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Atherosclerosis of the aorta is associated with increased risk of cardiovascular mortality and vascular events. We aim to describe the prevalence and distribution of non-calcified atherosclerotic plaque in the descending aorta as quantified by noncontrast cardiovascular magnetic resonance (CMR) in a community-dwelling cohort of adults.We used CMR to quantify noncalcified aortic plaque in 1726 participants (aged 65 ± 9 years, 46.7% men) from the Cohort Study Offspring cohort. ECG-gated, fat-suppressed, T2-weighted, black blood turbo spin echo sequence was used to acquire 36 transverse slices covering the descending aorta from just below the arch to the aortoiliac bifurcation. Plaque was defined as discrete luminal protrusions ≥1 mm; these were manually traced, then summed to determine total descending aortic plaque (DAP) and segmental thoracic and abdominal aortic plaque (TAP, AAP). Participants were stratified by sex and age group (55, 55-64, 65-74, ≥75y). A healthy referent group (without clinical cardiovascular disease, smoking, diabetes, impaired renal function; (N = 768, 43.8% men) was used to determine upper 90th percentile cutpoints for DAP and AAP which were then applied to the overall study cohort.Prevalence of DAP was similar between men (47.3%) and women (48.9%), p = 0.50, as was AAP prevalence (men: 44.5%, women: 46.7%, p = 0.16); TAP was less prevalent in both sexes (men: 8.9%, women: 7.1%, p = 0.15). Both prevalence and burden of DAP, AAP and TAP increased with advancing age.Noncalcified plaque prevalence, visualized on CMR, in community-dwelling adults is similar between the sexes, and both prevalence and burden of aortic plaque increase with greater age.

The association of mitral regurgitation (MR) severity and mortality in heart failure with preserved ejection fraction (HFpEF) is uncertain. We sought to evaluate the relation between MR severity on transthoracic echocardiography (TTE) and subsequent all-cause mortality in Medicare beneficiaries with HFpEF. We linked 57,608 patients referred for TTE at Beth Israel Deaconess Medical Center to Medicare inpatient claims from 2003 to 2017. In those with a history of HF and a physician-reported left ventricular ejection fraction ≥50%, we evaluated the relation of MR severity and time to the primary end point of all-cause mortality using Kaplan-Meier methods. A total of 7,778 individuals (14.5%) met inclusion criteria (mean age 75.5 years ± 11.9, 55.9% female). Over a median follow-up of 8.1 years, 2,016 (25.9%) died at a median (interquartile range) of 1.7 (0.3 to 4.1) years. At 1 year, 15.8% with 3 to 4+ MR had died versus 10.5% with 0 to 2+ MR (hazard ratio 1.54, 95% confidence interval 1.22 to 1.95, p0.001). After multivariable adjustment, 3 to 4+ MR continued to be associated with increased all-cause mortality (hazard ratio 1.48, 95% confidence interval 1.14 to 1.94, p = 0.004) except in the subset with atrial fibrillation (interaction p = 0.03) or recent (3 months) HF hospitalization (p = 0.54). In conclusion, in this large, single-institution retrospective study of Medicare beneficiaries with HFpEF who underwent TTE, moderate-to-severe and severe MR were significantly associated with an increased risk of all-cause mortality after multivariable adjustment, except in those with atrial fibrillation or recent HF. Prospective studies are needed to assess the role of MR reduction in mitigating this risk.

OBJECTIVE: Assess cognitive impairment (global cognition and executive functioning) in older incarcerated males overall, and according to education and race. DESIGN: Cross-sectional PARTICIPANTS: The sample included 239 racially diverse (37.7% White, 41.4% Black, 20.9% Hispanic/Other) incarcerated males age ≥50 (mean age = 56.4±6.1; range 50–79 years). MEASUREMENTS: Global cognitive impairment assessed using the Montreal Cognitive Assessment (MoCA) – standard MoCA scoring (1-point adjustment for ≤12 years education, and score

Highlights •Invasive X-ray angiography and coronary computed tomography angiography are established gold standards for coronary angiography. •Coronary cardiovascular magnetic resonance angiography could provide a safe, noninvasive, radiation and iodinated contrast-free alternative. •Technological innovations including advanced motion correction, image acceleration, and reconstruction techniques have transformed the field of coronary cardiovascular magnetic resonance angiography. •Multicenter clinical trials implementing these technological advances are needed to validate the improvements needed for more widespread clinical use.

Objectives This study sought to determine whether myocardial tissue heterogeneity scanned by native T1 mapping could improve risk stratification in patients with nonischemic dilated cardio...

