Contribution of Vascular Risk Factors to the Progression in Alzheimer Disease

Background: Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, low-density lipoprotein [LDL-C], and triglyceride concentrations) may be predictors for progression of Alzheimer disease (AD). Objective: To determine whether prediagnosis vascular risk factors are associated with progression of AD. Design: Inception cohort followed up longitudinally for a mean of 3.5 (up to 10.2) years. Setting: Washington Heights/Inwood Columbia Aging Project, New York, New York. Patients: One hundred fifty-six patients with incident AD (mean age at diagnosis, 83 years). Main Outcome Measure: Change in a composite score of cognitive ability from diagnosis onward. Results: In generalized estimating equation models (adjusted for age, race/ethnicity, and years of education), higher cholesterol (total cholesterol and LDL-C) concentrations and history of diabetes were associated with faster cognitive decline. Each 10-U increase in cholesterol and LDL-C was associated with a 0.10-SD decrease in cognitive score per year of follow-up (P < .001 for total cholesterol; P = .001 for LDL-C). High-density lipoprotein cholesterol and triglyceride concentrations were not associated with rate of decline. A history of diabetes was associated with an additional 0.05-SD decrease in cognitive score per year (P = .05). History of heart disease and stroke were associated with cognitive decline only in carriers of the apolipoprotein E ε4 (APOE-ε4) gene. In a final generalized estimating equation model that included high-density lipoprotein cholesterol and LDL-C concentrations and history of diabetes, only higher LDL-C was independently associated with faster cognitive decline. Conclusion: Higher prediagnosis total cholesterol and LDL-C concentrations and history of diabetes were associated with faster cognitive decline in patients with incident AD, which provides further evidence for the role of vascular risk factors in the course of AD

Natural killer cells require selectins for suppression of subcutaneous tumors

Natural killer (NK) cells recognize and destroy cancer cells through a variety of mechanisms. They may also modulate the adaptive immune response to cancer by interacting with DCs and T cells. Although NK cells play an important role in tumor suppression, little is known about the mechanisms of their recruitment to tumors. Previously it has been shown that subcutaneous tumor growth is enhanced in mice lacking selectins, a family of cell adhesion molecules that mediate the first step of immune cell entry into tissue from the blood. Here we demonstrate that NK cell recruitment to tumors is defective in selectin-deficient mice. In vivo NK cell depletion, either pharmacologic or genetic, leads to enhanced subcutaneous tumor growth, similar to the phenotype observed in the selectin-deficient animals. We also show that, although NK cells from selectin-deficient mice appear developmentally normal, and are functional in in vitro assays, their in vivo function is impaired. This study reveals a role for selectins in NK cell recruitment to tumors and in regulation of effective tumor immunity

Renewable energy in remote communities

This article is the result of a competitively tendered University-funded project, this brings together two major Government Policy areas: sustainable communities and use of carbon fuels, and is aimed at influencing the policy debate on the difficulties of linking remote communities to renewable energy production because of poor distribution networks. Linkage with the Sustainable Communities agenda is an essential ingredient, as the proposal is that the renewable energy technologies will be installed and maintained by the communities themselves

Variability in motor threshold

Funding Information: GC was funded by Funda??o para a Ci?ncia e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017). AJO-M was funded by FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School ? Portugal Program (HMSP-ICJ/0020/2011). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Funda??o para a Ci?ncia e Tecnologia, Harvard University or its affiliated academic health care centers. Funding Information: GC was funded by Fundação para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship ( SFRH/BD/130210/2017 ). AJO-M was funded by FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School – Portugal Program ( HMSP-ICJ/0020/2011 ). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER , under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Fundação para a Ciência e Tecnologia, Harvard University or its affiliated academic health care centers. Funding Information: AJO-M was national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019–2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36 and 2020-001348-25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33). AP-L is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Magstim Inc., Radiant Hearts, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. None of the aforementioned agencies or companies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. The remaining authors have declared that they have no potential conflicts of interest involving this work, including relevant financial activities outside the submitted work and any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing what is written.publishersversionpublishe

