Author: "Dale J" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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1. SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

Author: Brander, Danielle M, Friedman, Daphne R, Volkheimer, Alicia D, Christensen, Dale J, Rassenti, Laura Z, Kipps, Thomas J, Guadalupe, Eross, Chen, Youwei, Zhang, Dadong, Wang, Xi, Davis, Carter, Owzar, Kouros, and Weinberg, J Brice
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Lymphoma, Cancer, Rare Diseases, Clinical Research, Hematology, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Alternative Splicing, DNA-Binding Proteins, Disease-Free Survival, Female, Histone Chaperones, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Neoplasm Proteins, Protein Isoforms, RNA, Messenger, RNA, Neoplasm, Survival Rate, Transcription Factors, chronic lymphocytic leukaemia, SET, PP2A, alternative RNA splicing, phosphatase, SET, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology
Abstract: Alteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms, SETA and SETB (SETα and SETβ), significantly correlate with disease severity (overall survival and time-to-first-treatment) in CLL patients. In addition, we demonstrate that relative increase of SETA to SETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications of IGHV mutated and favourable hierarchical fluorescence in situ hybridisation groups. We validate our finding by showing comparable relationships of SET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing of SET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes.
Published: 2019

2. Evaluation of coping as a mediator of the relationship between stressful life events and cancer-related distress.

Author: Langford, Dale J, Cooper, Bruce, Paul, Steven, Humphreys, Janice, Keagy, Carolyn, Conley, Yvette P, Hammer, Marilyn J, Levine, Jon D, Wright, Fay, Melisko, Michelle, Miaskowski, Christine, and Dunn, Laura B
Subjects: Humans, Neoplasms, Prevalence, Survival Analysis, Stress, Psychological, Life Change Events, Middle Aged, Female, Male, Mental Health, Cancer, Behavioral and Social Science, Clinical Research, Mind and Body, cancer, chemotherapy, distress, life stressors, coping, Medical and Health Sciences, Education, Psychology and Cognitive Sciences, Public Health
Abstract: ObjectiveLifetime stressful life events (SLEs) may predispose oncology patients to cancer-related distress (i.e., intrusive thoughts, hyperarousal, avoidance). Coping may influence cancer-related distress by mediating this relationship. This study sought to (a) determine the prevalence and impact of lifetime SLEs among oncology outpatients receiving chemotherapy and (b) examine the relationship between SLEs and cancer-related distress and the mediating role of coping on this relationship.MethodPatients (n = 957), with breast, gastrointestinal, gynecologic or lung cancer, who were undergoing chemotherapy, completed the Life Stressor Checklist-Revised (LSC-R), a measure of lifetime SLEs. Cancer-related distress was assessed with the Impact of Event Scale-Revised. Coping strategies since beginning chemotherapy were assessed with the Brief COPE; 2 latent variables (engagement and disengagement coping) were identified based on these scores. LSC-R scores (number of SLEs and perceived impact during the prior year) were evaluated in relation to demographic and clinical characteristics. Structural equation modeling was used to evaluate the relationship between LSC-R and Impact of Event Scale-Revised scores and the mediating role of engagement and disengagement coping on this relationship.ResultsOn average, patients reported 6.1 (SD = 4.0; range = 0-23 out of 30) SLEs. Patients who were not married/partnered, had incomes
Published: 2017

3. Trajectories of fear of recurrence in women with breast cancer.

Author: Dunn, Laura B, Langford, Dale J, Paul, Steven M, Berman, Molly B, Shumay, Dianne M, Kober, Kord, Merriman, John D, West, Claudia, Neuhaus, John M, and Miaskowski, Christine
Subjects: Humans, Breast Neoplasms, Neoplasm Recurrence, Local, Postoperative Period, Adaptation, Psychological, Fear, Anxiety Disorders, Quality of Life, Middle Aged, Survivors, Health Services Needs and Demand, Female, Mind and Body, Cancer, Behavioral and Social Science, Mental Health, Clinical Research, Patient Safety, Breast Cancer, 7.3 Management and decision making, 7.1 Individual care needs, Management of diseases and conditions, Oncology, Breast cancer, Fear of recurrence, Psychological symptoms, Symptom trajectories, Hierarchical linear modeling, Medical and Health Sciences, Psychology and Cognitive Sciences, Oncology & Carcinogenesis
Abstract: PurposeAlthough fear of recurrence (FCR) is common among cancer survivors, it remains unclear what factors predict initial levels (e.g., prior to surgery) or changes in FCR in the post-treatment period. Among women treated for breast cancer, this study evaluated the effects of demographic, clinical, symptom, and psychosocial adjustment characteristics on the initial (preoperative) levels of FCR and trajectories of FCR over 6 months following surgery.MethodsPrior to and for 6 months following breast cancer surgery, 396 women were assessed for demographic and clinical (disease and treatment) characteristics, symptoms, psychological adjustment characteristics, and quality of life (QOL). FCR was assessed using a four-item subscale from the QOL instrument. Hierarchical linear modeling was used to examine changes in FCR scores and to identify predictors of inter-individual differences in preoperative FCR levels and trajectories over 6 months.ResultsFrom before surgery to 6 months post-operatively, women with breast cancer showed a high degree of inter-individual variability in FCR. Preoperatively, women who lived with someone, experienced greater changes in spiritual life, had higher state anxiety, had more difficulty coping, or experienced more distress due to diagnosis or distress to family members reported higher FCR scores. Patients who reported better overall physical health and higher FCR scores at enrollment demonstrated a steeper decrease in FCR scores over time.ConclusionsThese findings highlight inter-individual heterogeneity in initial levels and changes in FCR over time among women undergoing breast cancer surgery. Further work is needed to identify and provide interventions for women experiencing FCR during and after breast cancer treatment.
Published: 2015

