release of radiation sterilised males or those harbouring Wolbachia) to control diseases transmitted by urban Aedes mosquitoes, including dengue, chikungunya, and Zika, has revealed the need for an economical and rapid diagnostic tool to assess the mating competitiveness of released males against wild counterparts for receptive females. Our report details the optimisation of rhodamine B labelling of male seminal fluid and visible body staining via sugar-feeding with no significant impact on survival or mating competitiveness, as well as proof-of-principle field releases. These results reveal rhodamine B labelling to be an economical and rapid evaluation method for male-based control strategies as well as a viable body marking technique for male focused mark-release-recapture experiments without the negative side-effects of traditional marking methods. The use of this method has the potential to enable operators to determine the efficacy of their control method quickly and easily, allowing them to optimise releases to achieve optimal population suppression.

Invasive fungal diseases of the heart are rare, frequently fatal causes of cardiac masses. On imaging, they are difficult to distinguish from other entities, such as thrombi or tumors. The combined use of multiple imaging modalities can aid in diagnosis when integrated with clinical data.1 However, no imaging findings are pathognomonic for invasive fungal disease. We report 4 cases of invasive fungal disease of the heart. Two patients had undergone solid organ transplantation, another had myelodysplastic syndrome, and one was an intravenous drug user. Two patients had invasive aspergillosis, one with valvular endocarditis and another with an intramyocardial abscess, whereas 2 patients had mucormycosis and candidiasis, respectively. Although fungal infections do not have robust central perfusion on cardiac magnetic resonance imaging (a feature of many malignant masses), they often demonstrate delayed peripheral enhancement around the mass, a nonspecific feature suggestive of an infectious cause.2 A 26-year-old woman with cystic fibrosis, status-post bilateral lung transplantation presented with skin lesions and a positive Galactomannan assay concerning for disseminated aspergillosis. She …

Study Objective To test the effectiveness of a 4-week behavioral Sleep Intervention Program (SIP: sleep compression, modified stimulus control, and sleep hygiene) compared to a 4-week information-only control (IC) among older adults attending a VA Adult Day Health Care (ADHC) program in a double-blind, randomized, clinical trial. Methods Forty-two individuals (mean age: 77 years, 93% male) enrolled in a VA ADHC program were randomized to receive SIP or IC. All completed in-person sleep and health assessments at baseline, post-treatment and 4-months follow-up that included 3 days/nights of wrist actigraphy, the Pittsburgh Sleep Quality Index (PSQI), and the Insomnia Severity Index (ISI). Mixed repeated measures analysis was used to compare sleep outcomes at post-treatment and 4-months follow-up, with baseline values as covariates. Results SIP participants (n = 21) showed significant improvement on actigraphy sleep efficiency (p = .007), number of nighttime awakenings (p = .016), and minutes awake at night (p = .001) at post-treatment, compared to IC participants (n = 21). Benefits were slightly attenuated but remained significant at 4-month follow-up (all p's < .05). There were no differences in total sleep time between groups. There was significant improvement on PSQI factor 3 (daily disturbances) at 4-month follow-up (p = .016), but no differences were observed between SIP and IC on other PSQI components or ISI scores at post-treatment or 4-month follow-up. Conclusions A short behavioral sleep intervention may have important benefits in improving objectively measured sleep in older adults participating in ADHC. Future studies are needed to study implementation of this intervention into routine clinical care within ADHC.

DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond to D1 agonists. Because of a species difference in affinity for DETQ, all rodent experiments used transgenic mice expressing the human D1 receptor (hD1 mice). When given alone, DETQ reversed the locomotor depression caused by a low dose of reserpine. DETQ also acted synergistically with L-DOPA to reverse the strong hypokinesia seen with a higher dose of reserpine. These results indicate potential as both monotherapy and adjunct treatment in Parkinson's disease. DETQ markedly increased release of both acetylcholine and histamine in the prefrontal cortex, and increased levels of histamine metabolites in the striatum. In the hippocampus, the combination of DETQ and the cholinesterase inhibitor rivastigmine increased ACh to a greater degree than either agent alone. DETQ also increased phosphorylation of the AMPA receptor (GluR1) and the transcription factor CREB in the striatum, consistent with enhanced synaptic plasticity. In the Y-maze, DETQ increased arm entries but (unlike a D1 agonist) did not reduce spontaneous alternation between arms at high doses. DETQ enhanced wakefulness in EEG studies in hD1 mice and decreased immobility in the forced-swim test, a model for antidepressant-like activity. In rhesus monkeys, DETQ increased spontaneous eye-blink rate, a measure that is known to be depressed in Parkinson's disease. Together, these results provide support for potential utility of D1 potentiators in the treatment of several neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, cognitive impairment in schizophrenia, and major depressive disorder.