Introduction Major depressive disorder in older adults or late-life major depression (LLMD) often responds poorly to antidepressants and increases risks of morbidity, mortality, and dementia. Psychological resilience, or the ability to quickly return to a pre-stimulus state after a stressful event, is an understudied construct with potential clinical implications for LLMD. Higher baseline resilience is associated with LLMD remission. While resilience is often treated as a trait, it is better conceptualized as a dynamic pattern of adaptation that can change over time. Little is known regarding possible changes in resilience that accompany LLMD. The impact of resilience on cognitive functioning in LLMD is also unclear. Resilience may prevent cognitive decline by attenuating the negative effects of chronic stress or greater cognitive control may augment an individual's resilience. Our aim within the following study is to observe whether long-term changes in resilience occur in LLMD. Secondly, if changes in resilience are observed to be present, we sought to determine if these changes correlate with changes in cognition and mood over a two year period. Methods All subjects (n = 123) were enrolled in NBOLD, an IRB approved, NIMH R01 funded study at UConn Health. All subjects provided informed consent to participate. All subjects met criteria for major depression as established by a geriatric psychiatrist. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to measure depression severity. Each subject completed several self-report measures, including the Brief Resilience Scale (BRS). Participants also underwent neuropsychological evaluations to assess cognition. Assessments were repeated at 12 and 24 months post-enrollment. This was a naturalistic observation study; all participants were offered open-label treatment with sertraline at study onset, but could have been maintained on another antidepressant, or elected not to undergo treatment. Statistical analysis: Demographic differences were compared between individuals above and below the median BRS score. Linear regressions were used to assess the relationship between changes in BRS score, MADRS, and cognitive variables due to the availability of repeated measures. Results The median baseline BRS score was 17 (IQR: 13 – 20). Individuals with low resilience (less than median BRS) were more likely to be female (66%, n =40) vs high resilience (28.6% female, n = 18, p With linear regression, increased BRS from baseline to 12 months was associated with lower MADRS score at 24 months (β(SE) = -0.36(0.16), p = 0.03) after adjusting for confounders (including baseline MADRS). BRS score change from baseline to 24 months was not associated with lower MADRS score at 24 months (β(SE) = -0.1(0.15), p = 0.5). For cognition, higher baseline resilience was associated with decreased change in Logical Memory II score at 24 months (β(SE)= -0.27(0.12), p = 0.02). Conclusions Resilience is shown to be a dynamic process variable that changes during LLMD treatment. We also demonstrated that shorter term changes in resilience (first 12 months of treatment) are more strongly associated with MADRS score at two years as compared to changes in resilience during the entire treatment period. These “early resilience responders” to treatment may represent a unique subpopulation particularly well-matched to antidepressant therapy. While increases in resilience are a predictor of decreased MADRS at 24 months, we report that higher baseline resilience correlated to decreased cognitive gains on the LMII. This might be due to near-ceiling effects on cognitive tests in high resilient individuals. Future directions include assessing the value of resilience therapy. Prior studies have demonstrated that resilience can be increased with meditation and behavioral therapy. These modalities could guide new therapeutic techniques for individuals with LLMD. Funding Funding is provided by the National Institute of Mental Health–funded R01 grant entitled, “Neurobiology and Adverse Outcomes of Neuroticism in Late-life Depression” (MH096725)

Noninvasive transthoracic echocardiography (TTE) is commonly performed in the evaluation of syncope. However, despite its utility as a diagnostic tool, TTE for syncope is associated with higher costs and length of stay, without a mortality impact ([1][1]). Therefore, risk stratification of syncope

Background : Recent data suggest that beta blockers are associated with increased perioperative risk in hypertensive patients. We investigated whether beta blockers were associated with an increased risk in elderly patients with raised preoperative arterial blood pressure. Methods We conducted a propensity-score-matched cohort study of primary care data from the UK Clinical Practice Research Datalink (2004–13), including 84 633 patients aged 65 yr or over. Conditional logistic regression models, including factors that were significantly associated with the outcome, were constructed for 30-day mortality after elective noncardiac surgery. The effects of beta blockers (primary outcome), renin–angiotensin system (RAS) inhibitors, calcium-channel blockers, thiazides, loop diuretics, and statins were investigated at systolic and diastolic arterial pressure thresholds. Results Beta blockers were associated with increased odds of postoperative 30-day mortality in patients with systolic hypertension (defined as systolic BP >140 mm Hg; adjusted odds ratio [aOR]: 1.92; 95% confidence interval [CI]: 1.05–3.51). After excluding patients for whom prior data suggest benefit from perioperative beta blockade (patients with prior myocardial infarction or heart failure), rather than adjusting for them, the point estimate shifted slightly (aOR: 2.06; 95% CI: 1.09–3.89). Compared with no use, statins (aOR: 0.35; 95% CI: 0.17–0.75) and thiazides (aOR: 0.28; 95% CI: 0.10–0.78) were associated with lower mortality in patients with systolic hypertension. Conclusions These data suggest that the safety of perioperative beta blockers may be influenced by preoperative blood pressure thresholds. A randomised controlled trial of beta-blocker withdrawal, in select populations, is required to identify a causal relationship.