4. Preoperative Breast Pain Predicts Persistent Breast Pain and Disability After Breast Cancer Surgery.

Author: Langford, Dale J, Schmidt, Brian, Levine, Jon D, Abrams, Gary, Elboim, Charles, Esserman, Laura, Hamolsky, Deborah, Mastick, Judy, Paul, Steven M, Cooper, Bruce, Kober, Kord, Dodd, Marylin, Dunn, Laura, Aouizerat, Bradley, and Miaskowski, Christine
Subjects: Breast, Humans, Breast Neoplasms, Pain, Postoperative, Pain Measurement, Disability Evaluation, Prognosis, Severity of Illness Index, Linear Models, Longitudinal Studies, Prospective Studies, Quality of Life, Middle Aged, Female, Preoperative Period, Breast cancer, linear modeling, persistent postsurgical pain, preoperative pain, Chronic Pain, Clinical Research, Pain Research, Rehabilitation, Cancer, Breast Cancer, Medical and Health Sciences, Anesthesiology
Abstract: ContextApproximately 30% of the women report pain in the affected breast before breast cancer surgery.ObjectivesThe purpose of this secondary analysis of our prospective study was to determine how women who experienced both preoperative and persistent postsurgical breast pain (n=107) differed from women who did not report preoperative breast pain and did (n=158) or did not (n=122) experience persistent postsurgical breast pain.MethodsDifferences in demographic and clinical characteristics were evaluated. Linear mixed effects (LME) modeling was used to evaluate for group differences in symptom severity, function, sensation, and quality of life (QOL) over time.ResultsBetween-group differences in demographic and clinical characteristics as well as trajectories of shoulder function and QOL were identified. Women with both preoperative and persistent postsurgical breast pain were younger; were more likely to report swelling, strange sensations, hardness, and numbness in the affected breast before surgery; and were more likely to have reconstruction at the time of surgery. Women with both preoperative and persistent postsurgical breast pain had more biopsies in the prior year, more lymph nodes removed, and reported more severe acute postsurgical pain than women without preoperative breast pain. The LME modeling revealed significant group effects for most outcomes evaluated. Over the six months of the study, women with both preoperative and persistent postsurgical pain had persistently poorer shoulder flexion and physical well-being than women without preoperative breast pain.ConclusionInvestigations of the etiology and molecular mechanisms of preoperative breast pain, as well as interventions for this high-risk group, are needed.
Published: 2015

5. Associations between catecholaminergic, GABAergic, and serotonergic genes and self-reported attentional function in oncology patients and their family caregivers.

Author: Merriman, John D, Aouizerat, Bradley E, Cataldo, Janine K, Dunn, Laura B, Kober, Kord, Langford, Dale J, West, Claudia, Cooper, Bruce A, Paul, Steven M, and Miaskowski, Christine
Subjects: Humans, Breast Neoplasms, Catecholamines, gamma-Aminobutyric Acid, Serotonin Agents, Cytokines, Longitudinal Studies, Family, Attention, Genotype, Phenotype, Polymorphism, Single Nucleotide, Aged, Middle Aged, Caregivers, California, Female, Male, Self Report, Attentional function, Cancer, Gamma-aminobutyric acid, Neurotransmission, Serotonin, Genetic Testing, Genetics, 2.1 Biological and endogenous factors, Aetiology, Nursing, Oncology and Carcinogenesis
Abstract: Purpose of the researchEvaluate for associations between variations in genes involved in catecholaminergic, gamma-aminobutyric acid (GABA)-ergic, and serotonergic mechanisms of neurotransmission and attentional function latent classes.Patients and methodsThis descriptive, longitudinal study was conducted at two radiation therapy departments. The sample included three latent classes of individuals with distinct trajectories of self-reported attentional function during radiation therapy, who were previously identified using growth mixture modeling among 167 oncology patients and 85 of their family caregivers. Multivariable models were used to evaluate for genotypic associations of neurotransmission genes with attentional function latent class membership, after controlling for covariates.ResultsVariations in catecholaminergic (i.e., ADRA1D rs4815675, SLC6A3 rs37022), GABAergic (i.e., SLC6A1 rs2697138), and serotonergic (i.e., HTR2A rs2296972, rs9534496) neurotransmission genes were significant predictors of latent class membership in multivariable models.ConclusionsFindings suggest that variations in genes that encode for three distinct but related neurotransmission systems are involved in alterations in attentional function. Knowledge of both phenotypic and genetic markers associated with alterations in attentional function can be used by clinicians to identify patients and family caregivers who are at higher risk for this symptom. Increased understanding of the genetic markers associated with alterations in attentional function may provide insights into the underlying mechanisms for this significant clinical problem.
Published: 2015

