251 results on '"Bruce Levin"'
Search Results
2. Proof of a Key Inequality for Lattice Event Probabilities with Equal Odds
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Bruce Levin and Cheng-Shiun Leu
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Statistics and Probability ,Modeling and Simulation - Published
- 2022
3. A key inequality for lower bound formulas for lattice event probabilities
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Bruce Levin and Cheng-Shiun Leu
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Statistics and Probability ,Modeling and Simulation - Published
- 2021
4. HIV Care Coordination promotes care re-engagement and viral suppression among people who have been out of HIV medical care: an observational effectiveness study using a surveillance-based contemporaneous comparison group
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Mary K. Irvine, Sarah L. Braunstein, McKaylee Robertson, Denis Nash, Sarah Gorrell Kulkarni, and Bruce Levin
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medicine.medical_specialty ,Short Report ,HIV Infections ,Case management ,Care re-engagement ,Virology ,Medicine ,Humans ,HIV care continuum ,Pharmacology (medical) ,Retrospective Studies ,Medical case management ,Public health ,business.industry ,Ryan White ,Odds ratio ,Continuity of Patient Care ,Viral Load ,RC581-607 ,Viral suppression ,Family medicine ,Propensity score matching ,North America ,Molecular Medicine ,Cohort studies ,Observational study ,Health education ,Immunologic diseases. Allergy ,business ,Viral load ,HIV surveillance ,Cohort study - Abstract
Background Medical care re-engagement is critical to suppressing viral load and preventing HIV transmission, morbidity and mortality, yet few rigorous intervention studies address this outcome. We assessed the effectiveness of a Ryan White Part A-funded HIV Care Coordination Program relative to ‘usual care,’ for short-term care re-engagement and viral suppression among people without recent HIV medical care. Methods The Care Coordination Program was launched in 2009 at 28 hospitals, health centers, and community-based organizations in New York City. Designed for people with HIV (PWH) experiencing or at risk for poor HIV outcomes, the Care Coordination Program provides long-term, comprehensive medical case management utilizing interdisciplinary teams, structured health education and patient navigation. The intervention was implemented as a safety-net services program, without a designated comparison group. To evaluate it retrospectively, we created an observational, matched cohort of clients and controls. Using the HIV surveillance registry, we identified individuals meeting program eligibility criteria from December 1, 2009 to March 31, 2013 and excluded those dying prior to 12 months of follow-up. We then matched clients to controls on baseline status (lacking evidence of viral suppression, consistently suppressed, inconsistently suppressed, or newly diagnosed in the past 12 months), start of follow-up and propensity score. For this analysis, we limited to those out of care at baseline (defined as having no viral load test in the 12 months pre-enrollment) and still residing within jurisdiction (defined as having a viral load or CD4 test reported to local surveillance and dated within the 12-month follow-up period). Using a GEE model with binary error distribution and logit link, we compared odds of care re-engagement (defined as having ≥ 2 laboratory events ≥ 90 days apart) and viral suppression (defined as having HIV RNA ≤ 200 copies/mL on the most recent viral load test) at 12-month follow-up. Results Among 326 individuals out of care at baseline, 87.2% of clients and 48.2% of controls achieved care re-engagement (Odds Ratio: 4.53; 95%CI 2.66, 7.71); 58.3% of clients and 49.3% of controls achieved viral suppression (Odds Ratio: 2.05; 95%CI 1.30, 3.23). Conclusions HIV Care Coordination shows evidence of effectiveness for care and treatment re-engagement.
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- 2021
5. An Evolution-Based Model of Causation for Aging-Related Diseases and Intrinsic Mortality: Explanatory Properties and Implications for Healthy Aging
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Gilberto Levy and Bruce Levin
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Gompertz distribution ,complex etiology ,healthy aging ,Risk Factors ,aging-related diseases ,Public Health, Environmental and Occupational Health ,Weibull distribution ,Environmental Exposure ,Public aspects of medicine ,RA1-1270 ,sufficient and component causes - Abstract
Aging-related diseases are the most prevalent diseases in advanced countries nowadays, accounting for a substantial proportion of mortality. We describe the explanatory properties of an evolution-based model of causation (EBMC) applicable to aging-related diseases and intrinsic mortality. The EBMC takes the sufficient and component causes model of causation as a starting point and develops it using evolutionary and statistical theories. Genetic component causes are classified as “early-onset” or “late-onset” and environmental component causes as “evolutionarily conserved” or “evolutionarily recent.” Genetic and environmental component causes are considered to occur as random events following time-to-event distributions, and sufficient causes are classified according to whether or not their time-to-event distributions are “molded” by the declining force of natural selection with increasing age. We obtain for each of these two groups different time-to-event distributions for disease incidence or intrinsic mortality asymptotically (i.e., for a large number of sufficient causes). The EBMC provides explanations for observations about aging-related diseases concerning the penetrance of genetic risk variants, the age of onset of monogenic vs. sporadic forms, the meaning of “age as a risk factor,” the relation between frequency and age of onset, and the emergence of diseases associated with the modern Western lifestyle. The EBMC also provides an explanation of the Gompertz mortality model at the fundamental level of genetic causes and involving evolutionary biology. Implications for healthy aging are examined under the scenarios of health promotion and postponed aging. Most importantly from a public health standpoint, the EBMC implies that primary prevention through changes in lifestyle and reduction of environmental exposures is paramount in promoting healthy aging.
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- 2022
6. Positivity of cumulative sums for multi-index function components explains the lower bound formula in the Levin-Robbins-Leu family of sequential subset selection procedures
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Cheng-Shiun Leu and Bruce Levin
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Statistics and Probability ,62F07, 62F35, 62L10, 74Q20 ,Selection (relational algebra) ,Probability (math.PR) ,Mathematics - Statistics Theory ,020206 networking & telecommunications ,Index function ,Statistics Theory (math.ST) ,02 engineering and technology ,Function (mathematics) ,01 natural sciences ,Upper and lower bounds ,Combinatorics ,010104 statistics & probability ,Modeling and Simulation ,FOS: Mathematics ,0202 electrical engineering, electronic engineering, information engineering ,Sequential selection ,0101 mathematics ,Mathematics - Probability ,Mathematics - Abstract
We exhibit some strong positivity properties of a certain function which implies a key inequality that in turn implies the lower bound formula for the probability of correct selection in the Levin-Robbins-Leu family of sequential subset selection procedures for binary outcomes. These properties provide a more direct and comprehensive demonstration of the key inequality than was discussed in previous work.
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- 2020
7. The Nosology of Lewy Body Disorders From Analytic–Epidemiologic and Statistical Vantage Points
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Eliasz Engelhardt, Bruce Levin, and Gilberto Levy
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Lewy Body Disease ,Nosology ,medicine.medical_specialty ,Parkinson's disease ,Lewy body ,Dementia with Lewy bodies ,business.industry ,medicine.disease ,Neurology ,alpha-Synuclein ,medicine ,Etiology ,Humans ,Lewy Bodies ,Neurology (clinical) ,Psychiatry ,business - Published
- 2020
8. Why Plea Bargains are A Bad Deal for Some
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Michael O. Finkelstein and Bruce Levin
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Statistics and Probability ,Plea ,Political science ,Law and economics - Abstract
In US federal courts, defendants are often encouraged to plead guilty in exchange for lighter sentences. But not all of those taking a plea might have been found guilty had their cases gone to trial. Michael O. Finkelstein and Bruce Levin estimate the scale of the problem
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- 2020
9. Impact of an HIV Care Coordination Program on the Timeliness of Viral Suppression and Immune Recovery Among Clients Newly Diagnosed with HIV
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Denis Nash, Kate Penrose, McKaylee Robertson, Mary K. Irvine, Bruce Levin, Graham Harriman, and Sarah L. Braunstein
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medicine.medical_specialty ,Social Psychology ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Viral suppression ,Proportional Hazards Models ,Medical case management ,030505 public health ,Transmission (medicine) ,business.industry ,Public health ,Hazard ratio ,Public Health, Environmental and Occupational Health ,Viral Load ,Confidence interval ,CD4 Lymphocyte Count ,Health psychology ,Infectious Diseases ,0305 other medical science ,business ,Case Management - Abstract
We compared the time to immune recovery and viral suppression (VS) among people newly diagnosed with HIV who enrolled in the HIV Care Coordination Program (CCP), a comprehensive medical case management program, with a propensity matched group of newly diagnosed people who did not enroll. CCP enrollees had more rapid VS (≤ 200 copies/mL) [hazards ratio (HR) 1.17; 95% confidence interval 1.02–1.34] but no more rapid immune recovery (≥ two successive CD4 counts > 500 cells/mm(3)) (HR 0.98; 0.84–1.13). Relative to usual care, the CCP may expedite VS (though not immune recovery) for newly diagnosed HIV patients and therefore lower forward transmission risk.
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- 2019
10. Echoes of William Gowers's concept of abiotrophy
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Gilberto Levy, Bruce Levin, and Eliasz Engelhardt
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Male ,History and Philosophy of Science ,Neurology ,General Neuroscience ,Humans ,Neurology (clinical) - Abstract
Among William Gowers's many contributions to neurology, the concept of abiotrophy ("an essential failure of vitality") has been relatively overlooked. In this article, we review the echoes of Gowers's concept in neurology, ophthalmology, and aging research. We also argue that abiotrophy is broader than both heredodegeneration and neurodegeneration. Unlike the common view that it simply means premature aging, abiotrophy currently can be understood as a progressive degenerative process of a mature specialized tissue, which is nonsynchronous with normal aging and may affect organs or systems early in life, resulting from the age-dependent effects of genetic mutations or variants, even if environmental factors may also causally contribute to the process. Although the term has largely fallen out of use, there are likely to be everlasting echoes of Gowers's concept, through which he is to be considered a source of the modern thinking about the etiology and nosology of neurological diseases.
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- 2021
11. Advancing the Genetics of Lewy Body Disorders with Disease‐Modifying Treatments in Mind
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Gilberto Levy, Bruce Levin, and Eliasz Engelhardt
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Genetics ,Molecular Biology ,Biochemistry - Published
- 2022
12. Is Interview Length Associated With Blood Test Participation? Evidence From Three Population-Based HIV Impact Assessment Surveys Conducted From 2016 to 2017
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Choice Ginindza, Neena M. Philip, Anton Palma, Kristin Brown, Rachel Bray, John L.P. Thompson, Lloyd Mulenga, and Bruce Levin
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education.field_of_study ,Time Factors ,medicine.diagnostic_test ,Impact assessment ,Population ,Human immunodeficiency virus (HIV) ,HIV Infections ,Population based ,medicine.disease_cause ,Logistic regression ,Health Surveys ,HIV Testing ,Interviews as Topic ,Infectious Diseases ,Respondent ,medicine ,HIV-1 ,Blood test ,Humans ,Pharmacology (medical) ,Duration (project management) ,education ,Psychology ,Demography - Abstract
BACKGROUND High response rates in surveys are critical to ensuring that findings are unbiased and representative of the target population. Questionnaire length affects response rates, with long interviews associated with partially complete surveys, higher item nonresponse ("don't know" and "refuse" responses), and willingness to participate in future surveys. Our aim is to determine the impact of questionnaire length on blood test participation in population-based HIV surveys. METHODS Data are from population-based HIV impact assessments conducted in Zambia, Eswatini, and Lesotho in 2016-2017. The population-based HIV impact assessments consist of an interview followed by a blood draw. Consent for blood draw was obtained before the interview in Eswatini and after the interview in Zambia and Lesotho. Interview length was measured by the survey tablet as the time to complete the survey (interview duration) and the number of questions answered by the participant (questionnaire length). We assessed the effects of questionnaire length and interview duration on blood test participation using logistic regression. RESULTS Across all 3 surveys, the median interview duration was 16 minutes and the median number of questions was 77. In adjusted analyses, there was a negative impact of interview duration on blood draw consent for individuals with unknown status in Lesotho and a positive relationship between questionnaire length and blood draw consent in Zambia for those with HIV-negative and unknown status. CONCLUSION Although interview length is an important consideration to reduce respondent burden, a longer questionnaire does not necessarily result in lower consent rates for blood testing.