It remains challenging to integrate clinical neuroscience into clinical practice. Hindrances at the training level (e.g., lack of qualified faculty and curriculum) contribute to this impasse. To help address this, we present a model of training in clinical neuroscience. We expand on a growing literature on incorporating neuroscience into psychiatry training by emphasizing two points. That is, 1) we propose a training model designed for the geriatric-minded clinician; and 2) that extends across several phases of education and career development. Considering the relevance of dementia to our population of interest, and the potential impact expertise in clinical neuroscience can have in elders with cognitive impairment, we provide relevant curriculum examples at various training stages. Clinical research, both as a practitioner and consumer, figures prominently into our training model. We discuss two mentoring programs, T32 fellowships and Research Career Institute in the Mental Health of Aging, as ways to engage geriatric psychiatrists early in their training and transition them successfully to post-residency clinical investigator positions. Although there is increasing opportunity for geriatric psychiatrists and other clinicians to become leaders in the field of neuroscience, this remains a work in progress; ours and others' training programs continue to evolve based on input from trainers and trainees alike, as well as from the increasing literature on this important topic.

Continuous high frequency in situ observations of hydrogen have been made at the Mace Head atmospheric research station on the Atlantic Ocean coastline of Ireland from April 1994 through to December 2017. These 40-minute observations represent one of the most comprehensive records of this trace gas carried out anywhere in the world. Hydrogen mixing ratios in northern hemisphere baseline air masses had a mean value of 508.81 ppb and exhibited a highly statistically significant upwards trend of +0.44 +0.16 -0.28 ppb year-1. Trends were strongest during the months of January, February and November and weakest during the months of May - July, inclusive. Monthly mean baseline mixing ratios exhibited a seasonal cycle with a spring maximum and an autumn minimum, the latter being relatively unusual at this baseline station. The transport of European regionally-polluted air masses to Mace Head historically brought elevated levels of hydrogen above baseline. Over the years of this study, these elevated levels have declined to the extent that the hydrogen levels in European regional pollution events are now almost indistinguishable from baseline levels. Photochemical Trajectory Model studies have confirmed that the decline in European excess hydrogen levels accurately reflects the widespread fitting of three-way catalysts and evaporative cannisters to petrol-engined motor vehicles across Europe and the reductions in emissions of carbon monoxide, oxides of nitrogen and volatile organic compounds that they have brought about.

Human milk is a dynamic protein-protease system that delivers bioactive peptides to infants. The pH of milk changes from the mother’s mammary gland to the infant’s digestive tract. Although the release of human milk peptides has been studied during in vivo or in vitro digestion, these models did not explicitly vary nor observe the effect of pH. The objective of this research was to determine the effect of pH on the proteolysis of human milk. Using high-resolution accurate-mass Orbitrap mass spectrometry, profiles of endogenous human milk peptides before and after incubation at various pH levels have been mapped. Over 5000 peptides were identified. Comparative analyses classified 74 peptides that were consistently found independent of pH alterations, and 8 peptides that were released only at pH 4 or 5 (typical infant gastric pH). Results documented that the proteolysis of milk proteins, particularly β-casein, polymeric immunoglobulin receptor, and α-lactalbumin, is pH-dependent.

In an ideal world every single meeting between law students and professors, or between beginning lawyers and their supervisors, should leave supervisors impressed by their charges and junior lawyers/students with a clear sense of direction for their work. We do not live in that ideal world. This Article seeks to improve those supervisory meetings, and to do so from the perspective of the ones under supervision. We posit there is a genuine art to getting the best supervision possible, and that doing so can be both learned and taught. We first unpack some of the disconnects and hidden assumptions that can hinder effective supervisory meetings. We observe that participants in supervisory meetings may have very different expectations about the roles of the participants. We further explore the relational aspects of supervision and note that a shared sense of responsibility for supervision promotes more effective supervisory interactions. Next, the Article turns to considering what law professors can do to prepare law students to get the most out of feedback from their supervisors. We conclude that teaching law students to adjust their attributions toward growth, to set clear and achievable goals, and to be thoughtfully self-reflective, will maximize their learning in any academic and professional supervision.

Paclitaxel is a well-known cancer drug that functions as a mitotic inhibitor. This work focuses on a copper based crystal that encapsulates the pharmaceutical agent and serves as a drug delivery agent. A Copper10-Pacitaxil1 chloride (CU10PAC1) complex is synthesized and tested against the National Cancer Institute’s sixty cell line panel. The 10:1 ratio results in a crystal that was examined by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spec (MALDI-TOF-MS), Scanning Electron Microscopy (SEM) and Proton (1H) and Carbon (13C) Nuclear Magnetic Resonance (NMR). The potential attributes of a copper based crystal as an in vivo drug carrier for Paclitaxel are discussed.

Ground-level ozone (O3) concentrations have been elevating in the last century. While there has been a notable progress in understanding O3 effects on vegetation, O3 effects on ecological stoichiometry remain unclear, especially early in the oxidative stress. Ethyelenediurea (EDU) is a chemical compound widely applied in research projects as protectant of plants against O3 injury, however its mode of action remains unclear. To investigate O3 and EDU effects early in the stress, we sprayed willow (Salix sachalinensis) plants with 0, 200 or 400 mg EDU L−1, and exposed them to either low ambient O3 (AOZ) or elevated O3 (EOZ) levels during the daytime, for about one month, in a free air O3 controlled exposure (FACE); EDU treatment was repeated every nine days. We collected samples for analyses from basal, top, and shed leaves, before leaves develop visible O3 symptoms. We found that O3 altered the ecological stoichiometry, including impacts in nutrient resorption efficiency, early in the stress. The relation between P content and Fe content seemed to have a critical role in maintaining homeostasis in an effort to prevent O3-induced damage. Photosynthetic pigments and P content appeared to play an important role in EDU mode of action. This study provides novel insights on the stress biology which are of ecological and toxicological importance.

