New Constraint on the Local Relic Neutrino Background Overdensity with the First KATRIN Data Runs.

We report on the direct search for cosmic relic neutrinos using data acquired during the first two science campaigns of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity molecular tritium gas source are analyzed by a high-resolution MAC-E filter around the end point at 18.57 keV. The analysis is sensitive to a local relic neutrino overdensity ratio of η<9.7×10^{10}/α (1.1×10^{11}/α) at a 90% (95%) confidence level with α=1 (0.5) for Majorana (Dirac) neutrinos. A fit of the integrated electron spectrum over a narrow interval around the end point accounting for relic neutrino captures in the tritium source reveals no significant overdensity. This work improves the results obtained by the previous neutrino mass experiments at Los Alamos and Troitsk. We furthermore update the projected final sensitivity of the KATRIN experiment to η<1×10^{10}/α at 90% confidence level, by relying on updated operational conditions.

Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function.

OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD. METHODS: Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized. RESULTS: Rare variants were found in known AD risk genes including AKAP9, CD33, CR1, EPHA1, INPP5D, NME8, PSEN1, SORL1, TREM2 and UNC5C. Three families had five variants of interest in linkage regions with LOD>2. Genes with segregating alterations in these peaks include CD163L1 and CLECL1, two genes that have both been implicated in immunity, CTNNA1, which encodes a catenin in the cerebral cortex and MIEF1, a gene that may induce mitochondrial dysfunction and has the potential to damage neurons. Four genes were identified with alterations in more than one family include PLEKHG5, a gene that causes Charcot-Marie-Tooth disease and THBS2, which promotes synaptogenesis. CONCLUSION: Utilizing large families with a heavy burden of disease allowed for the identification of rare variants co-segregating with disease. Variants were identified in both known AD risk genes and in novel genes.

Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease.

Several variants in the gene ABCA7 have been identified as potential causal variants for late-onset Alzheimer's disease (LOAD). In order to replicate these findings, and search for novel causal variants, we performed targeted sequencing of this gene in cohorts of non-Hispanic White (NHW) and African-American (AA) LOAD cases and controls. We sequenced the gene ABCA7 in 291 NHW LOAD cases and 103 controls. Variants were prioritized for rare, damaging variants and previously reported variants associated with LOAD, and were follow-up genotyped in 4076 NHW and 1157 AA cases and controls. We confirm three previously associated ABCA7 risk variants and extend two of these associations to other populations, an intronic variant in NHW (P=3.0×10-3) (originally reported in a Belgian population), and a splice variant originally associated in the Icelandic population, which was significantly associated in the NHW cohort (P=1.2×10-6) and nominally associated in the AA cohort (P=0.017). We also identify a 3'-UTR splice variant that segregates in four siblings of one family and is nominally associated with LOAD (P=0.040). Multiple variants in ABCA7 contribute to LOAD risk.

Psychosocial Predictors of Mortality Following Lung Transplantation.

Lung transplantation has become an increasingly common treatment for patients with end-stage lung disease. Few studies have examined psychosocial risk factors for mortality in transplant recipients, despite evidence suggesting that elevated levels of negative affect are associated with greater mortality following major cardiac surgery. We therefore examined the relationship between negative affect early after lung transplantation and long-term survival in a sample of 132 lung transplant recipients (28 cystic fibrosis, 64 chronic obstructive pulmonary disease, 26 idiopathic pulmonary fibrosis, 14 other) followed for up to 13.5 years (median 7.4 years) following transplantation. Patients underwent both medical and psychosocial assessments 6 months following transplantation, which included the Beck Depression Inventory-II (BDI-II), Spielberger Anxiety Inventory, and General Health Questionnaire (GHQ). Over the course of follow-up, 80 (61%) participants died. Controlling for demographic factors, native lung disease, disease severity, family income, education level, social support, and frequency of posttransplant rejection, elevated symptoms of depression (BDI-II: HR = 1.31, p = 0.011) and distress (GHQ: HR = 1.28, p = 0.003) were associated with increased mortality. Higher levels of depression and general distress, but not anxiety, measured 6 months following lung transplantation are associated with increased mortality, independent of background characteristics and medical predictors.

Adjusted prognostic association of depression following myocardial infarction with mortality and cardiovascular events: individual patient data meta-analysis.