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- 2021
13. Stigma, gender dysphoria, and nonsuicidal self-injury in a community sample of transgender individuals
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Curtis Dolezal, Judy Honig, Bruce Levin, Walter O. Bockting, and Kasey B. Jackman
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Adult ,Male ,Gender dysphoria ,050103 clinical psychology ,Adolescent ,Social Stigma ,Population ,Transgender identity ,Ethnic group ,Logistic regression ,Transgender Persons ,Article ,Young Adult ,03 medical and health sciences ,Transgender ,medicine ,Humans ,0501 psychology and cognitive sciences ,Longitudinal Studies ,Child ,Gender Dysphoria ,education ,Biological Psychiatry ,Aged ,education.field_of_study ,030505 public health ,05 social sciences ,Gender Identity ,Middle Aged ,medicine.disease ,Minority stress ,Psychiatry and Mental health ,Cross-Sectional Studies ,Life course approach ,Female ,Independent Living ,0305 other medical science ,Psychology ,Self-Injurious Behavior ,Clinical psychology - Abstract
We investigated rates of nonsuicidal self-injury (NSSI) and correlates of past-year NSSI among transgender people to better understand factors contributing to this health disparity. A community-based sample of 332 transgender people participated in quantitative in-person interviews. The mean age of participants was 34.56 years (SD = 13.78, range = 16–87). The sample was evenly divided between transfeminine spectrum (50.3%) and transmasculine spectrum identities (49.7%) and was diverse in race/ethnicity. We evaluated associations between sociodemographic characteristics, stigma, hypothesized resilience factors, and identity variables with past-year NSSI. 53.3% of participants reported ever having self-injured in their lifetime. Past-year NSSI was reported by 22.3% of the sample and did not significantly differ based on gender identity. In logistic regression models, past-year NSSI was associated with younger age and felt stigma (perceived or anticipated rejection), but not enacted stigma (actual experiences of discrimination), and with gender dysphoria. Efforts to address the high rates of NSSI among transgender people should aim to reduce felt stigma and gender dysphoria, and promote transgender congruence. Future research using a developmental approach to assess variations in NSSI across the life course and in relation to transgender identity development may illuminate additional processes that affect NSSI in this population.
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- 2018
14. Randomized Selection Designs
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Cheng-Shiun Leu, Shing M. Lee, and Bruce Levin
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business.industry ,Computer science ,Artificial intelligence ,business ,Machine learning ,computer.software_genre ,computer ,Selection (genetic algorithm) - Published
- 2020
15. Embryonic lethal genetic variants and chromosomally normal pregnancy loss
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Jennie Kline, Sonja Kytömaa, Avinash Abhyankar, Andrew Tang, Bruce Levin, Badri N. Vardarajan, Nara Sobreira, Amanda Thomas-Wilson, Vaidehi Jobanputra, and Ruiwei Zhang
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Proband ,medicine.medical_specialty ,Candidate gene ,Chromosomal Proteins, Non-Histone ,Fibrillin-2 ,DNA Mutational Analysis ,Karyotype ,Mutation, Missense ,Physiology ,Biology ,Compound heterozygosity ,Risk Assessment ,symbols.namesake ,Loss of Function Mutation ,Pregnancy ,Risk Factors ,Epidemiology ,Exome Sequencing ,medicine ,Chromosomes, Human ,Humans ,Lethal allele ,Exome ,Loss function ,Exome sequencing ,Genetics ,Tissue Inhibitor of Metalloproteinase-2 ,business.industry ,Obstetrics and Gynecology ,Odds ratio ,medicine.disease ,Confidence interval ,Abortion, Spontaneous ,Reproductive Medicine ,Case-Control Studies ,Karyotyping ,Mendelian inheritance ,symbols ,Autism ,Female ,business ,Trisomy - Abstract
STUDY QUESTIONAre rare genetic variants in the conceptus associated with chromosomally normal pregnancy loss?SUMMARY ANSWERThe proportion of probands with at least one rare variant is increased in chromosomally normal loss conceptuses compared with controls.WHAT IS ALREADY KNOWNAmong non-consanguineous families, one study of seven chromosomally normal losses to four couples with recurrent pregnancy loss (RPL) and a case report of a family with RPL of which one was known to be chromosomally normal identify compound heterozygote variants in three different genes as possibly causal. Among consanguineous families, RPL of chromosomally normal pregnancies with non-immune hydrops fetalis (NIHF) has been attributed to recessive variants in genes previously implicated for NIHF and new candidate genes.STUDY DESIGN, SIZE, DURATIONThe starting sample was 52 chromosomally normal losses to 50 women, identified in 2003-2005 as part of a cohort study on trisomy and ovarian aging. The analytic sample comprises 19 conceptus-parent trios with DNA from 17 biologic parents (cases). The control group derives from the National Institutes of Mental Health’s National Database for Autism Research (NDAR). It comprises 547 trios of unaffected siblings of autism cases and their parents.PARTICIPANTS/MATERIALS, SETTING, METHODSWe use exome sequencing to identify rare variants in the coding region of the genome. We defined variant rarity in two ways: ultra-rare (absent in gnomAD) and rare (heterozygote −3in gnomAD). For autosomal recessives, we further required that the variant was absent as a homozygote in gnomAD. We compare the rates of rare predicted damaging variants (loss of function and missense – damaging) and the proportions of probands with at least one such variant in cases versus controls. Secondarily, 1) we repeat the analysis limiting it to variants in genes considered causal in fetal anomalies and 2) we compare the proportions of cases and controls with damaging variants in genes which we classified as possibly embryonic lethal based on a review which was blinded to case-control status.MAIN RESULTS AND THE ROLE OF CHANCEThe rates of ultra-rare damaging variants (allde novo) are 0.21 and 0.17 in case and control probands, respectively. The corresponding rates for rare potentially pathogenicde novovariants are 0.37 and 0.24, respectively; for autosomal recessive variants they 0.11 and 0.03. The proportions of probands with at least one rare potentially damaging variant were 36.8% among cases and 22.9% among controls (odds ratio (OR) = 2.0, 95% CI 0.9, 3.0). Secondary analyses show no damaging variants in fetal anomaly genes among case probands; the proportion with variants in possibly embryonic lethal genes was increased in case probands (OR=14.5, 95% CI 3.4, 61.1). Cases had variants in possibly embryonic lethal genesBAZ1A, FBN2andTIMP2. Post hocreview of these cases suggests thatCDH5may also be an embryonic lethal gene.LIMITATIONS, REASONS FOR CAUTIONThe number of case trios (n=19) limits the precision of our point estimates. We observe a moderate association between rare damaging variants and chromosomally normal loss with a confidence interval that includes unity. A larger sample is needed to estimate the magnitude of the association with precision and to identify the relevant biological pathways.WIDER IMPLICATIONS OF THE FINDINGSOur data add to a very small literature on this topic. They suggest rare genetic variants in the conceptus may be a cause of chromosomally normal loss.TRIAL REGISTRATION NUMBERN/A.STUDY FUNDING/COMPETING INTERESTS(S)Exome sequencing of case trios was performed by Baylor-Hopkins Center for Mendelian Genomics through National Human Genome Research Institute grant 5U54HG006542.Data used in the preparation of this manuscript were obtained from the National Institute of Mental Health (NIMH) Data Archive (NDA). NDA is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in mental health. Dataset identifier(s): src_subject_id. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or of the Submitters submitting original data to NDA.No author has a competing interest.
- Published
- 2020
16. Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial)
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Conrado J. Estol, Susan Graham, Ronald S. Freudenberger, Douglas L. Mann, Piotr Ponikowski, Richard Buchsbaum, Min Qian, Stefan D. Anker, John L.P. Thompson, Arthur J. Labovitz, Marco R. Di Tullio, Ralph L. Sacco, John R. Teerlink, Siqin Ye, Tetz C. Lee, Dirk J. Lok, Jay P. Mohr, Koki Nakanishi, Gregory Y.H. Lip, Shunichi Homma, Bruce Levin, and Patrick M. Pullicino
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Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Severity of Illness Index ,Article ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Thromboembolism ,Internal medicine ,Atrial Fibrillation ,Severity of illness ,Humans ,Medicine ,030212 general & internal medicine ,Heart Failure ,Aspirin ,Ejection fraction ,business.industry ,Warfarin ,Anticoagulants ,Stroke Volume ,Atrial fibrillation ,Odds ratio ,Middle Aged ,medicine.disease ,Confidence interval ,Treatment Outcome ,Heart failure ,Quality of Life ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.
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- 2018
17. Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment
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Warcef Investigators, Susan Graham, Piotr Ponikowski, Stefan D. Anker, Shunichi Homma, Ralph L. Sacco, Conrado J. Estol, Marco R. Di Tullio, Ronald S. Freudenberger, Gregory Y.H. Lip, John L P Thompson, Douglas L. Mann, Dirk J. Lok, Bruce Levin, John R. Teerlink, Patrick M. Pullicino, Min Qian, Jay P. Mohr, Arthur J. Labovitz, and Richard Buchsbaum
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medicine.medical_specialty ,Aspirin ,Ejection fraction ,business.industry ,Warfarin ,Atrial fibrillation ,030204 cardiovascular system & hematology ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Heart failure ,Antithrombotic ,medicine ,Cardiology ,Platelet aggregation inhibitor ,030212 general & internal medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Author(s): Di Tullio, Marco R; Qian, Min; Thompson, John LP; Labovitz, Arthur J; Mann, Douglas L; Sacco, Ralph L; Pullicino, Patrick M; Freudenberger, Ronald S; Teerlink, John R; Graham, Susan; Lip, Gregory YH; Levin, Bruce; Mohr, Jay P; Buchsbaum, Richard; Estol, Conrado J; Lok, Dirk J; Ponikowski, Piotr; Anker, Stefan D; Homma, Shunichi; WARCEF Investigators | Abstract: AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range g60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.
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- 2018
18. Using Registry Data to Construct a Comparison Group for Programmatic Effectiveness Evaluation
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Levi Waldron, Denis Nash, Kate Penrose, Sarah L. Braunstein, Mary K. Irvine, Rebekkah S. Robbins, Stephanie Chamberlin, Sarah Gorrell Kulkarni, Bruce Levin, and McKaylee Robertson
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musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Epidemiology ,Extramural ,business.industry ,Human immunodeficiency virus (HIV) ,Psychological intervention ,MEDLINE ,medicine.disease_cause ,030112 virology ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Viral Load result ,Family medicine ,medicine ,Registry data ,Observational study ,030212 general & internal medicine ,skin and connective tissue diseases ,Construct (philosophy) ,business - Abstract
Many nonrandomized interventions rely upon a pre-post design to evaluate effectiveness. Such designs cannot account for events external to the intervention that may produce the outcome. We describe a method to construct a surveillance registry-based comparison group, which allows for estimating the effectiveness of the intervention while controlling for secular trends in the outcome of interest. Using data from the population-based, human immunodeficiency virus Surveillance Registry in New York City, we created a contemporaneous comparison group for persons enrolled in the New York City human immunodeficiency virus Care Coordination Program (CCP) from December 2009 to March 2013. Inclusion in the Registry-based (non-CCP) comparison group required meeting CCP eligibility criteria. To control for secular trends in the outcome, we randomly assigned persons in the non-CCP, Registry-based comparison group a pseudoenrollment date such that the distribution of pseudoenrollment dates matched the distribution of enrollment dates among CCP enrollees. We then matched CCP to non-CCP persons on propensity for enrollment in the CCP, enrollment dates, and baseline viral load. Registry-based comparison group estimates were attenuated relative to pre-post estimates of program effectiveness. These methods have broad applicability for observational intervention effectiveness studies and programmatic evaluations for conditions with surveillance registries.