6. Cytokine gene variations associated with trait and state anxiety in oncology patients and their family caregivers.

Author: Miaskowski, Christine, Cataldo, Janine K, Baggott, Christina R, West, Claudia, Dunn, Laura B, Dhruva, Anand, Merriman, John D, Langford, Dale J, Kober, Kord M, Paul, Steven M, Cooper, Bruce A, and Aouizerat, Bradley E
Subjects: Humans, Neoplasms, Cytokines, Severity of Illness Index, Regression Analysis, Anxiety, Age Distribution, Sex Distribution, Genotype, Phenotype, Aged, Middle Aged, Caregivers, Female, Male, Genetic Variation, Behavioral and Social Science, Cancer, Genetics, Mental Health, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Radiation therapy, Single nucleotide polymorphism, Family caregiver, Trait anxiety, State anxiety, Medical and Health Sciences, Psychology and Cognitive Sciences, Oncology & Carcinogenesis
Abstract: PurposeAnxiety is common among cancer patients and their family caregivers (FCs) and is associated with poorer outcomes. Recently, associations between inflammation and anxiety were identified. However, the relationship between variations in cytokine genes and anxiety warrants investigation. Therefore, phenotypic and genotypic characteristics associated with trait and state anxiety were evaluated in a sample of 167 oncology patients with breast, prostate, lung, or brain cancer and 85 of their FCs.MethodsUsing multiple regression analyses, the associations between participants' demographic and clinical characteristics as well as variations in cytokine genes and trait and state anxiety were evaluated.ResultsIn the bivariate analyses, a number of phenotypic characteristics were associated with both trait and state anxiety (e.g., age, functional status). However, some associations were specific only to trait anxiety (e.g., number of comorbid conditions) or state anxiety (e.g., participation with a FC). Variations in three cytokine genes (i.e., interleukin (IL) 1 beta, IL1 receptor 2 (IL1R2), nuclear factor kappa beta 2 (NFKB2)) were associated with trait anxiety, and variations in two genes (i.e., IL1R2, tumor necrosis factor alpha (TNFA)) were associated with state anxiety.ConclusionsThese findings suggest that both trait and state anxiety need to be assessed in oncology patients and their FCs. Furthermore, variations in cytokine genes may contribute to higher levels of anxiety in oncology patients and their FCs.
Published: 2015

7. Cytokine gene associations with self-report ratings of morning and evening fatigue in oncology patients and their family caregivers.

Author: Dhruva, Anand, Aouizerat, Bradley E, Cooper, Bruce, Paul, Steven M, Dodd, Marylin, West, Claudia, Wara, William, Lee, Kathryn, Dunn, Laura B, Langford, Dale J, Merriman, John D, Baggott, Christina, Cataldo, Janine, Ritchie, Christine, Kober, Kord M, Leutwyler, Heather, and Miaskowski, Christine
Subjects: Humans, Neoplasms, Fatigue, Genetic Markers, Cytokines, Regression Analysis, Haplotypes, Phenotype, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Time, Middle Aged, Caregivers, Female, Male, Genetic Association Studies, breast cancer, cytokines, evening fatigue, genetics, interleukin 4, morning fatigue, tumor necrosis factor alpha, Clinical Research, Cancer, Genetics, Aging, 2.1 Biological and endogenous factors, Aetiology, Nursing
Abstract: The purpose of this study was to evaluate for differences in variations in pro- and anti-inflammatory cytokine genes between participants who were classified as having low and high levels of morning and evening fatigue and to evaluate for differences in phenotypic characteristics between these two groups. In a sample of 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their family caregivers, growth mixture modeling was used to identify latent classes of individuals based on ratings of morning and evening fatigue obtained prior to, during, and for 4 months following completion of radiation therapy. Differences in single nucleotide polymorphisms and haplotypes in 15 cytokine genes were evaluated between the latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on morning and evening fatigue class membership. Associations were found between morning fatigue and number of comorbidities as well as variations in tumor necrosis factor alpha (TNFA) rs1800629 and rs3093662. Evening fatigue was associated with caring for children at home and variations in interleukin 4 (IL4) rs2243248 and TNFA rs2229094. Younger age and lower performance status were associated with both morning and evening fatigue. These findings suggest that inflammatory mediators are associated with the development of morning and evening fatigue. However, because different phenotypic characteristics and genomic markers are associated with diurnal variations in fatigue, morning and evening fatigue may be distinct but related symptoms.
Published: 2015