Enzyme-dependent post-translational modifications (PTMs) mediate the cellular regulation of proteins and can be discovered using proteomics. However, even where the peptides of interest can be enriched for analysis with state-of-the-art LC-MS/MS tools and informatics, only a fraction of peptide ions can be identified confidently. Thus, many PTM sites remain undiscovered and unconfirmed. In this minireview, we use a case study to discuss how the use of inclusion lists, turning off isotopic exclusion, and manual validation significantly increased depth of coverage, facilitating discovery of acetylation sites in targets of an acetyltransferase virulence factor. These underutilized strategies have the potential to help answer many mechanistic biological questions that large-scale proteomic studies cannot.

Dysfunctional neural activity in the cortical reward system network has been implicated in food addiction. This is the first study exploring the potential therapeutic effects of high definition transcranial pink noise stimulation (HD-tPNS) targeted at the anterior cingulate cortex (ACC) on craving and brain activity in women with obesity who showed features of food addiction (Yale Food Addiction Scale score of ≥3). Sixteen eligible females participated in a randomized, double-blind, parallel group study. Participants received six 20-minute sessions of either 1 mA (n = 8) or sham (n = 8) stimulation with HD-tPNS over two weeks. Anode was placed above the ACC (Fz) with 4 cathodes (F7, T3, F8, and T4). Food craving was assessed using the Food Cravings Questionnaire State (FCQ-S) and brain activity was measured using electroencephalogram (EEG). Assessments were at baseline, and two days, four weeks, and six weeks after stimulation. A 22% decrease (mean decrease of −1.11, 95% CI -2.09, −0.14) was observed on the 5-point ‘intense desire to eat’ subscale two days after stimulation in the HD-tPNS group compared to sham. Furthermore, whole brain analysis showed a significant decrease in beta 1 activity in the ACC in the stimulation group compared to sham (threshold 0.38, p = 0.04). These preliminary findings suggest HD-tPNS of the ACC transiently inhibits the desire to eat and, thus, warrants further examination as a potential tool in combating food craving.

In situ floc size and turbulent shear stress were measured together with suspended sediment concentration to investigate the floc properties under changing hydrodynamic forcing over the intertidal mudflat. A tripod system was established in the field for a period of approximately one month, including ~ 6 days of stormy conditions in the middle of the investigation period. Mean floc size exhibited strong temporal variations within a tidal cycle, and inverse relationship was found between mean floc size and shear stress. Suspended sediment concentration (SSC) can modulate the flocculation dynamics when shear stress decreases down to enhancing flocculation. Asymmetrical behaviors of floc sizes between flood and ebb phases were identified, with overall larger floc sizes in flood than in ebb tide under the same shear stresses. Floc structure showed different properties under calm and stormy conditions, and the variable fractal dimension and variable primary particle size were more convincing in simulating the variation of floc effective density with mean floc size during the storm period, which was inferred to be related to the resuspension of bed sediment as well as organic matter. A total of 110 mm bed erosion was measured during the storm, and erosion events occurred only around low water, due to the high current-wave combined bed shear stress and off-shore current. After the storm, ~ 40% of the erosion recovered within one week, and the fast settling of large flocs around high water plays significant role in the deposition process, leading to ~ 60% of the recovery.

Ground-level ozone (O₃) levels are nowadays elevated in wide regions of the Earth, causing significant effects on plants that finally lead to suppressed productivity and yield losses. Ethylenediurea (EDU) is a chemical compound which is widely used in research projects as phytoprotectant against O₃ injury. The EDU mode of action remains still unclear, while there are indications that EDU may contribute to plants with nitrogen (N) when the soil is poor in N and the plants have relatively small leaf area. To reveal whether the N content of EDU acts as a fertilizer to plants when the soil is not poor in N and the plants have relatively large total plant leaf area, willow plants (Salix sachalinensis Fr. Schm) were exposed to low ambient O₃ levels and treated ten times (9-day interval) with 200 mL soil drench containing 0, 800 or 1600 mg EDU L⁻¹. Fertilizer was added to a nutrient-poor soil, and the plants had an average plant leaf area of 9.1 m² at the beginning of EDU treatments. Indications for EDU-induced hormesis in maximum electron transport rate (Jmax) and ratio of intercellular to ambient CO₂ concentration (Ci:Cₐ) were observed at the end of the experiment. No other EDU-induced effects on leaf greenness and N content, maximum quantum yield of photosystem II (Fv/Fm), gas exchange, growth and matter production suggest that EDU did not act as N fertilizer and did not cause toxicity under these experimental conditions.