- Published
- 2018
19. Pediatric acute respiratory distress syndrome associated with human metapneumovirus and respiratory syncytial virus
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John S. Baird, Lisa Saiman, Joy D. Howell, Amanda Gomez, Ilana Harwayne-Gidansky, Thomas J. Connors, Nathan Neill, Bruce Levin, and Thyyar M. Ravindranath
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,ARDS ,animal structures ,viruses ,Respiratory Syncytial Virus Infections ,03 medical and health sciences ,0302 clinical medicine ,Human metapneumovirus ,Risk Factors ,Nasopharynx ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Respiratory system ,Retrospective Studies ,Pediatric intensive care unit ,Respiratory Distress Syndrome ,Paramyxoviridae Infections ,biology ,business.industry ,Incidence ,Incidence (epidemiology) ,Infant ,medicine.disease ,biology.organism_classification ,Comorbidity ,Reverse transcriptase ,Respiratory failure ,Child, Preschool ,Respiratory Syncytial Virus, Human ,Pediatrics, Perinatology and Child Health ,Female ,Metapneumovirus ,business - Abstract
OBJECTIVES To study the incidence, risk factors, clinical course, and outcome of ARDS in children with HMP and RSV. WORKING HYPOTHESIS We hypothesized that ARDS in children with HMP was similar in incidence, risk factors, clinical course, and outcomes to ARDS in children with RSV. STUDY DESIGN Retrospective, observational study over 2 years. PATIENT-SUBJECT SELECTION Patients included were
- Published
- 2018
20. Limb-Leaf designs for adaptive exploration of the dose-response curve
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Bin Cheng, John Spivack, and Bruce Levin
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Mathematical optimization ,Dose-Response Relationship, Drug ,Familywise error rate ,Context (language use) ,General Medicine ,01 natural sciences ,Power (physics) ,010104 statistics & probability ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,0302 clinical medicine ,Clinical Trials, Phase III as Topic ,Research Design ,Sample size determination ,Data Interpretation, Statistical ,Adaptive design ,Humans ,Dose addition ,Pharmacology (medical) ,0101 mathematics ,030217 neurology & neurosurgery ,Selection (genetic algorithm) ,Mathematics - Abstract
We propose a two-stage strategy, called the Limb-Leaf method, to explore the dose-response curve using dose promotion and addition in the context of adaptive seamless Phase II/III trials. Strong control of the overall type 1 familywise error rate of the proposed method is enforced by the closed testing principle. The design constants are determined to minimize the risk-adjusted expected total sample size while maintaining a target power. In the case of a nonmonotonic dose response curve where more doses are required to adequately explore the curve, substantial savings in sample size are achieved compared with a traditional strategy which offers only selection and promotion from among initial first stage doses.
- Published
- 2018
21. Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients
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Shunichi Homma, Douglas L. Mann, John R. Teerlink, Min Qian, Stefan D. Anker, Dirk J. Lok, Natalie A. Bello, Gregory Y.H. Lip, Bruce Levin, Seitetz C. Lee, Ronald S. Freudenberger, Marco R. Di Tullio, Jay P. Mohr, Piotr Ponikowski, Warcef Investigators, Susan Graham, Arthur J. Labovitz, Ralph L. Sacco, and John L.P. Thompson
- Subjects
medicine.medical_specialty ,Aspirin ,Ejection fraction ,Proportional hazards model ,business.industry ,Hazard ratio ,Warfarin ,030204 cardiovascular system & hematology ,medicine.disease ,Confidence interval ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Heart failure ,ACE inhibitor ,medicine ,Cardiology ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Objectives The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Background Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue. Methods We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events). Results After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates. Conclusions Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients. (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial [WARCEF]; NCT00041938)
- Published
- 2017
22. Adaptive sequential selection procedures with random subset sizes
- Author
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Cheng-Shiun Leu and Bruce Levin
- Subjects
Statistics and Probability ,020206 networking & telecommunications ,Context (language use) ,02 engineering and technology ,computer.software_genre ,01 natural sciences ,010104 statistics & probability ,Modeling and Simulation ,0202 electrical engineering, electronic engineering, information engineering ,Ethical concerns ,Sequential selection ,Data mining ,0101 mathematics ,Early phase ,computer ,Selection (genetic algorithm) ,Mathematics - Abstract
We introduce a new family of sequential selection procedures wherein the subsets selected have random sizes. In comparison to subset selection procedures that select subsets of fixed size, the new procedures alleviate the need to specify the subset size prior to the experiment. We discuss the application of such procedures in the context of early phase clinical trials. The new procedures retain the adaptive features of the Levin-Robbins-Leu family of sequential subset selection procedures for selecting subsets of fixed size, namely, sequential elimination of inferior treatments and sequential recruitment of superior treatments. These two adaptive features respectively address ethical concerns that diminish interest in nonadaptive procedures and also allow promising treatments to be brought forward for further testing without having to wait until the end of the trial. The new procedures differ from the classical subset selection procedures of Shanti S. Gupta in terms of their respective goals and o...
- Published
- 2017
23. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy
- Author
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Francisco Javier Aguirre‐Rodríguez, Susana G. Kalko, Elena Martín-Hernández, Fabiola Mavillard, Michio Hirano, Javier Torres-Torronteras, Bruce Levin, Marcos Madruga-Garrido, Cecilia Jimenez-Mallebrera, Yuqi Tu, Juan P. Morealejo‐Aycinena, Yuelin Long, Karin Kleinsteuber, Ramon Martí, Itxaso Marti, Jasim Uddin, Olga Serrano, Caterina Garone, Concepcion Álvarez del Vayo, M. Alice Donati, Francina Munell, John L.P. Thompson, Carmen Paradas, Cristina Domínguez-González, Andrés Nascimento, M. Dolores Sardina, Kristen Engelstad, Dominguez-Gonzalez C., Madruga-Garrido M., Mavillard F., Garone C., Aguirre-Rodriguez F.J., Donati M.A., Kleinsteuber K., Marti I., Martin-Hernandez E., Morealejo-Aycinena J.P., Munell F., Nascimento A., Kalko S.G., Sardina M.D., Alvarez del Vayo C., Serrano O., Long Y., Tu Y., Levin B., Thompson J.L.P., Engelstad K., Uddin J., Torres-Torronteras J., Jimenez-Mallebrera C., Marti R., Paradas C., Hirano M., Instituto de Salud Carlos III, Generalitat de Catalunya, European Commission, Muscular Dystrophy Association (US), and Arturo Estopinan TK2 Research Fund
- Subjects
0301 basic medicine ,Adult ,Compassionate Use Trials ,Male ,medicine.medical_specialty ,Neurology ,Side effect ,medicine.medical_treatment ,Deoxyribonucleosides ,Walk Test ,Gastroenterology ,Thymidine Kinase ,Article ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,Internal medicine ,tk2, myopathy, nucleosides, therapy ,medicine ,Humans ,Myopathy ,Child ,Feeding tube ,Mechanical ventilation ,business.industry ,Discontinuation ,Diarrhea ,030104 developmental biology ,Child, Preschool ,Female ,Neurology (clinical) ,GDF15 ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
[Objective] Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies., [Methods] We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2‐deficient patients under a compassionate use program., [Results] In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6‐minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose‐dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy., [Interpretation] This open‐label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293–303, This work was supported in part by grants from the Spanish Carlos III Health Institute (PMP15/00025 for C.P., F.Ma., and R.M.; PI16/00579 and CP09/00011 for C.J.‐M.), Muscular Dystrophy Association (577391), Arturo Estopinan TK2 Research Fund, Generalitat de Catalunya PERIS program (SLT002/16/00370 for J.T‐T.), and European Regional Development Fund.
- Published
- 2019
24. Association between mortality and implantable cardioverter-defibrillators by aetiology of heart failure: a propensity-matched analysis of the WARCEF trial
- Author
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Lan Mu, Ralph L. Sacco, Min Qian, Gregory Y.H. Lip, Tetz C. Lee, Susan Graham, Koki Nakanishi, Richard Buchsbaum, Marco R. Di Tullio, John L.P. Thompson, Bruce Levin, Siqin Ye, Patrick M. Pullicino, Shunichi Homma, Conrado J. Estol, Dirk J. Lok, Jay P. Mohr, Ronald S. Freudenberger, Douglas L. Mann, John R. Teerlink, Piotr Ponikowski, Stefan D. Anker, Warcef Investigators, and Arthur J. Labovitz
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Male ,medicine.medical_treatment ,Left ,Cardiomyopathy ,030204 cardiovascular system & hematology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular ,Ventricular Function, Left ,0302 clinical medicine ,Risk Factors ,Original Research Articles ,Cause of Death ,Medicine ,Ventricular Function ,Original Research Article ,030212 general & internal medicine ,Ejection fraction ,Hazard ratio ,Non‐ischaemic cardiomyopathy ,Middle Aged ,Implantable cardioverter-defibrillator ,Heart failure with reduced ejection fraction ,Non-ischaemic cardiomyopathy ,Defibrillators, Implantable ,3. Good health ,Survival Rate ,Heart Disease ,Echocardiography ,Cardiology ,Platelet aggregation inhibitor ,Female ,Implantable ,Cardiology and Cardiovascular Medicine ,Cardiomyopathies ,medicine.medical_specialty ,Heart Ventricles ,Lower risk ,03 medical and health sciences ,Clinical Research ,Internal medicine ,Propensity score matching ,Humans ,Propensity Score ,Radionuclide Ventriculography ,Retrospective Studies ,Aged ,Heart Failure ,Aspirin ,business.industry ,Proportional hazards model ,Anticoagulants ,Stroke Volume ,medicine.disease ,Confidence interval ,United States ,Warfarin ,business ,WARCEF Investigators ,Platelet Aggregation Inhibitors ,Implantable cardioverter‐defibrillator ,Follow-Up Studies ,Defibrillators - Abstract
Author(s): Lee, Tetz C; Qian, Min; Mu, Lan; Di Tullio, Marco R; Graham, Susan; Mann, Douglas L; Nakanishi, Koki; Teerlink, John R; Lip, Gregory YH; Freudenberger, Ronald S; Sacco, Ralph L; Mohr, Jay P; Labovitz, Arthur J; Ponikowski, Piotr; Lok, Dirk J; Estol, Conrado; Anker, Stefan D; Pullicino, Patrick M; Buchsbaum, Richard; Levin, Bruce; Thompson, John LP; Homma, Shunichi; Ye, Siqin; WARCEF Investigators | Abstract: AimsThere is debate on whether the beneficial effect of implantable cardioverter-defibrillators (ICDs) is attenuated in patients with non-ischaemic cardiomyopathy (NICM). We assess whether any ICD benefit differs between patients with NICM and those with ischaemic cardiomyopathy (ICM), using data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial.Methods and resultsWe performed a post hoc analysis using WARCEF (N = 2293; ICM, n = 991 vs. NICM, n = 1302), where participants received optimal medical treatment. We developed stratified propensity scores for having an ICD at baseline using 41 demographic and clinical variables and created 1:2 propensity-matched cohorts separately for ICM patients with ICD (N = 223 with ICD; N = 446 matched) and NICM patients (N = 195 with ICD; N = 390 matched). We constructed a Cox proportional hazards model to assess the effect of ICD status on mortality for patients with ICM and those with NICM and tested the interaction between ICD status and aetiology of heart failure. During mean follow-up of 3.5 ± 1.8 years, 527 patients died. The presence of ICD was associated with a lower risk of all-cause death among those with ICM (hazard ratio: 0.640; 95% confidence interval: 0.448 to 0.915; P = 0.015) but not among those with NICM (hazard ratio: 0.984; 95% confidence interval: 0.641 to 1.509; P = 0.941). There was weak evidence of interaction between ICD status and the aetiology of heart failure (P = 0.131).ConclusionsThe presence of ICD is associated with a survival benefit in patients with ICM but not in those with NICM.