8. Persistent Arm Pain Is Distinct From Persistent Breast Pain Following Breast Cancer Surgery

Author: Langford, Dale J, Paul, Steven M, West, Claudia, Abrams, Gary, Elboim, Charles, Levine, Jon D, Hamolsky, Deborah, Luce, Judith A, Kober, Kord M, Neuhaus, John M, Cooper, Bruce A, Aouizerat, Bradley E, and Miaskowski, Christine
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Cancer, Breast Cancer, Rehabilitation, Pain Research, Clinical Research, Women's Health, Chronic Pain, Arm, Breast, Breast Neoplasms, Female, Hand Strength, Humans, Middle Aged, Motor Activity, Pain Measurement, Pain, Postoperative, Range of Motion, Articular, Shoulder, Time Factors, Arm pain, breast cancer surgery, pain qualities, pain interference, range of motion, grip strength, sensory changes, persistent pain, chronic pain, grip strength
Abstract: UnlabelledPersistent pain following breast cancer surgery is well documented. However, it is not well characterized in terms of the anatomic site affected (ie, breast, arm). In 2 separate growth mixture modeling analyses, we identified subgroups of women (N = 398) with distinct breast pain and arm pain trajectories. The fact that these latent classes differed by anatomic site, types of tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. The purposes of this companion study were to identify demographic and clinical characteristics that differed between the 2 arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection sites, pain qualities, pain interference, and hand and arm function, as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the moderate arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and axillary lymph node dissection site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility.PerspectiveFor persistent breast and arm pain, changes in sensation following breast cancer surgery were notable. Persistent arm pain was associated with sustained interference with daily functioning and upper body mobility impairments. Long-term management of persistent pain following breast cancer surgery is warranted to improve the quality of survivorship for these women.
Published: 2014

9. Persistent Breast Pain Following Breast Cancer Surgery Is Associated With Persistent Sensory Changes, Pain Interference, and Functional Impairments

Author: Langford, Dale J, Paul, Steven M, West, Claudia, Levine, Jon D, Hamolsky, Deborah, Elboim, Charles, Schmidt, Brian L, Cooper, Bruce A, Abrams, Gary, Aouizerat, Bradley E, and Miaskowski, Christine
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Women's Health, Cancer, Pain Research, Breast Cancer, Chronic Pain, Rehabilitation, Neurosciences, Arm, Breast, Breast Neoplasms, Cicatrix, Female, Humans, Middle Aged, Motor Activity, Pain Measurement, Pain, Postoperative, Breast pain, breast cancer surgery, pain qualities, pain interference, range of motion, grip strength, sensory changes, persistent pain, chronic pain
Abstract: UnlabelledInterindividual variability exists in persistent breast pain following breast cancer surgery. Recently, we used growth mixture modeling to identify 3 subgroups of women (N = 398) with distinct persistent breast pain trajectories (ie, mild, moderate, severe) over 6 months following surgery. The purposes of this study were to identify demographic and clinical characteristics that differed among the breast pain classes and, using linear mixed effects modeling, to examine how changes over time and in sensitivity in the breast scar area, pain qualities, pain interference, and hand and arm function differed among these classes. Several demographic and clinical characteristics differentiated the breast pain classes. Of note, 60 to 80% of breast scar sites tested were much less sensitive than the unaffected breast. Significant group effects were observed for pain qualities and interference scores, such that, on average, women in the severe pain class reported higher scores than women in the moderate pain class. In addition, women in the moderate pain class reported higher scores than women in the mild pain class. Compared to women in the mild pain class, women in the severe pain class had significantly impaired grip strength, and women in the moderate and severe pain classes had impaired flexion and abduction.PerspectiveSubgroups of women with persistent postsurgical breast pain differed primarily with respect to the severity rather than the nature or underlying mechanisms of breast pain. Pervasive sensory loss and the association between persistent breast pain and sustained interference with function suggest the need for long-term clinical follow-up.
Published: 2014