To reduce transthoracic echocardiography (TTE) interpretation error rates, the American Society of Echocardiography has called for quality assurance (QA) TTE protocols, and the Intersocietal Accreditation Commission (IAC) has developed accreditation standards [(1)][1]. We sought to examine the

The frontline tuberculosis (Tb) antibiotic isoniazid has been repurposed using a three component complex aimed at increasing the delivery efficiency and adding new avenues to its mechanism of action. This study focuses on pharmacokinetic studies of the isoniazid-sucrose–copper (II)-PEG-3350 complex. The assays include the Plasma Protein Binding Assay (85.8%), Caco-2 Permeability Assay (B→AP app , 0.13 × 10 −6 cm/s), Cytochrome P450 Inhibition Assay (i.e. CYP2B6, IC 50 = 7.26 μM), In vitro microsomal Stability Assay (t 1/2 NADPH-Dependent > 240 min), and HepG2 Cytotoxicity (no toxicity). The National Cancer Institute's 60 cell line panel is used to measure activity against cancer cells. The percent growth values averaged over all 60 cell lines indicates the complex has no anti-cancer activity, which also suggests a lack of general toxicity. It also provides data for the complexes specificity against Mycobacterium tuberculosis .

Introduction Stress is thought to exacerbate cognitive decline in older adults, especially those with late life depression (LLD); however, the specific aspects of stress that are especially deleterious and the aspects of cognition they affect are not clear. For example, it is not known whether the effects result from the exposure to stressful life events or whether it is the perception of stress that is salient, and whether these relate to the domains of cognition affected. We hypothesized that the number of stressful events and the magnitude of perceived stress in older adults with LLD at baseline would be associated with cognitive decline over 2 years. Methods lder adults (ages 60-90 years) with LLD (n=124, mean age 71.5 years) and never-depressed elderly healthy controls (HCs) (n=39, mean age 74.6 years) were assessed at three time points each one year apart for number of stressful life events within the prior year using the Duke Depression Evaluation Scale, and perceived stress within the prior six months, and with five neurocognitive tests that included the Trail Making (Trail Making B – Trail Making A), Benton Visual Retention Test, Symbol Digit Modalities Test (Processing Speed), Logical Memory Delayed Recall II and Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. Associations were examined (Spearman correlations) between baseline measures of the number of stressful life events and the perception of stress with change in cognitive test performance over time from baseline to year 1 and to year 2. Associations between stress measures and changes in the cognitive measures were considered significant at p Results Only the LLD group showed a significant association between stress and cognitive changes. The level of perceived stress at baseline was associated with a decline on Trail Making from baseline to 1 year (r=0.22, pcorr=0.022); this association was stronger when assessed from baseline to 2 years (r=0.29, p=0.0058). Conclusions This study suggests that for older adults with LLD it was the perception of stress at baseline, not the number of stressful life events at baseline, that was associated with decline in executive functioning in the following 2 years. The findings highlight the importance of assessing the perception of stress in LLD, as individuals with LLD and high levels of perceived stress may be at risk for decline in executive functioning. Further study is warranted on adverse effects of perceived stress in LLD and the potential for preventing decline in executive functioning by reducing levels of perceived stress. Funding National Institute of Mental Health Grant R01 MH108578; The Leo and Anne Albert Charitable Trust

Introduction Late-life depression (LLD) refers to depression occurring in older age and is associated with a multitude of psychosocial and biological factors, including conditions related to pathological aging, including cardiovascular and cerebrovascular diseases, and dementia. Relevant psychosocial factors comprise personality disorders, neuroticism, trauma and stress. Depending on the relative contribution of conditions related to pathological aging versus psychosocial factors, some patients may not respond to antidepressants and others may be prone to relapse even when they achieved initial remission on an antidepressant. The neural mechanisms related to recurrence of LLD are not clear. About 50% of individuals who have recovered from a first episode of depression will suffer from at least one additional episode. Therefore, identifying patients prone to relapse is important for developing tailored treatment regimens, preventing suicide, and reducing economic burdens and other morbidities. To understand the neural mechanisms related to relapse of depression, and identify neuroimaging markers to predict individuals who tend to relapse, we conducted a secondary data analysis on clinical and fMRI data collected from our NBOLD project. We hypothesized that, compared with individuals who did not relapse during a two-year clinical follow-up period, those who relapsed would show significantly altered resting-state activity patterns in core neural networks related to LLD including the default mode, executive control and salience networks. Methods The sample included 102 adults with LLD who were free of medication for at least two weeks before study enrollment. Depression severity was measured by MADRS and was assessed by a study psychiatrist at each study visit, which occurred frequently while the subject remained depressed and quarterly when remission was achieved. Among the enrolled participants, 52 (age range of 60 – 89) achieved depression remission after antidepressant treatment (MADRS 15 for at least two weeks. Individuals were classified as non-relapsed if they maintained a MADRS Results There were no significant differences between relapsed and non-relapsed groups in age, gender, state anxiety or neuroticism. Those who relapsed during the two-year follow-up had less severe depressive symptoms at baseline (mean (SD) MADRS= 18.40(4.06) than those non-depressed group (mean (SD) MADRS=20.81(6.23) with p=0.001), whereas the relapsed group had higher STAI-trait anxiety than the non-relapsed group (p=0.04). Two-sample t-tests on FC showed that the relapsed group had a lower FC between the right parahippocampus and the superior and inferior parietal cortex. The relapsed group also had a reduced FC between the right globus pallidum and the right superior frontal gyrus. In addition, the relapsed group had significantly greater ALFF in the left amygdala and globus pallidum compared with the non-relapsed group; however, the significance was lost after controlling for depression severity and STAI-trait anxiety. Conclusions This is one of few studies that have examined clinical and neural characters in relapsed LLD. Lower FC between the right parahippocampus and the superior and inferior parietal cortex suggests a potential reduction in attention for memory. Low FC between the right globus pallidum and the right superior frontal gyrus may indicate reduced executive function in relapsed individuals. Importantly, the relapsed group also showed lower depressive symptoms yet higher trait anxiety. These results suggest that depression comorbid with anxiety might be an essential factor of relapse tendency. Future studies will examine whether the relapsed group also has lower executive function.