- Published
- 2019
25. Smoking, alcohol and caffeine in relation to two hormonal indicators of ovarian age during the reproductive years
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Bruce Levin, Jennie Kline, and A. Tang
- Subjects
Adult ,Anti-Mullerian Hormone ,endocrine system ,medicine.medical_specialty ,Alcohol Drinking ,Abortion ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Follicle-stimulating hormone ,Follicle ,chemistry.chemical_compound ,0302 clinical medicine ,Ovarian Follicle ,Pregnancy ,Caffeine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,030219 obstetrics & reproductive medicine ,business.industry ,Reproduction ,Ovary ,Smoking ,Obstetrics and Gynecology ,Middle Aged ,Antral follicle ,medicine.disease ,Cross-Sectional Studies ,Endocrinology ,chemistry ,Atresia ,Female ,Follicle Stimulating Hormone ,business ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Objective To examine whether or not cigarette smoking, alcohol and caffeine intake are related to two indicators of ovarian age–anti-Mullerian hormone (AMH) and follicle stimulating hormone (FSH). Study design Cross-sectional study of 477 women with a recent index spontaneous abortion (SA) (105 trisomic, 93 non-trisomic) or livebirth (LB) (279) with hormones measured on days 2–4 of an apparently normal menstrual cycle after the index pregnancy. Results Current smoking is associated with about a 15% increase in median FSH (β for ln(FSH) = 0.14, 95% CI 0.03,0.25). It is not significantly related to AMH (β for ln(AMH) = −0.25, 95% CI −0.56,0.06). Neither alcohol 2–7 days per week nor caffeine 122– Conclusions The observation that current smoking is associated with FSH, but not with AMH, suggests that current smoking either impairs the development of antral follicles or dysregulates the hypothalamic–pituitary–ovarian axis. The absence of an association with AMH argues against mechanisms related to accelerated follicle atresia.
- Published
- 2016
26. The first prognostic model for stroke and death in patients with systolic heart failure
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Douglas L. Mann, Shunichi Homma, Susan Graham, Ralph L. Sacco, Conrado J. Estol, John R. Teerlink, Ronald S. Freudenberger, Gregory Y.H. Lip, Dirk J. Lok, Jay P. Mohr, Piotr Ponikowski, Bin Cheng, Stefan D. Anker, Alexandra R. Sanford, Richard Buchsbaum, John L.P. Thompson, Bruce Levin, Arthur J. Labovitz, Marco R. Di Tullio, and Patrick M. Pullicino
- Subjects
Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Risk Factors ,Cause of Death ,Internal medicine ,Humans ,Medicine ,Stroke ,Aged ,Cause of death ,Aspirin ,Models, Statistical ,Ejection fraction ,business.industry ,Warfarin ,Anticoagulants ,Middle Aged ,Prognosis ,medicine.disease ,Blood pressure ,Area Under Curve ,Heart failure ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Risk assessment ,Algorithms ,030217 neurology & neurosurgery ,Heart Failure, Systolic ,medicine.drug - Abstract
Background Patients with systolic heart failure (HF) are at increased risk of both ischemic stroke and death. Currently, no risk scores are available to identify HF patients at high risk of stroke or death. The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial studied 2305 HF patients, in sinus rhythm, followed for up to 6 years (3.5 ± 1.5 years). This trial showed no overall difference in those treated with warfarin vs aspirin with regard to death or stroke. The present study develops the first prognostic model to identify patients at higher risk of stroke or death based on their overall risk profile. Methods and results A scoring algorithm using 8 readily obtainable clinical characteristics as predictors, age, gender, hemoglobin, blood urea nitrogen, ejection fraction, diastolic blood pressure, diabetes status, and prior stroke or transient ischemic attack (C-index = 0.65, 95% CI: 0.613–0.681), was developed. It was validated internally using a bootstrap method. In predicting 1-year survival for death alone, our 8-predictor model had an AUC of 0.63 (95% CI: 0.579–0.678) while the 14-predictor Seattle model had an AUC of 0.72. The Seattle model did not report stroke. Conclusions This novel prognostic model predicts the overall risk of ischemic stroke or death for HF patients. This model compares favorably for death with the Seattle model and has the added utility of including stroke as an endpoint. Use of this model will help identify those patients in need of more intensive monitoring and therapy and may help identify appropriate populations for trials of new therapies. Clinical Trial Registration http://www.Clinicatrials.gov NCT00041938 .
- Published
- 2016
27. CHA2DS2-VASc score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm
- Author
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Stefan D. Anker, Siqin Ye, John L.P. Thompson, Patrick M. Pullicino, Dirk J. Lok, Jay P. Mohr, Min Qian, Shunichi Homma, Richard Buchsbaum, Bruce Levin, Marco R. Di Tullio, Gregory Y.H. Lip, Arthur J. Labovitz, Conrado J. Estol, Susan Graham, Ralph L. Sacco, Piotr Ponikowski, Ronald S. Freudenberger, Douglas L. Mann, Bo Zhao, and John R. Teerlink
- Subjects
medicine.medical_specialty ,Framingham Risk Score ,Ejection fraction ,business.industry ,Proportional hazards model ,Hazard ratio ,Stroke volume ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Heart failure ,Anesthesia ,medicine ,Cardiology ,Sinus rhythm ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Stroke - Abstract
AIMS The aim of this study was to determine whether the CHA2 DS2 -VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm. METHODS AND RESULTS CHA2 DS2 -VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage. Using proportional hazards models, we found that each 1-point increase in the CHA2 DS2 -VASc score was associated with increased hazard of death or ischaemic stroke events [hazard ratio (HR) for the warfarin arm = 1.21, 95% confidence interval (CI) 1.13-1.30, P < 0.001; for aspirin, HR = 1.20, 95% CI 1.11-1.29, P < 0.001]. Similar increased hazards for higher CHA2 DS2 -VASc scores were observed for death alone, ischaemic stroke alone, and major haemorrhage. Overall performance of the CHA2 DS2 -VASc score was assessed using c-statistics for full models containing the risk score, treatment assignment, and score-treatment interaction, with the c-statistics for the full models ranging from 0.57 for death to 0.68 for major haemorrhage. CONCLUSIONS The CHA2 DS2 -VASc score predicted adverse outcomes in patients with systolic heart failure in sinus rhythm, with modest prediction accuracy.
- Published
- 2016
28. On lattice event probabilities for Levin-Robbins-Leu subset selection procedures
- Author
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Cheng-Shiun Leu and Bruce Levin
- Subjects
Statistics and Probability ,education.field_of_study ,Conjecture ,Population ,Binary number ,020206 networking & telecommunications ,02 engineering and technology ,01 natural sciences ,Upper and lower bounds ,Combinatorics ,010104 statistics & probability ,Family member ,Arbitrarily large ,Modeling and Simulation ,Lattice (order) ,0202 electrical engineering, electronic engineering, information engineering ,Sequential selection ,0101 mathematics ,education ,Mathematics - Abstract
The Levin-Robbins-Leu (LRL) family of sequential subset selectionprocedures admits of a simple formula that provides a lower bound for the probability of various types of subset selection events. Here we demonstrate that a corresponding lower bound formula holds for lattice events when using the nonadaptive family member with binary outcomes. Lattice events are more general than the type of events that we previously considered in demonstrating that the nonadaptive LRL procedure selects “acceptable” subsets with an arbitrarily large prespecified probability irrespective of the true population parameters. Interestingly, the proof of the lower bound formula for lattice events that we present here simplifies the methods previously used and sheds additional light on why the lower bound formula holds. As for acceptable subset selection, we conjecture that the other LRL family members, which allow for adaptive elimination of inferior candidates and/or recruitment of superior candidates, obey the same low...
- Published
- 2016
29. Airway CD8+ T Cells Are Associated with Lung Injury during Infant Viral Respiratory Tract Infection
- Author
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Kara L. Bickham, Thomas J. Connors, Thyyar M. Ravindranath, John S. Baird, Donna L. Farber, Claire L. Gordon, Feifan Zhang, and Bruce Levin
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,T cell ,Acute Lung Injury ,Clinical Biochemistry ,CD8-Positive T-Lymphocytes ,Lung injury ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Viral Respiratory Tract Infection ,medicine ,Humans ,Cytotoxic T cell ,Lymphocyte Count ,Lung ,Respiratory Tract Infections ,Molecular Biology ,Demography ,Original Research ,Models, Statistical ,Respiratory tract infections ,Interleukin-6 ,business.industry ,Age Factors ,Infant ,Cell Differentiation ,Cell Biology ,Lymphocyte Subsets ,030104 developmental biology ,medicine.anatomical_structure ,Respiratory failure ,Immunology ,Female ,business ,030215 immunology - Abstract
Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. The objectives of the present study were to characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Daily airway secretions were sampled from infants and children 4 years of age and younger receiving mechanical ventilation owing to respiratory failure from viral infection or noninfectious causes. Samples were examined for immune cell composition and markers of T cell activation. These parameters were then correlated with clinical disease severity. Innate immune cells and total CD3(+) T cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T cell ratio was markedly increased in the airways of patients with viral infection compared with uninfected patients, and specifically in infected infants with acute lung injury. T cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. We identified a significant increase in airway cytotoxic CD8(+) T cells in infants with lung injury from viral respiratory tract infection that was distinct from the T cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage.
- Published
- 2016
30. Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials
- Author
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Bruce C.V. Campbell, Richard Buchsbaum, Xuya Huang, Bruce Levin, Mark W Parsons, Rachael L. MacIsaac, Christopher R Levi, Christopher F. Bladin, John L.P. Thompson, E. Clarke Haley, and Keith W. Muir
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Tenecteplase ,030204 cardiovascular system & hematology ,Tissue plasminogen activator ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Fibrinolytic Agents ,Randomized controlled trial ,Modified Rankin Scale ,law ,medicine ,Humans ,Thrombolytic Therapy ,Stroke ,Aged ,Randomized Controlled Trials as Topic ,Intracerebral hemorrhage ,business.industry ,Thrombolysis ,medicine.disease ,Surgery ,Neurology ,Tissue Plasminogen Activator ,Anesthesia ,Female ,business ,030217 neurology & neurosurgery ,Fibrinolytic agent ,medicine.drug - Abstract
Background Tenecteplase, a modified plasminogen activator with higher fibrin specificity and longer half-life, may have advantages over alteplase in acute ischemic stroke thrombolysis. Aims We undertook an individual patient data meta-analysis of randomized controlled trials that compared alteplase with tenecteplase in acute stroke. Methods Eligible studies were identified by a MEDLINE search, and individual patient data were acquired. We compared clinical outcomes including modified Rankin Scale at three months, early neurological improvement at 24 h, intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality at three months between all dose tiers of tenecteplase and alteplase. Results Three relevant studies (Haley et al., Parsons et al., and ATTEST) included 291 patients and investigated three doses of tenecteplase (0.1, 0.25, 0.4 mg/kg). There were no differences between any dose of tenecteplase and alteplase for either efficacy or safety end points. Tenecteplase 0.25 mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p = 0.093), excellent functional outcome (modified Rankin Scale 0–1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p = 0.28), with reduced odds of intracerebral hemorrhage (OR [95%CI] 0.6 [0.2, 1.8], P = 0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4 mg/kg, which showed increased odds of symptomatic intracerebral hemorrhage compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). Conclusions While no significant differences between tenecteplase and alteplase were found, point estimates suggest potentially greater efficacy of 0.25 and 0.1 mg/kg doses with no difference in symptomatic intracerebral hemorrhage, and potentially higher symptomatic intracerebral hemorrhage risk with the 0.4 mg/kg dose. Further investigation of 0.25 mg/kg tenecteplase is warranted.