Clinical implications

Funding: GC was funded by Fundaçao para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017). AJOM was funded by FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School e Portugal Program (HMSP-ICJ/0020/2011). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Fundaçao para a Ciência e Tecnologia, Harvard University or its affiliated academic health care centers. AJO-M was national coordinator for Portugal of a noninterventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019e2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36 and 2020-001348- 25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33). AP-L is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim Inc., Nexstim, Cognito, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. None of the aforementioned agencies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. The remaining authors have declared that they have no potential conflicts of interest involving this work, including relevant financial activities outside the submitted work and any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing what is written.Background: When repetitive transcranial magnetic stimulation (rTMS) is used to treat medication refractory depression, the treatment pulse intensity is individualized according to motor threshold (MT). This measure is often acquired only on the first day of treatment, as per the protocol currently approved by Food and Drug Administration. Objective: Here, we aimed to assess daily MT variability across an rTMS treatment course and simulate the effects of different schedules of MT assessment on treatment intensity. Methods: We conducted a naturalistic retrospective study with 374 patients from a therapeutic rTMS program for depression that measures MT daily. Results: For each patient, in almost half the TMS sessions, MT varied on average more than 5% as compared to the baseline MT acquired in the first treatment day. Such variability was only minimally impacted by having different TMS technicians acquiring MT in different days. In a smaller cohort of healthy individuals, we confirmed that the motor hotspot localization method, a critical step for accurate MT assessment, was stable in different days, arguing that daily MT variability reflects physiological variability, rather than an artifact of measurement error. Finally, in simulations of the effect of one-time MT measurement, we found that half of sessions would have been 5% or more above or below target intensity, with almost 5% of sessions 25% above target intensity. The simulated effects of weekly MT measurements were significantly improved. Conclusions: In conclusion, MT varies significantly across days, not fully dependent on methods of MT acquisition. This finding may have important implications for therapeutic rTMS practice regarding safety and suggests that regular MT assessments, daily or at least weekly, would ameliorate the effect.publishersversionpublishe

New Hubble Space Telescope Discoveries of Type Ia Supernovae at z > 1: Narrowing Constraints on the Early Behavior of Dark Energy

We have discovered 21 new Type Ia supernovae (SNe Ia) with the Hubble Space Telescope (HST) and have used them to trace the history of cosmic expansion over the last 10 billion years. These objects, which include 13 spectroscopically confirmed SNe Ia at z > 1, were discovered during 14 epochs of reimaging of the GOODS fields North and South over two years with the Advanced Camera for Surveys on HST. Together with a recalibration of our previous HST-discovered SNe Ia, the full sample of 23 SNe Ia at z > 1 provides the highest-redshift sample known. Combined with previous SN Ia datasets, we measured H(z) at discrete, uncorrelated epochs, reducing the uncertainty of H(z>1) from 50% to under 20%, strengthening the evidence for a cosmic jerk--the transition from deceleration in the past to acceleration in the present. The unique leverage of the HST high-redshift SNe Ia provides the first meaningful constraint on the dark energy equation-of-state parameter at z >1. The result remains consistent with a cosmological constant (w(z)=-1), and rules out rapidly evolving dark energy (dw/dz >>1). The defining property of dark energy, its negative pressure, appears to be present at z>1, in the epoch preceding acceleration, with ~98% confidence in our primary fit. Moreover, the z>1 sample-averaged spectral energy distribution is consistent with that of the typical SN Ia over the last 10 Gyr, indicating that any spectral evolution of the properties of SNe Ia with redshift is still below our detection threshold.Comment: typos, references corrected, minor additions to exposition 82 pages, 17 figures, 6 tables. Data also available at: http://braeburn.pha.jhu.edu/~ariess/R06. Accepted, Astrophysical Journal vol. 656 for March 10, 200