10. Cytokine gene variations associated with subsyndromal depressive symptoms in patients with breast cancer

Author: Saad, Shanwell, Dunn, Laura B, Koetters, Theresa, Dhruva, Anand, Langford, Dale J, Merriman, John D, West, Claudia, Paul, Steven M, Cooper, Bruce, Cataldo, Janine, Hamolsky, Deborah, Elboim, Charles, Aouizerat, Bradley E, and Miaskowski, Christine
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Clinical Research, Cancer, Women's Health, Depression, Mental Illness, Mental Health, Brain Disorders, Genetics, Breast Cancer, Adult, Age Factors, Aged, Breast Neoplasms, California, Causality, Comorbidity, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Interleukin-6, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interferon, Socioeconomic Factors, Tumor Necrosis Factor-alpha, Interferon gamma Receptor, Breast cancer, Cytokines, Depressive symptoms, Subsyndromal depression, Interleukin 6, Tumor necrosis factor alpha, Interferon gamma, Nursing, Oncology and Carcinogenesis, Oncology and carcinogenesis, Health services and systems
Abstract: PurposeThis study explored the relationships between variations in cytokines genes and depressive symptoms in a sample of patients who were assessed prior to and for six months following breast cancer surgery. Phenotypic differences between Resilient (n = 155) and Subsyndromal (n = 180) depressive symptom classes, as well as variations in cytokine genes were evaluated.MethodPatients were recruited prior to surgery and followed for six months. Growth mixture modeling was used to identify distinct latent classes based on Center for Epidemiological Studies Depression (CES-D) Scale scores. Eighty-two single nucleotide polymorphisms and 35 haplotypes among 15 candidate cytokine genes were evaluated.ResultsPatients in the Subsyndromal class were significantly younger, more likely to be married or partnered, and reported a significantly lower functional status. Variation in three cytokine genes (i.e., interferon gamma receptor 1 (IFNGR1 rs9376268), interleukin 6 (IL6 rs2069840), tumor necrosis factor alpha (TNFA rs1799964)), as well as age and functional status predicted membership in the Subsyndromal versus the Resilient class.ConclusionsA variation in TNFA that was associated with Subsyndromal depressive symptoms in a sample of patients and their family caregivers was confirmed in this sample. Variations in cytokine genes may place these patients at higher risk for the development of Subsyndromal levels of depressive symptoms.
Published: 2014

11. Disease and treatment characteristics do not predict symptom occurrence profiles in oncology outpatients receiving chemotherapy

Author: Miaskowski, Christine, Cooper, Bruce A, Melisko, Michelle, Chen, Lee‐May, Mastick, Judy, West, Claudia, Paul, Steven M, Dunn, Laura B, Schmidt, Brian L, Hammer, Marilyn, Cartwright, Frances, Wright, Fay, Langford, Dale J, Lee, Kathryn, and Aouizerat, Bradley E
Subjects: Cancer, Female, Humans, Individuality, Longitudinal Studies, Male, Middle Aged, Neoplasms, Outpatients, Precision Medicine, Quality of Life, Surveys and Questionnaires, Symptom Assessment, symptom profiles, chemotherapy, latent class analysis, quality of life, precision medicine, symptom clusters, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: BackgroundA large amount of interindividual variability exists in the occurrence of symptoms in patients receiving chemotherapy (CTX). The purposes of the current study, which was performed in a sample of 582 oncology outpatients who were receiving CTX, were to identify subgroups of patients based on their distinct experiences with 25 commonly occurring symptoms and to identify demographic and clinical characteristics associated with subgroup membership. In addition, differences in quality of life outcomes were evaluated.MethodsOncology outpatients with breast, gastrointestinal, gynecological, or lung cancer completed the Memorial Symptom Assessment Scale before their next cycle of CTX. Latent class analysis was used to identify subgroups of patients with distinct symptom experiences.ResultsThree distinct subgroups of patients were identified (ie, 36.1% in Low class; 50.0% in Moderate class, and 13.9% in All High class). Patients in the All High class were significantly younger and more likely to be female and nonwhite, and had lower levels of social support, lower socioeconomic status, poorer functional status, and a higher level of comorbidity.ConclusionsFindings from the current study support the clinical observation that some oncology patients experience a differentially higher symptom burden during CTX. These high-risk patients experience significant decrements in quality of life.
Published: 2014

12. Identification of patient subgroups and risk factors for persistent arm/shoulder pain following breast cancer surgery

Author: Miaskowski, Christine, Paul, Steven M, Cooper, Bruce, West, Claudia, Levine, Jon D, Elboim, Charles, Hamolsky, Deborah, Abrams, Gary, Luce, Judith, Dhruva, Anand, Langford, Dale J, Merriman, John D, Kober, Kord, Baggott, Christina, Leutwyler, Heather, and Aouizerat, Bradley E
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Clinical Sciences, Health Sciences, Breast Cancer, Clinical Research, Patient Safety, Cancer, Chronic Pain, Pain Research, Rehabilitation, Musculoskeletal, Activities of Daily Living, Arm, Breast Neoplasms, California, Female, Hand Strength, Humans, Longitudinal Studies, Mastectomy, Middle Aged, Pain Measurement, Pain, Postoperative, Prevalence, Prospective Studies, Quality of Life, Range of Motion, Articular, Risk Factors, Shoulder Pain, Surveys and Questionnaires, Arm pain, Shoulder pain, Persistent postsurgical pain, Risk factors, Breast cancer surgery, Growth mixture modeling, Latent class analysis, Chronic pain, Nursing, Oncology and Carcinogenesis, Oncology and carcinogenesis, Health services and systems
Abstract: PurposeIn this prospective, longitudinal study, we extend our findings on persistent breast pain in patients (n = 398) following breast cancer surgery and evaluate the prevalence and characteristics of persistent pain in the arm/shoulder. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the arm pain classes, were evaluated.Methods and samplePatients were recruited from Breast Care Centers located in a Comprehensive Cancer Center, two public hospitals, and four community practices. Patients were assessed prior to and monthly for six months following breast cancer surgery.ResultsUsing growth mixture modeling, patients were classified into no (41.6%), mild (23.6%), and moderate (34.8%) arm pain classes based on ratings of worst arm/shoulder pain. Compared to the no pain class, patients in the moderate pain class were significantly younger, had a higher body mass index, and were more likely to report preoperative breast pain and swelling in the affected breast. In addition, patients in the moderate pain class reported higher levels of depression, anxiety, and sleep disturbance than the no pain class.ConclusionsFindings suggest that approximately 35% of women experience persistent levels of moderate arm/shoulder pain in the first six months following breast cancer surgery. Moderate arm/shoulder pain is associated with clinically meaningful decrements in functional status and quality of life.
Published: 2014

13. Preliminary evidence of an association between an interleukin 6 promoter polymorphism and self-reported attentional function in oncology patients and their family caregivers.