- Published
- 2016
31. The futility study—Progress over the last decade
- Author
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Bruce Levin
- Subjects
medicine.medical_specialty ,Models, Statistical ,business.industry ,Management science ,Clinical study design ,General Medicine ,Article ,Clinical trial ,Clinical Trials, Phase II as Topic ,Research Design ,Humans ,Medicine ,Pharmacology (medical) ,Nervous System Diseases ,business ,Intensive care medicine - Abstract
We review the futility clinical trial design (also known as the non-superiority design) with respect to its emergence and methodologic developments over the last decade, especially in regard to its application to clinical trials for neurological disorders. We discuss the design’s strengths as a programmatic screening device to weed out unpromising new treatments, its limitations and pitfalls, and a recent critique of the logic of the method.
- Published
- 2015
32. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics
- Author
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Oliver Fiehn, Anthony L. Komaroff, W. Ian Lipkin, Dinesh Kumar Barupal, Bohyun Lee, Susan Levine, Bruce Levin, Dorottya Nagy-Szakal, Nancy G. Klimas, Jose G. Montoya, Ellie J. R. Kahn, Lucinda Bateman, Mady Hornig, J E Ukaigwe, Daniel L. Peterson, Xiaoyu Che, and Brent L. Williams
- Subjects
Male ,Sleep Wake Disorders ,0301 basic medicine ,lcsh:Medicine ,Orthostatic intolerance ,Disease ,Article ,Irritable Bowel Syndrome ,Pathogenesis ,Feces ,03 medical and health sciences ,Metabolomics ,medicine ,Chronic fatigue syndrome ,Humans ,Biomarker discovery ,lcsh:Science ,Fatigue ,Irritable bowel syndrome ,Fatigue Syndrome, Chronic ,Multidisciplinary ,business.industry ,lcsh:R ,Case-control study ,Middle Aged ,medicine.disease ,3. Good health ,Phenotype ,030104 developmental biology ,Case-Control Studies ,Immunology ,Female ,lcsh:Q ,Metagenomics ,business ,Biomarkers - Abstract
The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.
- Published
- 2018
33. Insulin Clearance After Oral and Intravenous Glucose Following Gastric Bypass and Gastric Banding Weight Loss
- Author
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Fatima Rimawi, Bruce Levin, Victoria Mark, Blandine Laferrère, Ankit Shah, James McGinty, Roxanne Dutia, and Marlena M. Holter
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,animal diseases ,Administration, Oral ,Bariatric Surgery ,Cohort Studies ,0302 clinical medicine ,Weight loss ,Insulin ,030212 general & internal medicine ,Longitudinal Studies ,Glucose tolerance test ,medicine.diagnostic_test ,virus diseases ,Middle Aged ,Postprandial Period ,Postprandial ,Liver ,Cohort ,Administration, Intravenous ,Female ,medicine.symptom ,Cohort study ,Adult ,medicine.medical_specialty ,Cardiovascular and Metabolic Risk ,Gastroplasty ,Metabolic Clearance Rate ,Gastric Bypass ,030209 endocrinology & metabolism ,03 medical and health sciences ,Internal medicine ,Diabetes mellitus ,Weight Loss ,Internal Medicine ,medicine ,Humans ,Advanced and Specialized Nursing ,business.industry ,Type 2 Diabetes Mellitus ,nutritional and metabolic diseases ,Glucose Tolerance Test ,medicine.disease ,Endocrinology ,Glucose ,Diabetes Mellitus, Type 2 ,Insulin Resistance ,business - Abstract
OBJECTIVE Hepatic insulin clearance is a significant regulator of glucose homestasis. We hypothesized that the improvement in insulin clearance rates (ICRs) under fasting conditions and in response to oral and intravenous (IV) glucose would improve similarly after Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) as a function of weight loss; the difference in ICR after oral and IV glucose stimulation will be enhanced after RYGB compared with AGB, an effect mediated by glucagon-like peptide 1 (GLP-1). RESEARCH DESIGN AND METHODS In study 1, the ICR was calculated under fasting condition (F-ICR), after oral glucose (O-ICR), and after an isoglycemic IV glucose clamp (IV-ICR) in individuals from an established cohort with type 2 diabetes mellitus (T2DM) before, after 10% matched weight loss, and 1 year after either RYGB (n = 22) or AGB (n = 12). In study 2, O-ICR was studied in a separate cohort of individuals with T2DM (n = 22), before and 3 months after RYGB, with and without exendin(9-39) infusion. RESULTS In study 1, age, BMI, T2DM duration and control, and ICR did not differ between RYGB and AGB preintervention. Weight loss at 1 year was two times greater after RYGB than after AGB (31.6 ± 5.9% vs. 16.6 ± 9.8%; P < 0.05). RYGB and AGB both significantly increased F-ICR, O-ICR, and IV-ICR at 1 year. ICR was inversely associated with insulinemia. The difference between IV-ICR and O-ICR was significantly greater after RYGB versus AGB. GLP-1 antagonism with exendin(9-39) led to an increase in O-ICR in subjects post-RYGB. CONCLUSIONS Weight loss increased ICR, an effect more pronounced after RYGB compared with AGB. Our data support a potential role for endogenous GLP-1 in the control of postprandial ICR after RYGB.
- Published
- 2018
34. Short-term effectiveness of HIV care coordination among persons with recent HIV diagnosis or history of poor HIV outcomes
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Rebekkah S. Robbins, Levi Waldron, Bisrat Abraham, Sarah Gorrell Kulkarni, Stephanie Chamberlin, Julie E. Myers, Sarah L. Braunstein, McKaylee Robertson, Kate Penrose, Denis Nash, Bruce Levin, and Mary K. Irvine
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0301 basic medicine ,RNA viruses ,Male ,Epidemiology ,Human immunodeficiency virus (HIV) ,lcsh:Medicine ,HIV Infections ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Geographical locations ,Cohort Studies ,Treatment status ,0302 clinical medicine ,Immunodeficiency Viruses ,immune system diseases ,Outcome Assessment, Health Care ,Public and Occupational Health ,Registries ,030212 general & internal medicine ,lcsh:Science ,skin and connective tissue diseases ,education.field_of_study ,Multidisciplinary ,HIV diagnosis and management ,Viral Load ,Continuity of Patient Care ,Middle Aged ,Vaccination and Immunization ,Socioeconomic Aspects of Health ,3. Good health ,Treatment Outcome ,Medical Microbiology ,HIV epidemiology ,Research Design ,Viral Pathogens ,Evidence-Based Practice ,Viruses ,Female ,Pathogens ,0305 other medical science ,Viral load ,Cohort study ,Research Article ,Adult ,musculoskeletal diseases ,medicine.medical_specialty ,Adolescent ,Anti-HIV Agents ,Immunology ,Population ,HIV diagnosis ,New York ,Antiretroviral Therapy ,Newly diagnosed ,Research and Analysis Methods ,Microbiology ,Young Adult ,03 medical and health sciences ,Antiviral Therapy ,Virology ,Internal medicine ,Retroviruses ,medicine ,Humans ,education ,Microbial Pathogens ,Aged ,Retrospective Studies ,Medicine and health sciences ,030505 public health ,business.industry ,Lentivirus ,lcsh:R ,Organisms ,Biology and Life Sciences ,HIV ,030112 virology ,Diagnostic medicine ,United States ,Health Care ,Relative risk ,North America ,New York City ,lcsh:Q ,Preventive Medicine ,People and places ,business ,Viral Transmission and Infection - Abstract
The New York City HIV Care Coordination Program (CCP) combines multiple evidence-based strategies to support persons living with HIV (PLWH) at risk for, or with a recent history of, poor HIV outcomes. We assessed the comparative effectiveness of the CCP by merging programmatic data on CCP clients with population-based surveillance data on all New York City PLWH. A non-CCP comparison group of similar PLWH who met CCP eligibility criteria was identified using surveillance data. The CCP and non-CCP groups were matched on propensity for CCP enrollment within four baseline treatment status groups (newly diagnosed or previously diagnosed and either consistently unsuppressed, inconsistently suppressed or consistently suppressed). We compared CCP to non-CCP proportions with viral load suppression at 12-month follow-up. Among the 13,624 persons included, 15·3% were newly diagnosed; among the 84·7% previously diagnosed, 14·2% were consistently suppressed, 28·9% were inconsistently suppressed, and 41 ·6% were consistently unsuppressed in the year prior to baseline. At 12-month follow-up, 59·9% of CCP and 53·9% of non-CCP participants had viral load suppression (Relative Risk=1.11, 95%CI:1.08-1.14). Among those newly diagnosed and those consistently unsuppressed at baseline, the relative risk of viral load suppression in the CCP versus non-CCP participants was 1.15 (95%CI:1.09-1.23) and 1.32 (95%CI:1.23-1.42), respectively. CCP exposure shows benefits over no CCP exposure for persons newly diagnosed or consistently unsuppressed, but not for persons suppressed in the year prior to baseline. We recommend more targeted case finding for CCP enrollment and increased attention to viral load suppression maintenance.
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- 2018
35. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT
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Tom Kindlon, David Tuller, Alem Matthees, Robert Courtney, Bruce Levin, Carolyn E. Wilshire, and Keith Geraghty
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Adult ,Chronic fatigue syndrome treatment ,medicine.medical_specialty ,medicine.medical_treatment ,lcsh:BF1-990 ,Treatment and control groups ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Chronic fatigue syndrome ,Humans ,Myalgic encephalomyelitis ,030212 general & internal medicine ,General Psychology ,Protocol (science) ,Fatigue Syndrome, Chronic ,Cognitive Behavioral Therapy ,Cognition ,General Medicine ,medicine.disease ,Exercise Therapy ,Graded exercise therapy ,3. Good health ,Cognitive behavioral therapy ,lcsh:Psychology ,Treatment Outcome ,Cognitive therapy ,Physical therapy ,Self Report ,Psychology ,030217 neurology & neurosurgery ,Follow-Up Studies ,Research Article - Abstract
Background The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome. Reports concluded that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the reported analyses did not consistently follow the procedures set out in the published protocol, and it is unclear whether the conclusions are fully justified by the evidence. Methods Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the trial as a whole. Results On the original protocol-specified primary outcome measure - overall improvement rates - there was a significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects were almost entirely confined to self-report measures. These effects did not endure beyond two years. Conclusions These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT and GET. The modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be reasonably accounted for by participant reporting biases.