Introduction Alcohol use disorder interferes with antidepressant treatment in older adults with major depression (LLD) and is associated with suicidal ideation. Less is known about the effects of moderate alcohol use in LLD on mood and cognitive outcomes over time. Much of the evidence on alcohol use and cognition and mood stems from epidemiological research and not clinical studies of depressed older adults. The purported benefits of moderate alcohol use on older adults’ cognitive functioning have often been reported. Yet, not all studies report a positive association between moderate alcohol use and cognitive functioning, and there is also other evidence to suggest moderate alcohol use is correlated with markers of poorer brain health in older adults (e.g., atrophy). In respect to mood, epidemiological research suggests little to no association between moderate alcohol use and depression in older adults or even an inverse association with increased social interactions as a mediator. Given the times at conflicting evidence and the lack of longitudinal studies in well-defined clinical samples, we hypothesized that depressed older adults who were moderate drinkers would experience greater cognitive decline compared to depressed non-drinkers. We also hypothesized that moderate alcohol use would have a detrimental effect on depression illness course in older adults with LLD. Methods This study used data from Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. NCODE participants underwent annual neuropsychological evaluations with the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) cognitive battery as well as other tests of executive functioning and processing speed (e.g., Trail Making Test). Participants also underwent annual depression severity ratings with a geriatric psychiatrist using the Montgomery Asberg Depression Rating Scale (MADRS). We used patients self-reported alcohol use at the time of study entry and characterized them as either abstainers (n=81) and moderate drinkers (n=30). We were also able to define a small sample of risky drinkers (n=10) and included this group for exploratory reasons. Alcohol use was based upon NIAAA guidelines for older adult alcohol consumption. Risky alcohol use exceeded NIAAA alcohol consumption guidelines for older adults (meaning >=3 drinks per day or >=8 drinks per week) and moderate alcohol use was defined as Results In terms of cognition, we found that the total CERAD score of moderate and heavy drinkers significantly declined compared to no alcohol use patients (e.g.,moderate alcohol use x time interaction term estimate = -.00410, DF = 898, t = -5.02, p Conclusions Moderate alcohol consumption appears to have a beneficial impact on depression severity and a detrimental impact on cognitive functioning in LLD patients followed for upwards of five years. Larger samples are needed to confirm the findings in this small and exploratory study.