Author: Merriman, John D, Aouizerat, Bradley E, Langford, Dale J, Cooper, Bruce A, Baggott, Christina R, Cataldo, Janine K, Dhruva, Anand, Dunn, Laura, West, Claudia, Paul, Steven M, Ritchie, Christine S, Swift, Patrick S, and Miaskowski, Christine
Subjects: Humans, Neoplasms, Interleukin-6, Family, Attention, Polymorphism, Single Nucleotide, Aged, Middle Aged, Caregivers, Female, Male, Promoter Regions, Genetic, attention, cancer, cytokines, genetic association studies, inflammation, radiotherapy, Genetics, Cancer, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Nursing
Abstract: Subgroups of individuals may be at greater risk of cytokine-induced changes in attentional function. The purposes of this study were to identify subgroups of individuals with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) differences among these subgroups. Self-reported attentional function was evaluated in 252 participants (167 oncology patients and 85 family caregivers) using the Attentional Function Index before radiation therapy and at six additional assessments over 6 months. Three latent classes of attentional function were identified using growth mixture modeling: moderate (36.5%), moderate-to-high (48.0%), and high (15.5%) attentional function. Participants in the moderate class were significantly younger, with more comorbidities and lower functional status, than those in the other two classes. However, only functional status remained significant in multivariable models. Included in the genetic association analyses were 92 single nucleotide polymorphisms (SNPs) among 15 candidate genes. Additive, dominant, and recessive genetic models were assessed for each SNP. Controlling for functional status, only Interleukin 6 (IL6) rs1800795 remained a significant genotypic predictor of class membership in multivariable models. Each additional copy of the rare "G" allele was associated with a 4-fold increase in the odds of belonging to the lower attentional function class (95% confidence interval: [1.78, 8.92]; p = .001). Findings provide preliminary evidence of subgroups of individuals with distinct trajectories of attentional function and of a genetic association with an IL6 promoter polymorphism.
Published: 2014

14. Variations in potassium channel genes are associated with breast pain in women prior to breast cancer surgery.

Author: Langford, Dale J, West, Claudia, Elboim, Charles, Cooper, Bruce A, Abrams, Gary, Paul, Steven M, Schmidt, Brian L, Levine, Jon D, Merriman, John D, Dhruva, Anand, Neuhaus, John, Leutwyler, Heather, Baggott, Christina, Sullivan, Carmen Ward, Aouizerat, Bradley E, and Miaskowski, Christine
Subjects: Humans, Breast Neoplasms, Pain, Genetic Predisposition to Disease, Potassium Channels, Regression Analysis, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Young Adult, Genetic Association Studies, breast cancer, breast pain, candidate genes, potassium channel genes, preoperative pain, Genetics, Neurosciences, Genetic Testing, Pain Research, Patient Safety, Breast Cancer, Clinical Research, Cancer, Chronic Pain, Aetiology, 2.1 Biological and endogenous factors, Clinical Sciences, Neurology & Neurosurgery
Abstract: Preoperative breast pain in women with breast cancer may result from a number of causes. Previous work from our team found that breast pain occurred in 28.2% of women (n = 398) who were about to undergo breast cancer surgery. The occurrence of preoperative breast pain was associated with a number of demographic and clinical characteristics, as well as variation in two cytokine genes. Given that ion channels regulate excitability of sensory neurons, we hypothesized that variations in potassium channel genes would be associated with preoperative breast pain in these patients. Therefore, in this study, we evaluated for associations between single-nucleotide polymorphisms and inferred haplotypes among 10 potassium channel genes and the occurrence of preoperative breast pain in patients scheduled to undergo breast cancer surgery. Multivariable logistic regression analyses were used to identify those genetic variations that were associated with the occurrence of preoperative breast pain while controlling for age and genomic estimates of and self-reported race/ethnicity. Variations in four potassium channel genes: (1) potassium voltage-gated channel, delayed rectifier, subfamily S, member 1 (KCNS1); (2) potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); (3) KCNJ6; and (4) potassium channel, subfamily K, member 9 (KCNK9) were associated with the occurrence of breast pain. Findings from this study warrant replication in an independent sample of women who report breast pain following one or more breast biopsies.
Published: 2014

15. Association between an interleukin 1 receptor, type I promoter polymorphism and self-reported attentional function in women with breast cancer