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- 2018
36. Retrospective natural history of thymidine kinase 2 deficiency
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Miguel A. Martín, Andrés Nascimento, D. Ram, Julio Montoya, Marcos Madruga-Garrido, Christoph Karch, Sandeep Jayawant, M Imelda Hughes, Patrick F. Chinnery, Maria Alice Donati, Joshua Kriger, Emanuele Barca, Yolanda Cámara, Michio Hirano, Robert W. Taylor, Robert Schoenaker, Pirjo Isohanni, Carlos Ortez, John L.P. Thompson, Carlos Lopez Gomez, Mariana Loos, Carl Fratter, Salvatore DiMauro, Karin Kleinsteuber, J. Domínguez-Carral, Monika Hofer, Anu Suomalainen, Jeffrey W. Ralph, Ewen W. Sommerville, Bruce Levin, Caterina Garone, Cristina Domínguez-González, Grainne S. Gorman, Robert McFarland, Julie Evans, Sonia Emperador, Yuelin Long, Adnan Y. Manzur, Shamima Rahman, Neil D Thomas, Joanna Poulton, Timothy Kerr, Anupam Chakrapani, Garone C., Taylor R.W., Nascimento A., Poulton J., Fratter C., Dominguez-Gonzalez C., Evans J.C., Loos M., Isohanni P., Suomalainen A., Ram D., Imelda Hughes M., McFarland R., Barca E., Gomez C.L., Jayawant S., Thomas N.D., Manzur A.Y., Kleinsteuber K., Martin M.A., Kerr T., Gorman G.S., Sommerville E.W., Chinnery P.F., Hofer M., Karch C., Ralph J., Camara Y., Madruga-Garrido M., Dominguez-Carral J., Ortez C., Emperador S., Montoya J., Chakrapani A., Kriger J.F., Schoenaker R., Levin B., Thompson J.L.P., Long Y., Rahman S., Donati M.A., Dimauro S., Hirano M., Doctoral Programme in Clinical Research, Research Programs Unit, Anu Wartiovaara / Principal Investigator, Research Programme for Molecular Neurology, Children's Hospital, Clinicum, Lastenneurologian yksikkö, University of Helsinki, Doctoral Programme Brain & Mind, Neurologian yksikkö, Neuroscience Center, HUS Children and Adolescents, Lopez Gomez, Carlos [0000-0003-2699-451X], Martin, Miguel A [0000-0003-4741-772X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,metabolic disorder ,Male ,0302 clinical medicine ,Retrospective Studie ,Medicine ,Age of Onset ,Child ,Genetics (clinical) ,SPINAL MUSCULAR-ATROPHY ,MYOPATHIC FORM ,Facial weakness ,metabolic disorders ,MITOCHONDRIAL-DNA DEPLETION ,Middle Aged ,3. Good health ,Phenotypes ,Phenotype ,MTDNA DEPLETION ,muscle disease ,Child, Preschool ,Female ,Survival Analysi ,medicine.symptom ,clinical genetics ,TK2 GENE ,Natural history study ,Human ,Adult ,medicine.medical_specialty ,Weakness ,Neuromuscular disease ,Adolescent ,Genes, Recessive ,Genetic Association Studie ,PATIENT ,Thymidine Kinase ,Ophthalmoparesis ,Mitochondrial Proteins ,03 medical and health sciences ,Young Adult ,Muscular Diseases ,neuromuscular disease ,Internal medicine ,Genetics ,Humans ,Mitochondrial Protein ,Genetic Predisposition to Disease ,Genetic Testing ,Myopathy ,Muscle, Skeletal ,Genetic Association Studies ,Retrospective Studies ,Aged ,SPECTRUM ,MUTATIONS ,business.industry ,Muscular Disease ,clinical genetic ,Infant, Newborn ,Infant ,Spinal muscular atrophy ,medicine.disease ,Survival Analysis ,DELETIONS ,030104 developmental biology ,DEFECT ,Mutation ,3111 Biomedicine ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.ObjectiveTo perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.MethodsThe study was conducted by 42 investigators across 31 academic medical centres.ResultsWe identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion.ConclusionsIn TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.
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- 2018
37. Quality of Anticoagulation Control in Preventing Adverse Events in Patients With Heart Failure in Sinus Rhythm
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S. Shaw, Conrado J. Estol, Biykem Bozkurt, B. Donelly, R. Berkowitz, L. Berente, M. Jurczok, J. Simon, Sami Khella, A. Travis, M. Schoenauer, Ronald S. Freudenberger, Anikó Ilona Nagy, G. Marcinek, M. Hajkova, T. Siebert, R. Breedveld, W. Baker, P. Avellana, S. Kozhukhov, M. Diek, J. Jaros, R. Vicari, S. Timar, C. Schanz, J. Povolny, M. van Zagten, Shelley Zieroth, G. Rex, M. Apelian, M. Dzaiy, K. Hayward, A. Warner, L. Baliko, Piotr Ponikowski, S. Mathus, Arthur J. Labovitz, C. DeMers, E. Péterfai, Mariana Bolos, B. Stephens, F. Tito, Denise L. Janosik, N. Molakala, J. Dizes, R. van der Loo, A. van Bujisen-Nutters, K. Wolf, S. Nawaz, A. Boguschewski, D. Ferguson, A. McPhail, M. Rohwedder, M. Malkowski, R. Prodhan, P. Miekus, R. Pellegrino, M. Rossi, Michelle Bierig, E. Wirkowski, Zbigniew Gaciong, F. Guerlloy, D. Chupka, O. Kovtun, M. Padour, D. Horak, Elly M.C.J. Wajon, J. Carda, P. Gregor, M. Tilem, P. Kosolcharoen, R. Wensel, V. Garman, N. Torok, B. Benczur, E. Peña, G. Moe, B.M. Massie, S. Slomiak, C. Benesch, V. Orlyk, K. Greenan, M. Ogorek, I. Jedlinski, Shun Kohsaka, R. Haynes, Z. Lorenc, M. Kuchar, R. Pauer, T. Dugan, A. Juszczak, T. Schrader, A. Henriquez, K. Toth, M. Varga, J. Herman, M. Lee, M. Dunaj, L. Krizova, M. Bonora, P. Loviska, D. Aubin, M. Kokles, J. D. Easton, J. Meschia, A. Bruno, Steven Goldman, S. Voigt, D. Malchik, A. Tierney, Demetrios J. Sahlas, N. Elzebroek, Richard J. Hobbs, M. Charlet, B. Hattler, L. Regos, Dennis Wolf, A. Peljto, C. Lindsey, R. Winkler, J. Arredondo, B. Oze, C. Schuler, D. Bruck, E. Jones, G. Torre, S. Nabhan, G. Mallis, Jindřich Špinar, W. Graettinger, A. Ruiz, N. Holwerda, R. Katz, J. Gonzalez, Christine Gerula, P. Jansky, H. V. Anderson, B. Krizova, Andreas König, M. Moussavian, M. Konarzewski, G. Jakab, M. Liston, Elizabeth O. Ofili, L. Nikolaidis, Susan E. Ammon, Rebekka K. Schneider, M. Krauze-Wielicka, M. Zimmermann, J. Lynch, J. Minuk, F. Sokn, Douglas L. Mann, R. Sawyer, J. Partridge, D. Leifer, M. Bohdanowicz-Zazula, D. Barratt, C. Dewar, S. Kolomiets, T. Noonan, D. Beran, M. Jeserich, J. Wong, R. Bessoudo, M. Lichtenberger, E. Bednarova, R. Serafin, M. Scullin, I. Kosa, M. Hranai, E. Duverger, L. Joseph, A. M. Sindilar, I. Edes, E. Yakimenko, J. Hobbs-Williams, F. Novoa, A. Szczepanska, R. Wachter, P. A. de Milliano, L. Golan, Gregory W. Albers, K. Ammerman, Alexandra R. Sanford, W. Burgin, A. Richmond, A. Kleinrok, B. Dandapani, Laurie Gutmann, M. Houra, Udho Thadani, P. Schygiel, A. van Hessen, Christian Weber, S. Mehešová, P. Stein-Beal, E. Flanagan, R. Khadouri, P. Chang, Thomas P. Cappola, L. Konczarek, B. Mangariello, L. Atkins, C. McKay, J. Svoboda, O. Lesniak, L. Westbrook, S. J. Kim, C. Moy, M. Kuch, M. Nemec, M. Krobot, B. Kozlowski, M. Applegate, M. Kiorwantsi, J. Thierer, K. Craig, A. Slim, Y. Besaga, R. Kuba, P. Fulop, K. Crotto, R. Porcile, E. Falgout, E. Olgren, K. Kuc, Marcus F. Stoddard, W. Almeida, L. Pas, L. Williams, I. Sorokina, J. Rodl, S. Sparr, A. Coppes, E. Ronner, A. Jurczyk, S. Gass, John R. Teerlink, P. Kucera, H. J. Barnett, B. McGinnis, L. Wilson, Y. Tutov, R. MacFadyen, Gregory Y.H. Lip, V. Sorrell, T. Ochalek, J. Turner, M. Modzelewski, Matthew Wilson, A. Ogorodnichuk, C. Anderson, P. de Kort, B. Palossy, Alan B. Miller, T. Giles, H. Brown, Andrew H. Baker, P. Czaja, Roman Szełemej, J. Hanna, P. Gilbert, A. Metcalf, R. Piotrowski, D. Yip, B. Coull, P. Gitelman, Burkert Pieske, C. Rapallo, M. Morgil, M. Resch, A. Zachar, Jan Biegus, W. Watson, J. A. Hinchey, E. Polland, L. Caufield, D. Kopcik, E. Pechackova, M. Calderon, Stefan D. Anker, V. Virkud, R. Rothbart, L. Rudenko, W. Wicha, B. Jacques, Susan Graham, J. Donaldson, O. Girina, L. Guillory, S. Khoury, I. Padourova, Haissam Haddad, L. Kowalczyk, J. A. Swain, G. Prokop-Lewicka, R. Mattessich, K. Remmel, S. Tikhonova, S. Klochkov, J. Leppo, K. C. Johnston, D. Gohs, Peter K. Smith, Eric E. Smith, V. Hart, J. Vanyi, L. Voronkov, G. Allam, M. Klapholz, T. Varadyova, S. Daugherty, L. Witkin, K. Panizzon, B. Drachman, S. Locke, Ann‐Katrin Mojica Munoz, J. Love, T. Winder, P. Bailey, T. Huynh, G. A. Verheul, Tomasz J. Pasierski, J. Borbola, R. Liu, A. Elizalde, C. Walker, R. Kelley, Robert Côté, P. Frey, J. McGee, Peter E. Carson, T. Bator, Donald L. Patrick, K. Karsay, J. Plomp, O. Novikova, J. Vuijsters, Jay P. Mohr, A. Parkhomenko, A. Ducharme, C. Alteri, S. Borden, Siqin Ye, W. Felton, K. Peterson, M. Satori, N. Polenova, D. Karia, G. Turhan, R. Nagy, K. Amosova, J. Michalska, R. Libman, E. Frey, O. Najmanova, R. Yufe, O. Montaña, S. Bailey, M. Bodi, A. Ellis, J. Tarchalski, L. Sitwell, M. Del Valle, John P. Boehmer, J. Marler, P. Romia, K. Tea, E. Hartmann, R. Lebedova, V. Yurlov, O. Karpenko, Malcolm Arnold, P. Berkowski, J. Johnson, P. Ramappa, R. Ferkl, Dirk J. Lok, N. Bayer, S. Bezucha, A. Mercando, H. Tworek, R. Longaker, P. Jinkins, J. Kirmani, L. Svoboda, David Spence, Min Qian, John L.P. Thompson, N. Brodi, Y. Prokopovych, Sedat Sen, M. Nanna, S. T. Palmeri, M. Michalova, L. Giron, K. Wolkowska, D. Borts, K. Hamroui, G. Linssen, L. Arcement, A. McNulty, C. Jakobs, F. Bleyer, W. Lo, J. Bisognano, J. Kosits, Steven R. Levine, G. Berry, P. Heidrich, G. Kiss, G. Tullio, J. Yasen, G. Ortiz, B. O'Hare, P. Jackson, T. Rennie, Z. Davidovits, G. v Buchem-Damming, H. Dvorakova, W. Hermans, Zbigniew Kalarus, H. Morgil, C. Harris, M. Vissiennon, Shunichi Homma, André P. Gabriel, J. Aiub, I. Katzan, C. Zaidman, S. Sassone, A. Duszanska, J. Litvinova, P. Kralicek, M. Natour, E. Nagy, E. Nishime, M. J. Bos, S. Nowakowska, J. Beebe, B. Watson, N. Jacek, Ralph L. Sacco, A. Cwynar, S. Pezzella, B. George, B. Hott, T. Vegh, V. Mejia, E. Janzen, M. Eliasziw, Heribert Schunkert, L. Swydan, J. Gora, D. Drazek, C. Landau, L. Roffidal, L. Casazza, Andrew M Penn, Richard L. Hughes, V. Schumann, R. Santi, I. Sakharchuk, A. Adler, D. Taylor, C. F. Peerenboom-Fey, M. Dluzniewski, L. Cape, Attila Kovacs, E. Ziekenhuis, A. Bujdoso, L. Fischer, Richard Buchsbaum, Petr Arenberger, L. Pollak, J. Vosmerova, B. Donley, Patrick M. Pullicino, B. Darrow, A. Minagar, N. Jarmukli, J. Dissin, M. Daniels, L. Csuros, G. J. del Zoppo, E. Anthony, B. Metzkier-Wyrwa, A. Ronaszeki, I. Malek, R. Arbing, Gilberto Levy, D. Mauceri, Carlos J. Rodriguez, V. Kovalenko, J. Smith, O. Yaremenko, R. de Graaf Gasthuis, C. Donato, L. Spinarova, Martin M. Brown, F. Padour, O. Lovasz, Marco R. Di Tullio, K. Balaban, S. Donovan, S. Genth-Zotz, M. Maruskova, I. Varga, T. Drasnar, V. Berchou, R. Davies, Robert G. Hart, M. Lebedynska, G. Hageman, D. Disantis, W. Schneider, M. Frankel, A. Hajnalne, S. Baumann, P. Karpati, L. C. Pettigrew, Johnston Grier, A. Ellenberg, Bruce Levin, and Stephanie Hope Dunlap
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Intracerebral hemorrhage ,medicine.medical_specialty ,Aspirin ,Ejection fraction ,business.industry ,Warfarin ,030204 cardiovascular system & hematology ,medicine.disease ,3. Good health ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Heart failure ,Internal medicine ,medicine ,Cardiology ,Sinus rhythm ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Stroke ,medicine.drug - Abstract
Background— The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin. Methods and Results— We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P P =0.001), and improved net clinical benefit (adjusted P P =0.082 for ischemic stroke and adjusted P =0.109 for major hemorrhage). Conclusions— In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00041938.