Introduction Late-life depression (LLD) is associated with psychiatric comorbidities that may worsen mood outcomes in older adults, yet the neural mechanisms that underlie these comorbid conditions remain understudied. Anxiety and neuroticism have been independently associated with LLD, and its mood and cognitive outcomes. In a preliminary behavioral data analysis we found that anxiety measures correlated with depression measures in older adults. We also found that several baseline neuroticism and anxiety traits predicted depression scores over time. In this study, we analyzed neuroimaging data in the setting of anxiety and neuroticism measures in LLD and hypothesized that there would be differences in resting state activity patterns in the Salience network (SN), Default-Mode network (DMN) and Executive Control network (ECN) related to severity of: (1) generalized anxiety, (2) state and trait anxiety, and (3) neuroticism. Methods This was a cross-sectional secondary data analysis on clinical and MRI data collected from our NBOLD project. LLD patients without dementia were included. Generalized anxiety disorder (GAD) symptoms, state and trait anxiety, neuroticism and depression were assessed using a GAD questionnaire, State-Trait Anxiety Inventory (STAI), NEO Personality Inventory (NEO PI), and Montgomery-Asberg Depression Rating Scale (MADRS), respectively. A study psychiatrist confirmed or ruled out diagnosis of depression. There were 102 older adults with LLD, and among them, 87 subjects who had measures of STAI-trait, STAI-state anxiety, GAD symptoms and neuroticism as well as usable neuroimaging data were included into our final analyses. The neuroimaging data was collected from 3T Siemens Skyra scanner. The imaging parameters for T1-weighted images were: TR/TE=2200/2.8ms, flip angle=13o, matrix = 256 × 256 × 169, Voxelsize=1×1×1mm3. The 7-min resting-state fMRI data was collected using EPI sequence with FOV=240mm, flip angle=90o, TR/TE=2000/31ms, matrix=64×64×34, voxelsize = 3.8×3.8×3.75mm3. The fMRI data was preprocessed using the default protocol setting recommend by DPABI software. The Amplitude of Low-Frequency Fluctuations (ALFF) was calculated using DPABI. Multiple regression model was used to examine the association between ALFF and GAD, state and trait anxiety as well as neuroticism controlled for age, gender and depression severity (MADRS) using SPM12. Significance was set at p Results Data analyses revealed that trait anxiety was positively correlated with greater ALFF in the ECN (left dorsolateral prefrontal cortex - dlPFC, bilateral inferior parietal cortex - IPS, and precuneus) and lateral orbitofrontal cortex (OFC). Higher state anxiety was correlated with lower ALFF in bilateral OFC and frontal pole. GAD symptom severity was positively correlated with ALFF in the right superior temporal cortex (STG), Heschl's gyrus, and dorsomedial frontal cortex (dMFC). The GAD symptom severity was also negatively correlated with ALFF in the right hippocampus, parahippocampus and temporal pole (TP), whereas there was no significant clusters found between ALFF and neuroticism after regressing out the covariates. Conclusions This is one the few studies that examined resting state neural oscillation pattern (ALFF) specific to state and trait anxiety and GAD symptoms in LLD. Higher trait anxiety was associated with greater ALFF in the ECN and OFC, all of which are related to emotion regulation, whereas higher state anxiety was correlated with lower ALFF in regions related to emotion regulation. Higher GAD was specifically correlated with higher ALFF in brain regions related to sound and social information processing, but with lower ALFF in regions related to memory. No significant clusters were found related to neuroticism suggesting that neuroticism might be able explained by trait and state anxiety as well as GAD. These results suggests a distinct neural construct that may distinguish state and trait anxiety in LLD. Uncovering the brain connectivity changes related to state and trait anxiety would deepen our understanding in the neural mechanisms and mood outcomes of LLD. Future studies are needed to determine differences in these networks between depressed and non-depressed individuals. Funding The Leo and Anne Albert Charitable Trust, National Institute of Mental Health Grant R01 MH108578, The University of Connecticut Department of Psychiatry

Flocculation is an important dynamic process for fine sediment transport. A number of physical and biochemical factors affecting flocculation have been identified, but quantitative examination of floc structure and fractal property under varying physical conditions is still needed. In this contribution, we conducted lab experiments using an annular flume and natural sediment to evaluate changes in floc size distributions and fractal dimensions under varying turbulent shear G, salinity and suspended sediment concentration (SSC). The low-intrusive optical instrument of LabSFLOC-2 was deployed to capture images of flocs which enables calculation of floc sizes and settling velocities. Observations showed that the mean floc size in freshwater first increased with increasing G below a threshold of G = 40 s−1, followed by a decrease with further increases in shear. The shear threshold was smaller for saline water (salinity of 7 PSU), i.e., G = 20–30 s−1, than that in freshwater. The fractal dimension of flocs decreased with an increase in size, suggesting more fragile structure for macro-flocs. Turbulent shear appeared to play a dominant role in controlling floc structure. Flocs formed under large shear force were more compacted, and had larger fractal dimensions. The floc fractal dimension was 28–37% greater in freshwater than in saline water. An improved method considering both floc size and variable fractal dimension is proposed for better simulation of floc effective density. The improved understanding of flocculation dynamics and floc structure in this work have implications for fine sediment and adherent nutrients management in varying natural water environments.

The type-1 cannabinoid receptor (CB1) is a promising drug target for a wide range of diseases. However, many existing and novel candidate ligands for CB1 have shown only limited therapeutic potential. Indeed, no ligands are currently approved for the clinic except formulations of the phytocannabinoids Δ9-THC and CBD and a small number of analogues. A key limitation of many promising CB1 ligands are their on-target adverse effects, notably including psychoactivity (agonists) and depression/suicidal ideation (inverse agonists). Recent drug development attempts have therefore focussed on altering CB1 signalling profiles in two ways. Firstly, with compounds that enhance or reduce the signalling of endogenous (endo-) cannabinoids, namely allosteric modulators. Secondly, with compounds that probe the capability of selectively targeting specific cellular signalling pathways that may mediate therapeutic effects using biased ligands. This review will summarise the current paradigm of CB1 signalling in terms of the intracellular transduction pathways acted on by the receptor. The development of compounds that selectively activate CB1 signalling pathways, whether allosterically or via orthosteric agonist bias, will also be addressed.