BACKGROUND: The association between depression after myocardial infarction and increased risk of mortality and cardiac morbidity may be due to cardiac disease severity. AIMS: To combine original data from studies on the association between post-infarction depression and prognosis into one database, and to investigate to what extent such depression predicts prognosis independently of disease severity. METHOD: An individual patient data meta-analysis of studies was conducted using multilevel, multivariable Cox regression analyses. RESULTS: Sixteen studies participated, creating a database of 10 175 post-infarction cases. Hazard ratios for post-infarction depression were 1.32 (95% CI 1.26-1.38, P<0.001) for all-cause mortality and 1.19 (95% CI 1.14-1.24, P<0.001) for cardiovascular events. Hazard ratios adjusted for disease severity were attenuated by 28% and 25% respectively. CONCLUSIONS: The association between depression following myocardial infarction and prognosis is attenuated after adjustment for cardiac disease severity. Still, depression remains independently associated with prognosis, with a 22% increased risk of all-cause mortality and a 13% increased risk of cardiovascular events per standard deviation in depression z-score.

Baseline 6-min walk distance predicts survival in lung transplant candidates.

In a large, prospectively followed, two-center cohort of patients listed for lung transplantation (n = 376), we used Cox proportional hazards models to determine the importance of baseline 6-min walk distance (6MWD) in predicting patient survival. 6MWD used as a continuous variable was a significant predictor of survival after adjusting for other important covariates when transplant was considered as a time-varying covariate (HR for each 500 ft increase in 6MWD = 0.57, 95% CI: 0.43-0.77, p = 0.0002). 6MWD remained an important predictor of survival in models that considered only survival to transplant (HR for each 500 ft increase in 6MWD = 0.41, 95% CI: 0.27-0.62, p < 0.0001) or survival only after transplant (HR for each 500 ft increase in 6MWD = 0.40, 95% CI: 0.22-0.72, p = 0.002). Unadjusted Kaplan-Meier analysis demonstrates significantly different survival by 6MWD tertiles (<900, 900-1200, or >1200 ft, p-value = 0.0001). In the overall model, 6MWD prediction of survival was relatively homogeneous across disease category (6MWD by disease interaction term, p-value = 0.63). Our results demonstrate a significant relationship between baseline 6MWD and survival among patients listed for lung transplantation that exists across all native disease categories and extends through transplantation. The 6MWD is thus a useful measure of both urgency and utility among patients awaiting lung transplantation.

Longitudinal follow-up of late-onset Alzheimer disease families.

Historically, data for genetic studies are collected at one time point. However, for diseases with late onset or with complex phenotypes, such as Alzheimer disease (AD), restricting diagnosis to a single ascertainment contact may not be sufficient. Affection status may change over time and some initial diagnoses may be inconclusive. Follow-up provides the opportunity to resolve these complications. However, to date, previous studies have not formally demonstrated that longitudinally re-contacting families is practical or productive. To update data initially collected for linkage analysis of late-onset Alzheimer disease (LOAD), we successfully re-contacted 63 of 81 (78%) multiplex families (two to 17 years after ascertainment). Clinical status changed for 73 of the 230 (32%) non-affected participants. Additionally, expanded family history identified 20 additional affected individuals to supplement the data set. Furthermore, fostering ongoing relationships with participating families helped recruit 101 affected participants into an autopsy and tissue donation program. Despite similar presentations, discordance between clinical diagnosis and neuropathologic diagnosis was observed in 28% of those with tissue diagnoses. Most of the families were successfully re-contacted, and significant refinement and supplementation of the data was achieved. We concluded that serial contact with longitudinal evaluation of families has significant implications for genetic analyses.

Sex differences in chest pain in patients with documented coronary artery disease and exercise-induced ischemia: Results from the PIMI study.

BACKGROUND: Sex differences in the pathophysiologic course of coronary artery disease (CAD) are widely recognized, yet accurate diagnosis of coronary artery disease in women remains challenging. METHODS: To determine sex differences in the clinical manifestation of CAD, we studied chest pain reported during daily activities, exercise, and mental stress in 170 men and 26 women. All patients had documented CAD (>50% narrowing in at least 1 major coronary artery or prior myocardial infarction) and all had 1-mm ST-segment depression on treadmill exercise. We collected psychologic test results, serum samples (potassium, epinephrine, norepinephrine, cortisol, b-endorphin, and glucose), and cardiac function, sensory threshold, and autonomic function data at specified times before, during, or after exercise and mental stress tests to assess measures of depression, anxiety, and neurohormonal and thermal pain perception. RESULTS: Women reported chest pain more often than men during daily activities (P =.04) and during laboratory mental stressors (P =.01) but not during exercise. Men had lower scores than women on measures of depression, trait anxiety, harm avoidance, and reward dependence (P <.05 for all). Women had significantly lower plasma b-endorphin levels at rest (4.2 +/- 3.9 vs 5.0 +/- 2.5 pmol/L for men, P =.005) and at maximal mental stress (6.4 +/- 5.1 vs 7.4 +/- 3.5 pmol/L for men, P <.01). A higher proportion of women than men had marked pain sensitivity to graded heat stimuli applied to skin (hot pain threshold <41 degrees C, 33% vs 10%, P =.001). CONCLUSIONS: Our results reflect sex differences in the affective and discriminative aspects of pain perception and may help explain sex-related differences in clinical presentations.