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- 2015
38. Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders
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Lokendra V. Chauhan, Mady Hornig, Pål Surén, Bruce Levin, Siri Mjaaland, Milada Mahic, Michaeline Bresnahan, Xiaoyu Che, Ted Reichborn-Kjennerud, Thomas Briese, Ezra Susser, Per Magnus, W. Ian Lipkin, and Camilla Stoltenberg
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0301 basic medicine ,medicine.medical_specialty ,prenatal ,Offspring ,lcsh:QR1-502 ,autism ,serology ,Microbiology ,lcsh:Microbiology ,influenza virus ,Virus ,Serology ,Clinical Science and Epidemiology ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,mental disorders ,Epidemiology ,Medicine ,Risk factor ,Molecular Biology ,business.industry ,virus diseases ,birth cohort ,Odds ratio ,medicine.disease ,QR1-502 ,infection ,3. Good health ,030104 developmental biology ,Immunology ,Autism ,Gestation ,business ,Research Article - Abstract
The causes of most cases of autism spectrum disorders (ASD) are unknown. Some epidemiological studies suggest that maternal gestational influenza virus infection may increase the risk of ASD in offspring. Here, we describe an analysis of a large birth cohort with results based on questionnaires that prospectively addressed subjective reports of influenza-like illness and serological assays for objective determination of influenza virus infection. Although serologic evidence of gestational influenza virus infection alone was not associated with risk, positive serology and symptoms of influenza-like illness cannot yet be definitely ruled out as a risk factor., The literature concerning gestational maternal influenza virus infection and risk of autism spectrum disorders (ASD) is inconclusive. To address this uncertainty, we obtained information from questionnaires and samples from the Autism Birth Cohort, a prospective birth cohort comprising mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaires, referrals, and linkages to the Norwegian National Patient Registry, we identified 338 mothers of children with ASD and 348 frequency-matched controls for whom plasma samples that had been collected midpregnancy and after delivery were available for influenza virus serology via luciferase immunoprecipitation and hemagglutinin inhibition assays for influenza virus strains circulating during the study period. Assay data were combined to define serological status and integrated with self-reports of influenza-like illness to estimate ASD risk. Neither influenza A nor influenza B virus infection was associated with increased ASD risk. Integration of reports of symptoms of influenza-like illness with serology revealed an increase in risk for seropositive women with symptoms, but this increase did not achieve statistical significance (a level of P < 0.05) in the comparison with seronegative women without symptoms (adjusted odds ratio, 1.93; 95% confidence interval, 0.95 to 3.89; P = 0.068). Although chance may explain our findings, the magnitude of the potential association may be of biological importance, and dismissing our findings could result in failure to detect a bona fide association (type II error). If the association is true, we posit that the risk is due to activation of the maternal immune system following infection rather than direct fetal infection. Data on levels of cytokines or other mediators of inflammation would allow us to test the validity of this hypothesis. IMPORTANCE The causes of most cases of autism spectrum disorders (ASD) are unknown. Some epidemiological studies suggest that maternal gestational influenza virus infection may increase the risk of ASD in offspring. Here, we describe an analysis of a large birth cohort with results based on questionnaires that prospectively addressed subjective reports of influenza-like illness and serological assays for objective determination of influenza virus infection. Although serologic evidence of gestational influenza virus infection alone was not associated with risk, positive serology and symptoms of influenza-like illness cannot yet be definitely ruled out as a risk factor.
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- 2017
39. Correction for Mahic et al., 'Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring'
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Ted Reichborn-Kjennerud, Michaeline Bresnahan, Camilla Stoltenberg, Bruce Levin, Pål Surén, W. Ian Lipkin, Christine Roth, Deborah Hirtz, Synnve Schjølberg, Siri Mjaaland, Anne-Siri Øyen, Mady Hornig, Ezra Susser, Hege Bøvelstad, Xiaoyu Che, Milada Mahic, Per Magnus, and Nina Gunnes
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Pediatrics ,medicine.medical_specialty ,Offspring ,lcsh:QR1-502 ,medicine.disease_cause ,medicine.disease ,Microbiology ,lcsh:Microbiology ,QR1-502 ,Herpes simplex virus ,Autism spectrum disorder ,Immunology ,medicine ,Psychology ,Author Correction ,Molecular Biology - Abstract
Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to
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- 2017
40. Ventricular assist device elicits serum natural IgG that correlate with the development of primary graft dysfunction following heart transplantation
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Susan Restaino, George Vlad, Peter J. Kennel, P. Christian Schulze, Matthew P. Weber, Kortney Rogers, Veli K. Topkara, Elena R. Vasilescu, Feifan Zhang, Kevin J. Clerkin, Emmanuel Zorn, Bruce Levin, Donna M. Mancini, Sarah B. See, Debanjana Chatterjee, Maryjane Farr, Paolo C. Colombo, and Yoshifumi Naka
- Subjects
Pulmonary and Respiratory Medicine ,Male ,medicine.medical_treatment ,T-Lymphocytes ,Primary Graft Dysfunction ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Human leukocyte antigen ,030204 cardiovascular system & hematology ,030230 surgery ,Epitope ,Article ,03 medical and health sciences ,Epitopes ,0302 clinical medicine ,parasitic diseases ,medicine ,Humans ,cardiovascular diseases ,Sensitization ,Retrospective Studies ,Heart transplantation ,Heart Failure ,Transplantation ,B-Lymphocytes ,biology ,business.industry ,Angiography ,Middle Aged ,Allografts ,Flow Cytometry ,Antibodies, Anti-Idiotypic ,B-1 cell ,medicine.anatomical_structure ,Immunoglobulin G ,Immunology ,biology.protein ,Heart Transplantation ,Surgery ,Female ,Heart-Assist Devices ,biological phenomena, cell phenomena, and immunity ,Antibody ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Background Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. Methods IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. Results No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). Conclusions Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication.
- Published
- 2017
41. Reply to Magaret and Wald, 'Autism Link to Herpes Simplex Virus 2 Antibody in Pregnancy Likely To Be Spurious'
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Milada Mahic, Siri Mjaaland, Ezra Susser, Michaeline Bresnahan, Xiaoyu Che, Bruce Levin, Mady Hornig, W. Ian Lipkin, and Michael J. Imperiale
- Subjects
herpesviruses ,prenatal ,viruses ,lcsh:QR1-502 ,serology ,autism ,HSL and HSV ,medicine.disease_cause ,Microbiology ,lcsh:Microbiology ,Clinical Science and Epidemiology ,medicine ,Spurious relationship ,Molecular Biology ,Letter to the Editor ,Pregnancy ,biology ,birth cohort ,medicine.disease ,herpes simplex virus ,Virology ,infection ,QR1-502 ,Titer ,Herpes simplex virus ,Viral replication ,Immunology ,biology.protein ,Autism ,Antibody ,Psychology - Abstract
We thank Magaret and Wald ([1][1]) for comments on our paper that allow us to clarify our experimental design and reemphasize take-home points. They raise four concerns, namely, that (i) there is no correlation between high titers of antibody to HSV and viral replication or HSV acquisition, (ii) the
- Published
- 2017
42. Resting Heart Rate and Ischemic Stroke in Patients with Heart Failure
- Author
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Shunichi Homma, Conrado J. Estol, Richard Buchsbaum, Ronald S. Freudenberger, Ralph L. Sacco, Koki Nakanishi, Arthur J. Labovitz, Gregory Y.H. Lip, Douglas L. Mann, Dirk J. Lok, Susan Graham, John R. Teerlink, Min Qian, Patrick M. Pullicino, Jay P. Mohr, Bruce Levin, Marco R. Di Tullio, Stefan D. Anker, John L.P. Thompson, and Piotr Ponikowski
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Rest ,Adrenergic beta-Antagonists ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Article ,Brain Ischemia ,03 medical and health sciences ,Electrocardiography ,0302 clinical medicine ,Fibrinolytic Agents ,Heart Rate ,Risk Factors ,Internal medicine ,Heart rate ,Medicine ,Humans ,Sinus rhythm ,030212 general & internal medicine ,Beta blocker ,Stroke ,Aged ,Proportional Hazards Models ,Heart Failure ,Ejection fraction ,medicine.diagnostic_test ,business.industry ,Incidence ,Anticoagulants ,Middle Aged ,medicine.disease ,Prognosis ,3. Good health ,Neurology ,Heart failure ,Multivariate Analysis ,Cardiology ,Linear Models ,Platelet aggregation inhibitor ,Female ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors - Abstract
Background: Although high resting heart rate (RHR) is known to be associated with an increased risk of mortality and hospital admission in patients with heart failure, the relationship between RHR and ischemic stroke remains unclear. This study is aimed at investigating the relationship between RHR and ischemic stroke in patients with heart failure in sinus rhythm. Methods: We examined 2,060 patients with systolic heart failure in sinus rhythm from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. RHR was determined from baseline electrocardiogram, and was examined as both a continuous variable and a categorical variable using quartiles. Ischemic strokes were identified during follow-up and adjudicated by physician review. Results: During 3.5 ± 1.8 years of follow-up, 77 patients (5.3% from Kaplan-Meier [KM] curve) experienced an ischemic stroke. The highest incidence of ischemic stroke (21/503 [KM 6.9%]) was observed in the lowest RHR quartile (RHR 79 beats/min (p = 0.693). Multivariable Cox proportional hazards analysis revealed that RHR was significantly associated with ischemic stroke (hazard ratio per unit decrease: 1.07, 95% CI 1.02-1.13, when RHR p = 0.038), along with a history of stroke or transient ischemic attack and left ventricular ejection fraction. Conclusions: In contrast to its beneficial effect on mortality and hospital re-admissions, lower RHR may increase the risk of ischemic stroke in patients with systolic heart failure in sinus rhythm.