Author: Merriman, John D, Aouizerat, Bradley E, Cataldo, Janine K, Dunn, Laura, Cooper, Bruce A, West, Claudia, Paul, Steven M, Baggott, Christina R, Dhruva, Anand, Kober, Kord, Langford, Dale J, Leutwyler, Heather, Ritchie, Christine S, Abrams, Gary, Dodd, Marylin, Elboim, Charles, Hamolsky, Deborah, Melisko, Michelle, and Miaskowski, Christine
Subjects: Biomedical and Clinical Sciences, Immunology, Clinical Research, Genetics, Women's Health, Cancer, Aging, Breast Cancer, Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Alleles, Attention, Breast Neoplasms, Demography, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Logistic Models, Middle Aged, Models, Biological, Phenotype, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Receptors, Interleukin-1 Type I, Self Report, Breast cancer, Inflammation, Cytokine genes, Interleukin 1 receptor, type I, AFI, AIMs, Attentional Function Index, BIC, BLRT, BMI, Bayesian information criterion, CI, CNS, DNA, GMM, KPS, Karnofsky Performance Status, LD, MAF, OR, SCQ, SNP, Self-administered Comorbidity Questionnaire, VLMR, Vuong-Lo-Mendell-Rubin likelihood ratio test, ancestry informative markers, body mass index, bootstrapped likelihood ratio test, central nervous system, confidence interval, deoxyribonucleic acid, growth mixture modeling, linkage disequilibrium, minor allele frequency, odds ratio, single nucleotide polymorphism, Biochemistry and Cell Biology
Abstract: Subgroups of patients with breast cancer may be at greater risk for cytokine-induced changes in cognitive function after diagnosis and during treatment. The purposes of this study were to identify subgroups of patients with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) predictors of subgroup membership. Self-reported attentional function was evaluated in 397 patients with breast cancer using the Attentional Function Index before surgery and for six months after surgery (i.e., seven time points). Using growth mixture modeling, three attentional function latent classes were identified: High (41.6%), Moderate (25.4%), and Low-moderate (33.0%). Patients in the Low-moderate class were significantly younger than those in the High class, with more comorbidities and lower functional status than the other two classes. No differences were found among the classes in years of education, race/ethnicity, or other clinical characteristics. DNA was recovered from 302 patients' samples. Eighty-two single nucleotide polymorphisms among 15 candidate genes were included in the genetic association analyses. After controlling for age, comorbidities, functional status, and population stratification due to race/ethnicity, IL1R1 rs949963 remained a significant genotypic predictor of class membership in the multivariable model. Carrying the rare "A" allele (i.e., GA+AA) was associated with a twofold increase in the odds of belonging to a lower attentional function class (OR: 1.98; 95% CI: 1.18, 3.30; p=.009). Findings provide evidence of subgroups of women with breast cancer who report distinct trajectories of attentional function and of a genetic association between subgroup membership and an IL1R1 promoter polymorphism.
Published: 2014

16. Associations Between Cytokine Gene Variations and Severe Persistent Breast Pain in Women Following Breast Cancer Surgery

Author: Stephens, Kimberly, Cooper, Bruce A, West, Claudia, Paul, Steven M, Baggott, Christina R, Merriman, John D, Dhruva, Anand, Kober, Kord M, Langford, Dale J, Leutwyler, Heather, Luce, Judith A, Schmidt, Brian L, Abrams, Gary M, Elboim, Charles, Hamolsky, Deborah, Levine, Jon D, Miaskowski, Christine, and Aouizerat, Bradley E
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Health Sciences, Genetics, Breast Cancer, Chronic Pain, Cancer, Clinical Research, Women's Health, Pain Research, 2.1 Biological and endogenous factors, Breast, Breast Neoplasms, Cytokines, Female, Genotyping Techniques, Haplotypes, Humans, Interleukin-10, Linkage Disequilibrium, Logistic Models, Longitudinal Studies, Mastectomy, Middle Aged, Pain Measurement, Pain, Postoperative, Phenotype, Polymorphism, Single Nucleotide, Receptors, Interleukin-1 Type II, Severity of Illness Index, Surveys and Questionnaires, polymorphism, breast cancer surgery, candidate genes, persistent pain
Abstract: UnlabelledPersistent pain following breast cancer surgery is a significant clinical problem. Although immune mechanisms may play a role in the development and maintenance of persistent pain, few studies have evaluated for associations between persistent breast pain following breast cancer surgery and variations in cytokine genes. In this study, associations between previously identified extreme persistent breast pain phenotypes (ie, no pain vs severe pain) and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. In unadjusted analyses, the frequency of 13 SNPs and 3 haplotypes in 7 genes differed significantly between the no pain and severe pain classes. After adjustment for preoperative breast pain and the severity of average postoperative pain, 1 SNP (ie, interleukin [IL] 1 receptor 2 rs11674595) and 1 haplotype (ie, IL10 haplotype A8) were associated with pain group membership. These findings suggest a role for cytokine gene polymorphisms in the development of persistent breast pain following breast cancer surgery.PerspectiveThis study evaluated for associations between cytokine gene variations and the severity of persistent breast pain in women following breast cancer surgery. Variations in 2 cytokine genes were associated with severe breast pain. The results suggest that cytokines play a role in the development of persistent postsurgical pain.
Published: 2014

17. Associations between cytokine gene variations and self-reported sleep disturbance in women following breast cancer surgery.