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11b(DTR) mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

pii: zsw007 http://dx.doi.org/10.1093/sleep/zsx007 ORIGINAL ARTICLE Patient-Reported Usability of Positive Airway Pressure Equipment Is Associated With Adherence in Older Adults Constance H. Fung, MD, MS 1,2 ; Jennifer L. Martin, PhD 1,2 ; Ron D. Hays, PhD 2 ; Emily S. Patterson, PhD 3 ; Ravi Aysola, MD 2 ; Nananda Col, MD, MPP, MPH 4 ; Michael N. Mitchell, PhD 1 ; Cindy Truong, BS 1 ; Joseph M. Dzierzewski, PhD 1,5 ; Stella Jouldjian, MSW, MPH 1 ; Yeonsu Song, PhD, RN 1,2 ; Juan Carlos Rodriguez, MD, MPH 2,6 ; Karen Josephson, MPH 1 ; Cathy Alessi, MD 1,2 Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California; 2 Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; 3 School of Health and Rehabilitation Sciences, Ohio State University, Columbus, Ohio; 4 University of New England, Biddeford, Maine; Department of Psychology, Virginia Commonwealth University, Richmond, Virginia; 6 Pontificia Universidad Catolica de Chile, Santiago, Chile Study objectives: To examine the usability of positive airway pressure (PAP) devices and its association with PAP adherence among older adults with sleep-disordered breathing. Methods: We mailed questionnaires to patients aged ≥65 years prescribed PAP therapy during the prior 36 months from two large healthcare systems. Survey participants completed the Usability of Sleep Apnea Equipment-Positive Airway Pressure (USE-PAP) questionnaire, which assessed the usability of their PAP device. Other questionnaire items included demographics and self-rated health. We also abstracted adherence data (mean nightly hours of PAP use available from one site) and interface type from the electronic health record. Results: Five hundred sixty-four patients completed the survey (response rate = 33%). The mean USE-PAP score (0 = best to 100 = worst) was 20 (SD ± 20). Mean duration of PAP use (available in 189 respondents) was 5.2 hours per night (SD ± 2.0). In a nested regression model predicting nightly hours of PAP use, a 10-point (0.5 SD) increase in USE-PAP score corresponded to a 0.37 hour/night reduction in PAP use. The model including the USE-PAP score explained a signifi- cant proportion (R 2 = 15%) of the variation in nightly hours of PAP use above and beyond demographics, self-reported health, and interface type (∆R 2 = 12%). Conclusions: Our results demonstrate that PAP usability varies among older patients and is associated with PAP adherence, above and beyond other predic- tors of adherence. These results support measuring and improving PAP usability to further improve PAP adherence for older patients. Keywords: sleep apnea, adherence, usability, predictive modeling. Statement of Significance We conducted a survey to collect data on patient-reported usability of positive airway pressure (PAP) equipment among older patients, who may be more susceptible to user-device interaction design issues. We found variations in usability issues and showed that usability is significantly associated with PAP adherence. Patient-reported usability is not generally assessed in clinical practice. Because device usability may be a modifiable risk-factor for interventions aimed at improving PAP adherence, we recommend assessing patients’ beliefs about and experiences with PAP usability. INTRODUCTION Positive airway pressure (PAP) therapy is the most commonly prescribed treatment for sleep-disordered breathing (SDB). 1 Although PAP is an efficacious therapy for reducing the apnea-hypopnea index (AHI), many patients are non-adherent to PAP therapy, with estimates of non-adherence ranging from 28% to 60%. 2,3 Research on PAP non-adherence has focused on psychosocial factors (e.g., outcome expectancies, self-effi- cacy beliefs, socioeconomic characteristics), disease charac- teristics (e.g., AHI, sleepiness), technical aspects of devices such as interface type (i.e., nasal pillows versus nasal mask ver- sus full face mask), device modality/titration procedure (e.g., auto-titrating, continuous versus bi-level), and side effects (e.g., claustrophobia, irritation). 3 One category of barriers that has received little attention is the usability of PAP devices. 4–6 Device usability refers to design factors that impact inter- actions between individuals and devices. 7 The International Organization for Standardization defines usability as “the effec- tiveness, efficiency and satisfaction with which specified users achieve specified goals in particular environments.” 8 Usability may impact the accuracy and completeness with which patients achieve PAP therapy goals such as putting on a PAP mask, the resources expended to achieve these goals, the ease of learning how to use the PAP device, the ease of remembering how to use the device, and the degree to which the user finds the device acceptable and pleasant. 9 Beneficial outcomes of optimizing usability characteristics of medical devices include minimizing SLEEP, Vol. 40, No. 3, 2017 risk of error and ensuring device safety (i.e., promoting use of the device in a manner that does not result in harm to the patient or environment). 9 Usability test results are submitted to the Food and Drug Administration (FDA) during the pre-market device approval process. 9 In addition to impacting device safety, usability has the poten- tial to impact PAP adherence, which in turn may contribute to the overall impact that PAP has on health outcomes. 10,11 Making PAP easier to set up, use, and clean may positively affect adher- ence to therapy. Large-scale surveys of the usability of PAP devices are lacking, even though interviews with patients about their experiences with these devices suggest variability in PAP usability across patients. 5 Older adults may be more likely to experience usability problems due to the higher prevalence of physical and sensory impairments that occur with advanced age. In this study, we sought to measure PAP usability and to eval- uate the associations between PAP usability and PAP adherence among older adult patients prescribed PAP therapy for SDB. We hypothesized there would be a considerable range of PAP usability scores and that usability scores would be associated with adherence to PAP. METHODS Conceptual Model The FDA’s model for medical device usability, 9 which is based upon the International Organization for Standardization Patient-Reported PAP Usability and Adherence—Fung et al.