Depression, heart rate variability, and acute myocardial infarction.

BACKGROUND: Clinical depression is associated with an increased risk for mortality in patients with a recent myocardial infarction (MI). Reduced heart rate variability (HRV) has been suggested as a possible explanation for this association. The purpose of this study was to determine if depression is associated with reduced HRV in patients with a recent MI. METHODS AND RESULTS: Three hundred eighty acute MI patients with depression and 424 acute MI patients without depression were recruited. All underwent 24-hour ambulatory electrocardiographic monitoring after hospital discharge. In univariate analyses, 4 indices of HRV were significantly lower in patients with depression than in patients without depression. Variables associated with HRV were then compared between patients with and without depression, and potential confounds were identified. These variables (age, sex, diabetes, and present cigarette smoking) were entered into an analysis of covariance model, followed by depression status. In the final model, all but one HRV index (high-frequency power) remained significantly lower in patients with depression than in patients without depression. CONCLUSIONS: We conclude that greater autonomic dysfunction, as reflected by decreased HRV, is a plausible mechanism linking depression to increased cardiac mortality in post-MI patients.

Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease.

OBJECTIVE: Major depression is a common problem in patients with coronary heart disease (CHD) and is associated with an increased risk for cardiac morbidity and mortality. It is not known whether treating depression will improve medical prognosis in patients with CHD. Depression is also associated with elevated heart rate and reduced heart rate variability (HRV), which are known risk factors for cardiac morbidity and mortality that may explain the increased risk associated with depression. The purpose of this study was to determine whether treatment for depression with cognitive behavior therapy (CBT) is associated with decreased heart rate or increased HRV. METHODS: Thirty depressed patients with stable CHD, classified as either mildly or moderately to severely depressed, received up to 16 sessions of CBT. The 24-hour heart rate and HRV were measured in these patients and in 22 medically comparable nondepressed controls before and after treatment of the depressed patients. RESULTS: Average heart rate and daytime rMSSD (reflecting mostly parasympathetic activity) improved significantly in the severely depressed patients, but remained unchanged in the mildly depressed and the control patients. However, only rMSSD improved to a level comparable to the control patients. None of the remaining indices of HRV showed improvement. CONCLUSIONS: The results suggest that treating depression with CBT may reduce heart rate and increase short-term HRV. Thus, CBT may have a beneficial effect on a risk factor for mortality in depressed patients with coronary heart disease. A randomized, controlled study is needed to confirm these findings.

Psychosocial considerations in elderly patients with heart failure.

Neuropsychiatric conditions, such as Alzheimer's dementia, and complications, such as delirium, are common in elderly patients with heart failure. Persistent alcohol abuse and cigarette smoking sometimes contribute to the onset and progression of heart failure. Major depression and other depressive disorders are common in this population and have adverse effects on functional status, quality of life, and prognosis. Anxiety and social isolation are clinically significant problems in many cases. These problems often are treatable and deserve more clinical attention than they typically receive.

Depression and poor glycemic control: a meta-analytic review of the literature.

OBJECTIVE: Depression is common among patients with diabetes, but its relationship to glycemic control has not been systematically reviewed. Our objective was to determine whether depression is associated with poor glycemic control. RESEARCH DESIGN AND METHODS: Medline and PsycINFO databases and published reference lists were used to identify studies that measured the association of depression with glycemic control. Meta-analytic procedures were used to convert the findings to a common metric, calculate effect sizes (ESs), and statistically analyze the collective data. RESULTS: A total of 24 studies satisfied the inclusion and exclusion criteria for the meta-analysis. Depression was significantly associated with hyperglycemia (Z = 5.4, P < 0.0001). The standardized ES was in the small-to-moderate range (0.17) and was consistent, as the 95% CI was narrow (0.13-0.21). The ES was similar in studies of either type 1 or type 2 diabetes (ES 0.19 vs. 0.16) and larger when standardized interviews and diagnostic criteria rather than self-report questionnaires were used to assess depression (ES 0.28 vs. 0.15). CONCLUSIONS: Depression is associated with hyperglycemia in patients with type 1 or type 2 diabetes. Additional studies are needed to establish the directional nature of this relationship and to determine the effects of depression treatment on glycemic control and the long-term course of diabetes.

Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease.

OBJECTIVE: The purpose of this study was to investigate the relationship between depression and heart rate variability in cardiac patients. METHODS: Heart rate variability was measured during 24-hour ambulatory electrocardiographic (ECG) monitoring in 40 medically stable out-patients with documented coronary heart disease meeting current diagnostic criteria for major depression, and 32 nondepressed, but otherwise comparable, patients. Patients discontinued beta-blockers and antidepressant medications at the time of study. Depressed patients were classified as mildly (n = 21) or moderately-to-severely depressed (n = 19) on the basis of Beck Depression Inventory scores. RESULTS: There were no significant differences among the groups in age, gender, blood pressure, history of myocardial infarction, diabetes, or smoking. Heart rates were higher and nearly all indices of heart rate variability were significantly reduced in the moderately-to-severely versus the nondepressed group. Heart rates were also higher and mean values for heart rate variability lower in the mildly depressed group compared with the nondepressed group, but these differences did not attain statistical significance. CONCLUSION: The association of moderate to severe depression with reduced heart rate variability in patients with stable coronary heart disease may reflect altered cardiac autonomic modulation and may explain their increased risk for mortality.

Psychological Correlates of Mental Stress-induced Ischemia in the Laboratory: The Psychophysiological Investigation of Myocardial Ischemia (PIMI) Study.

Participants consisted of 184 patients (160 males, 24 females) with positive angiograms or prior myocardial infarctions who displayed at least 1 mm of ST segment depression on a standardized treadmill test. Mean scores on the Reward Dependence subscale of the Tridimensional Personality Questionnaire were higher in patients displaying ischemia during mental stress. Patients who reported higher levels of irritability/anger in response to the Speech stressor were also more likely to display ischemia. However, this result was primarily a result of the females in the sample whose ratings of interest and irritability were associated with ischemia during the Speech task. Psychometric measures previously found in prospective studies to predict acute cardiac events were unrelated to mental stress-induced ischemia in the laboratory.

Can treating depression reduce mortality after an acute myocardial infarction?

Major depression affects about one in five patients in the weeks after an acute myocardial infarction and is associated with an increased risk of cardiac morbidity and mortality. Consequently, there is considerable interest in the question of whether treating depression will improve medical prognosis in these patients. Safe, effective treatments for depression are available, but unless they also improve the underlying pathophysiological or behavioral mechanisms that contribute to cardiac morbidity and mortality, they may not have beneficial effects on prognosis. Altered cardiac autonomic tone is one of the leading candidate mechanisms. Unfortunately, a review of the available research reveals that cardiac autonomic tone often fails to normalize in patients treated for depression, and the research suggests that currently available treatments for depression will not necessarily improve cardiac event-free survival in patients who have had an acute myocardial infarction. Until there is convincing evidence that treatment can reduce the risk of cardiac morbidity and mortality, the principal reason to treat depression should continue to be to improve the quality of life of the patient who has had an acute myocardial infarction. Key words: depression, coronary heart disease, mortality.

Major depression, heart rate, and plasma norepinephrine in patients with coronary heart disease.

BACKGROUND: Although it is now well established that psychiatric depression is associated with adverse outcomes in patients with coronary heart disease (CHD), the mechanism underlying this association is unclear. Elevated heart rate (HR) and plasma norepinephrine (NE), possibly reflecting altered autonomic nervous system activity, have been documented in medically well depressed psychiatric patients, and this pattern is associated with increased risk for cardiac events in patients with CHD. The purpose of this study was to determine whether autonomic nervous system activity is altered in depressed CHD patients. METHODS: HR, plasma NE, and blood pressure (BP) were measured in 50 depressed and 39 medically comparable nondepressed CHD patients at rest and during orthostatic challenge. RESULTS: Resting HR (p = .005), and the change from resting HR at 2, 5, and 10 min after standing (p = .02, .004, and .02, respectively), were significantly higher in the depressed than in the nondepressed patients. There were no differences between the groups in NE or in BP at rest, or in standing minus resting change scores at any time during orthostatic challenge (p < .05). CONCLUSIONS: Depression is associated with altered autonomic activity in patients with CHD, as reflected by elevated resting HR and an exaggerated HR response to orthostatic challenge. Previously reported differences in NE levels between depressed and nondepressed patients were not replicated.