- Published
- 2017
43. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring
- Author
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Pål Surén, Deborah Hirtz, Nina Gunnes, Michaeline Bresnahan, Camilla Stoltenberg, W. Ian Lipkin, Milada Mahic, Hege Bøvelstad, Synnve Schjølberg, Ezra Susser, Anne-Siri Øyen, Ted Reichborn-Kjennerud, Per Magnus, Christine Roth, Siri Mjaaland, Mady Hornig, Xiaoyu Che, and Bruce Levin
- Subjects
0301 basic medicine ,prenatal ,Offspring ,lcsh:QR1-502 ,autism ,serology ,Biology ,medicine.disease_cause ,Microbiology ,lcsh:Microbiology ,Serology ,Clinical Science and Epidemiology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Molecular Biology ,Pregnancy ,Rubella virus ,birth cohort ,Odds ratio ,medicine.disease ,herpes simplex virus ,infection ,QR1-502 ,3. Good health ,030104 developmental biology ,Herpes simplex virus ,Autism spectrum disorder ,Immunology ,Autism ,030217 neurology & neurosurgery ,Research Article - Abstract
The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy., Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child’s birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy.
- Published
- 2017
44. Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients: From the WARCEF Trial
- Author
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John R, Teerlink, Min, Qian, Natalie A, Bello, Ronald S, Freudenberger, Bruce, Levin, Marco R, Di Tullio, Susan, Graham, Douglas L, Mann, Ralph L, Sacco, J P, Mohr, Gregory Y H, Lip, Arthur J, Labovitz, Seitetz C, Lee, Piotr, Ponikowski, Dirk J, Lok, Stefan D, Anker, John L P, Thompson, and Shunichi, Homma
- Subjects
Heart Failure ,Male ,Aspirin ,Anticoagulants ,Angiotensin-Converting Enzyme Inhibitors ,Stroke Volume ,Kaplan-Meier Estimate ,Middle Aged ,Hospitalization ,Angiotensin Receptor Antagonists ,Double-Blind Method ,Humans ,Cyclooxygenase Inhibitors ,Female ,Warfarin - Abstract
The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB).Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue.We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events).After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates.Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients. (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial [WARCEF]; NCT00041938).
- Published
- 2017
45. Prenatal fever and autism risk
- Author
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M L Eddy, Andrew F. Schultz, Deborah Hirtz, Camilla Stoltenberg, Mady Hornig, Nina Gunnes, Anne-Siri Øyen, Synnve Schjølberg, Per Magnus, Michaeline Bresnahan, J E Ukaigwe, Walter Ian Lipkin, Ezra Susser, Siri Mjaaland, Bruce Levin, Ted Reichborn-Kjennerud, Xiaoyu Che, and Kari Kveim Lie
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,Fever ,Autism Spectrum Disorder ,Genetic Linkage ,Maternal Fever ,Mothers ,Gestational Age ,Infections ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Surveys and Questionnaires ,Odds Ratio ,medicine ,Humans ,Prospective Studies ,Registries ,Autistic Disorder ,Psychiatry ,Prospective cohort study ,Molecular Biology ,Norway ,business.industry ,Infant, Newborn ,Infant ,Gestational age ,Odds ratio ,medicine.disease ,Immunity, Innate ,3. Good health ,Psychiatry and Mental health ,030104 developmental biology ,Maternal Exposure ,Pregnancy Trimester, Second ,Prenatal Exposure Delayed Effects ,Cohort ,Gestation ,Autism ,Original Article ,Female ,business ,030217 neurology & neurosurgery - Abstract
Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born greater than or equal to 32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09–1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28–7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD. publishedVersion
- Published
- 2017
46. Cat and Mouse: The Evolutionary Dynamics of Getting Around the Law
- Author
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Daria Roithmayr, Justin Chin, Bruce Levin, and Fei Fang
- Published
- 2017
47. Clinical and Functional Outcomes After 2 Years in the Early Detection and Intervention for the Prevention of Psychosis Multisite Effectiveness Trial
- Author
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William R. McFarlane, Deanna Williams, F. Lee Lucas, Tara A. Niendam, Tamara G. Sale, Sarah Lynch, Margaret Migliorati, Andrea M. Auther, Elizabeth Spring, Stephan F. Taylor, Barbara A. Cornblatt, Melina Salvador, Cameron S. Carter, J. Daniel Ragland, Mary Verdi, Steven Adelsheim, Roderick Calkins, Ryan P. Melton, Lori L. Travis, Bruce Levin, and Bentson H. McFarland
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First episode ,medicine.medical_specialty ,Psychosis ,medicine.medical_treatment ,Global Assessment of Functioning ,medicine.disease ,Lower risk ,030227 psychiatry ,3. Good health ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,Schizophrenia ,Internal medicine ,Severity of illness ,medicine ,Psychoeducation ,Young adult ,10. No inequality ,Psychiatry ,Psychology ,030217 neurology & neurosurgery - Abstract
Objective: To test effectiveness of the Early Detection, Intervention, and Prevention of Psychosis Program in preventing the onset of severe psychosis and improving functioning in a national sample of at-risk youth. Methods: In a risk-based allocation study design, 337 youth (age 12–25) at risk of psychosis were assigned to treatment groups based on severity of positive symptoms. Those at clinically higher risk (CHR) or having an early first episode of psychosis (EFEP) were assigned to receive Family-aided Assertive Community Treatment (FACT); those at clinically lower risk (CLR) were assigned to receive community care. Between-groups differences on outcome variables were adjusted statistically according to regression-discontinuity procedures and evaluated using the Global Test Procedure that combined all symptom and functional measures. Results: A total of 337 young people (mean age: 16.6) were assigned to the treatment group (CHR + EFEP, n = 250) or comparison group (CLR, n = 87). On the primary variable, positive symptoms, after 2 years FACT, were superior to community care (2 df, p < .0001) for both CHR (p = .0034) and EFEP (p < .0001) subgroups. Rates of conversion (6.3% CHR vs 2.3% CLR) and first negative event (25% CHR vs 22% CLR) were low but did not differ. FACT was superior in the Global Test (p = .0007; p = .024 for CHR and p = .0002 for EFEP, vs CLR) and in improvement in participation in work and school (p = .025). Conclusion: FACT is effective in improving positive, negative, disorganized and general symptoms, Global Assessment of Functioning, work and school participation and global outcome in youth at risk for, or experiencing very early, psychosis.
- Published
- 2014
48. Recurrent Stroke in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial
- Author
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Conrado J. Estol, Ronald S. Freudenberger, Marco R. Di Tullio, Ralph L. Sacco, Douglas L. Mann, Min Qian, Piotr Ponikowski, Patrick M. Pullicino, John R. Teerlink, Jay P. Mohr, Stefan D. Anker, John L.P. Thompson, Dirk J. Lok, Bruce Levin, Gregory Y.H. Lip, Shunichi Homma, and Susan Graham
- Subjects
Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Fibrinolytic Agents ,Recurrence ,Internal medicine ,medicine ,Humans ,heterocyclic compounds ,Sinus rhythm ,cardiovascular diseases ,Stroke ,Aged ,Heart Failure ,Aspirin ,Ejection fraction ,business.industry ,Warfarin ,Anticoagulants ,Stroke Volume ,Stroke volume ,Middle Aged ,medicine.disease ,3. Good health ,Neurology ,Heart failure ,Anesthesia ,Cardiology ,Female ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Fibrinolytic agent ,medicine.drug - Abstract
Background and Purpose: WARCEF randomized 2,305 patients in sinus rhythm with ejection fraction (EF) ≤35% to warfarin (INR 2.0-3.5) or aspirin 325 mg. Warfarin reduced the incident ischemic stroke (IIS) hazard rate by 48% over aspirin in a secondary analysis. The IIS rate in heart failure (HF) is too low to warrant routine anticoagulation but epidemiologic studies show that prior stroke increases the stroke risk in HF. In this study, we explore IIS rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified. Methods: We compared potential stroke risk factors between patients with baseline stroke and those without using the exact conditional score test for Poisson variables. We looked for risk factors for IIS, by comparing IIS rates between different risk factors. For EF we tried cut-off points of 10, 15 and 20%. The cut-off point 15% was used as it was the highest EF that was associated with a significant increase in IIS rate. IIS and EF strata were balanced as to warfarin/aspirin assignment by the stratified randomized design. A multiple Poisson regression examined the simultaneous effects of all risk factors on IIS rate. IIS rates per hundred patient years (/100PY) were calculated in patient groups with significant risk factors. Missing values were assigned the modal value. Results: Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2,048 (3.1%) without had IIS. IIS rate in patients with baseline stroke (2.37/100PY) was greater than patients without (0.89/100PY) (rate ratio 2.68, p < 0.001). Fourteen of 219 (6.4%) patients with ejection fraction (EF) Conclusions: In a WARCEF exploratory analysis, prior stroke and EF
- Published
- 2014
49. Prediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations
- Author
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Jacobo Mintzer, Devangere P. Devanand, David L. Sultzer, Susan K. Schultz, Seonjoo Lee, Sanjay Gupta, Danilo de la Pena, Howard Andrews, Gregory H. Pelton, Sylvia Colon, Corbett Schimming, Bruce Levin, and Anjali N. Patel
- Subjects
Male ,medicine.medical_specialty ,Psychosis ,Hallucinations ,medicine.medical_treatment ,Disease ,Kaplan-Meier Estimate ,Antipsychotic treatment ,Neuropsychological Tests ,Placebo ,Article ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Recurrence ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,Antipsychotic ,Aged ,Proportional Hazards Models ,Likelihood Functions ,Risperidone ,Behavioral neurology ,medicine.disease ,Discontinuation ,Intention to Treat Analysis ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,Female ,Psychology ,030217 neurology & neurosurgery ,medicine.drug ,Antipsychotic Agents - Abstract
In Alzheimer's disease, antipsychotic medications are often used for a period, with relief of symptoms, and then discontinued, after which relapse may occur. The authors sought to determine which neuropsychiatric symptoms predict relapse.In the Antipsychotic Discontinuation in Alzheimer's Disease trial, 180 patients with Alzheimer's disease and symptoms of agitation or psychosis were treated with risperidone for 16 weeks, after which patients who responded (N=110) were randomly assigned to continue risperidone for 32 weeks, to continue risperidone for 16 weeks followed by switch to placebo for 16 weeks, or to receive placebo for 32 weeks. As reported previously, discontinuation of risperidone was associated with a two- to fourfold increased risk of relapse over 16-32 weeks. In planned post hoc analyses, the authors examined associations between the 12 symptom domains in the Neuropsychiatric Inventory (NPI) and relapse in the first 16-week phase after randomization.Compared with patients with mild hallucinations or no hallucinations, patients with severe hallucinations as a presenting symptom at baseline had a higher likelihood of relapse (hazard ratio=2.96, 95% CI=1.52, 5.76). This effect was present for the subgroup with auditory hallucinations, but not the subgroup with visual hallucinations. Among patients with baseline hallucinations, 13 of 17 (76.5%) who discontinued risperidone relapsed, compared with 10 of 26 (38.5%) who continued risperidone (p0.02). This group difference remained significant for severe (77.8%) compared with mild (36%) hallucinations. NPI domain scores after the initial open-treatment phase were not associated with relapse.Patients with severe baseline hallucinations were more likely to relapse after randomization, and the presence of baseline hallucinations was associated with a higher risk of relapse after discontinuation of risperidone compared with continued risperidone treatment. For patients with hallucinations, particularly auditory hallucinations, antipsychotic discontinuation should be approached cautiously because of high relapse risk.
- Published
- 2016
50. The Perfect Must Not Overwhelm the Good: Response to Open Peer Commentaries on 'Selecting the Right Tool For the Job'
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Carolyn Plunkett, Arthur L. Caplan, and Bruce Levin
- Subjects
Issues, ethics and legal aspects ,business.industry ,Health Policy ,Key (cryptography) ,Public relations ,Form of the Good ,business ,Psychology ,Social psychology - Abstract
We thank each of the peer commentators for their contributions. The key points they raise fall into five broad but interrelated categories of questions: (1) What are the appropriate goals of resear...
- Published
- 2015
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