The Fall Prevention Center of Excellence designed three progressive-intensity fall prevention program models, Increasing Stability Through Evaluation and Practice (InSTEP), to reduce risk in community-dwelling older adults. Each model included physical activity, medical risk, and home safety components and was implemented as a 12-week program for small class sizes (12–15 people) in community and senior centers. Change in fall rates and fall risk factors was assessed using a battery of performance tests, self-reports of function, and fall diaries in a 3-group within-subjects (N = 200) design measured at baseline, immediately postintervention, and at 3 and 9 months postintervention. Overall, participants experienced a reduction in falls, improved self-perception of gait and balance, and improved dynamic gait function. The medium-intensity InSTEP model signifcantly (p = .003) reduced self-reported falls in comparison with the other models. InSTEP is a feasible model for addressing fall risk reduction in community-dwelling older adults.

Background— Cardiomyocyte hypertrophy is a critical precursor to the development of heart failure. Methods to phenotype cellular hypertrophy noninvasively are limited. The goal was to validate a cardiac magnetic resonance–based approach for the combined assessment of extracellular matrix expansion and cardiomyocyte hypertrophy. Methods and Results— Two murine models of hypertension (n=18, with n=15 controls) induced by l - N G -nitroarginine methyl ester (L-NAME) and pressure overload (n=11) from transaortic constriction (TAC) were imaged by cardiac magnetic resonance at baseline and 7 weeks after L-NAME treatment or up to 7 weeks after TAC. T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water ( τ ic ), a cell size–dependent parameter, and extracellular volume fraction, a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Cardiomyocyte diameter and length were measured on FITC–wheat germ agglutinin–stained sections. The τ ic correlated strongly with histological cardiomyocyte volume-to-surface ratio ( r =0.78, P r =0.75, P P ic between 2 and 7 weeks after TAC. Conclusion— The τ ic measured by contrast-enhanced cardiac magnetic resonance provides a noninvasive measure of cardiomyocyte hypertrophy. Extracellular volume fraction and τ ic can track myocardial tissue remodeling from pressure overload.

6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow. LY3130481 disrupted food-maintained responding in rats and spontaneous alternation in a Y-maze in mice. In rat fear conditioning, LY3130481 caused a deficit in trace (hippocampal-dependent), but not in delay fear conditioning. Although these effects on cognitive performances were observed, the known cognitive-impairing anticonvulsant, topiramate, did not always produce deficits under these assay conditions. LY3130481 produced modest increases in wake times in rats. In addition, LY3130481 was able to attenuate some impairing effects of standard antiepileptic drugs. The motor-impairing effects of the lacosamide were attenuated by LY3130481 as was the decrease in non-rapid-eye movement sleep induced by carbamazepine. Evaluation of the effect of LY3130481 on neurotransmitter and metabolite efflux in the rat medial prefrontal cortex, using in vivo microdialysis, revealed significant increases in the pro-cognitive and wake-promoting neurotransmitters, histamine and acetylcholine, as well as in serotonin, telemethylhistamine, 5-HIAA, HVA and MHPG. LY3130481 thus presents a novel behavioral profile that will have to be evaluated in patients to fully appreciate its implications for therapeutics. LY3130481 is currently under clinical development as CERC-611 as an antiepileptic.