Objective Neuroticism is a common yet understudied condition in older adults. We hypothesized that presence of high negativity affectivity (NA), a key feature of neuroticism, would be associated with different prefrontal cortex (PFC) activity and connectivity patterns in depressed and never-depressed older adults. Methods This is a baseline cross-sectional analysis of a cohort study of 52 depressed and 36 never-depressed older adults. Assessments included NA scores from the Type D Scale-14 and Montgomery-Asberg Depression Rating Scale scores. All subjects had a 3T brain functional magnetic resonance imaging resting scan, neuronal activity determined by amplitude of low-frequency fluctuations (ALFFs) were obtained, and resting state functional connectivity (FC) analyses were performed. Analyses of covariance were conducted on ALFFs and FC to examine significant differences between groups. Results In the ALFF analyses there were clearly different patterns between depressed and comparison groups in the correlation of ALFFs and NA. The correlation differences between the two groups were significant in the dorsomedial PFC, insula, amygdala, and posterior cingulate cortex (PCC). FC analyses revealed different between-group connectivity patterns. Significantly higher ventromedial PFC–amygdala FC with NA correlation was found in the depressed group than that in the never-depressed group. Conclusion This study confirms differential activity of the dorsal and ventral regions of the medial PFC in individuals with high neuroticism. Our findings suggest increased rostral medial PFC activity may be a marker of resilience to depression in the elderly and decreased anterior ventromedial PFC, PCC, and amygdala activity may be a result of successful emotion regulation in never-depressed higher NA individuals.

Tuberculosis is one of the infectious diseases with the greatest global burden, affecting millions of people. The rise of multi- and extensively-drug resistant forms of Mycobacterium tuberculosis over the last few decades has highlighted the urgent need for development of new drugs to treat the disease. Many drug development pipelines are based on in vitro assays examining a compound's effect on M. tuberculosis alone. These do not account for the effect of a compound on mammalian cells nor the interaction between host and pathogen. We therefore developed a live-cell fluorescence-based screen utilizing high content microscopy of mammalian macrophages infected with M. tuberculosis to screen for compounds with both substantial inhibition of M. tuberculosis growth and low cytotoxicity. Isoniazid, a first line tuberculosis drug, and staurosporine, a compound with well documented cytotoxic activity, were used to validate the assay. These and other control compounds showed results for M. tuberculosis growth consistent with the field. Together, this method of screening allows for high throughput testing of potential tuberculosis drugs while capturing more information per compound in a physiologically relevant context.

Background Preoperative blood pressure (BP) thresholds associated with increased postoperative mortality remain unclear. We investigated the relationship between preoperative BP and 30-day mortality after elective non-cardiac surgery. Methods We performed a cohort study of primary care data from the UK Clinical Practice Research Datalink (2004–13). Parsimonious and fully adjusted multivariable logistic regression models, including restricted cubic splines for numerical systolic and diastolic BP, for 30-day mortality were constructed. The full model included 29 perioperative risk factors, including age, sex, comorbidities, medications, and surgical risk scale. Sensitivity analyses were conducted for age (>65 vs Results A total of 251 567 adults were included, with 589 (0.23%) deaths within 30 days of surgery. After adjustment for all risk factors, preoperative low BP was consistently associated with statistically significant increases in the odds ratio (OR) of postoperative mortality. Statistically significant risk thresholds started at a preoperative systolic pressure of 119 mm Hg (adjusted OR 1.02 [95% confidence interval (CI) 1.01–1.02]) compared with the reference (120 mm Hg) and diastolic pressure of 63 mm Hg [OR 1.24 (95% CI 1.03–1.49)] compared with the reference (80 mm Hg). As BP decreased, the OR of mortality risk increased. Subgroup analysis demonstrated that the risk associated with low BP was confined to the elderly. Adjusted analyses identified that diastolic hypertension was associated with increased postoperative mortality in the whole cohort. Conclusions In this large observational study we identified a significant dose-dependent association between low preoperative BP values and increased postoperative mortality in the elderly. In the whole population, elevated diastolic, not systolic, BP was associated with increased mortality.

Objectives Neuroticism is a broad construct that conveys a predisposition to experience psychological distress and negative mood states. Vulnerability to stress (VS) is one neuroticism trait that has been linked to worse mood and cognitive outcomes in older adults. We hypothesized that elevated VS would be associated with worse illness course and cognitive decline in older adults with late-life major depression (LLD). Design Participants were enrolled in the Neurocognitive Outcomes of Depression in the Elderly (NCODE), a longitudinal investigation of the predictors of poor illness course and cognitive decline in LLD. Participants were followed upwards of 10 years. Setting NCODE operates in a naturalistic treatment milieu. Participants 112 participants aged 60 and older with a current diagnosis of major depressive disorder. Measurements Treatment response was assessed at least every 3 months and more often if clinically needed. Participants also completed the NEO Personality Inventory-Revised (NEO PI-R) and an annual cognitive examination. Neuroticism traits from the NEO PI-R included anxiety, depression, anger-hostility, self-consciousness, impulsivity, and VS. Results Higher neuroticism traits of VS, impulsivity, anger-hostility, and anxiety were associated with worse treatment response over time. High VS was the only neuroticism trait significantly associated with cognitive functioning. High VS negatively influenced the rate of global cognitive decline over time. Conclusions Individual personality traits within the neuroticism dimension are associated with treatment resistance and cognitive impairment in LLD. It remains to be seen whether these individual traits are associated with different neurobiological substrates and clinical characteristics of LLD.