Author: Alfaro, Emely, Dhruva, Anand, Langford, Dale J, Koetters, Theresa, Merriman, John D, West, Claudia, Dunn, Laura B, Paul, Steven M, Cooper, Bruce, Cataldo, Janine, Hamolsky, Deborah, Elboim, Charles, Kober, Kord, Aouizerat, Bradley E, and Miaskowski, Christine
Subjects: Humans, Breast Neoplasms, Interleukin-6, Cytokines, Preoperative Care, Incidence, Multivariate Analysis, Logistic Models, Risk Assessment, Longitudinal Studies, Age Distribution, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, NF-kappa B p52 Subunit, Genetic Variation, Self Report, Surveys and Questionnaires, Sleep Wake Disorders, Breast cancer, Cytokine genes, Growth mixture modeling, Insomnia, Sleep disturbance, Symptom trajectories, Nursing, Oncology and Carcinogenesis
Abstract: Purpose of the researchTo attempt to replicate the associations found in our previous study of patients and family caregivers between interleukin 6 (IL6) and nuclear factor kappa beta 2 (NFKB2) and sleep disturbance and to identify additional genetic associations in a larger sample of patients with breast cancer.Methods and samplePatients with breast cancer (n = 398) were recruited prior to surgery and followed for six months. Patients completed a self-report measure of sleep disturbance and provided a blood sample for genomic analyses. Growth mixture modeling was used to identify distinct latent classes of patients with higher and lower levels of sleep disturbance.Key resultsPatients who were younger and who had higher comorbidity and lower functional status were more likely to be in the high sustained sleep disturbance class. Variations in three cytokine genes (i.e., IL1 receptor 2 (IL1R2), IL13, NFKB2) predicted latent class membership.ConclusionsPolymorphisms in cytokine genes may partially explain inter-individual variability in sleep disturbance. Determination of high risk phenotypes and associated molecular markers may allow for earlier identification of patients at higher risk for developing sleep disturbance and lead to the development of more targeted clinical interventions.
Published: 2014

18. Differences in morning and evening fatigue in oncology patients and their family caregivers.

Author: Dhruva, Anand, Aouizerat, Bradley E, Cooper, Bruce, Paul, Steven M, Dodd, Marylin, West, Claudia, Wara, William, Lee, Kathryn, Dunn, Laura B, Langford, Dale J, Merriman, John D, Baggott, Christina, Cataldo, Janine, Ritchie, Christine, Kober, Kord, Leutwyler, Heather, and Miaskowski, Christine
Subjects: Humans, Neoplasms, Fatigue, Ambulatory Care, Severity of Illness Index, Analysis of Variance, Risk Assessment, Chi-Square Distribution, Longitudinal Studies, Age Factors, Sex Factors, Circadian Rhythm, Adult, Aged, Middle Aged, Caregivers, Ambulatory Care Facilities, Cancer Care Facilities, Female, Male, Cancer treatment, Diurnal variability, Evening fatigue, Growth mixture modeling, Latent class analysis, Morning fatigue, Radiation therapy, Cancer, Nursing, Oncology and Carcinogenesis
Abstract: Purpose of the researchTo identify distinct latent classes of individuals based on ratings of morning and evening fatigue; evaluate for differences in phenotypic characteristics, as well as symptom and quality of life scores, among these latent classes; and evaluate for an overlap in morning and evening fatigue class membership.Patients and methodsIn a sample of 167 oncology outpatients and 85 of their FCs, growth mixture modeling was used to identify distinct latent classes based on ratings of morning and evening fatigue obtained before, during, and after radiation therapy. Analyses of variance and Chi Square analyses were used to evaluate for differences among the morning and evening fatigue latent classes.ResultsThree distinct latent classes for morning fatigue were identified. Participants in the High Morning Fatigue class (47%) were younger and had lower functional status. Three distinct latent classes for evening fatigue were identified. Participants in the High Evening Fatigue class (61%) were younger, more likely to be female, more likely to have children at home, and more likely to be a FC. Only 10.3% of participants were classified in both the Very Low Morning and Low Evening Fatigue classes and 41.3% were classified in both the High Morning and High Evening Fatigue classes.ConclusionsDifferent characteristics were associated with morning and evening fatigue, which suggests that morning and evening fatigue may be distinct but related symptoms. Additional research is needed to elucidate the mechanisms that may underlie diurnal variability in fatigue.
Published: 2013

19. Cytokine gene variation is associated with depressive symptom trajectories in oncology patients and family caregivers.

Author: Dunn, Laura B, Aouizerat, Bradley E, Langford, Dale J, Cooper, Bruce A, Dhruva, Anand, Cataldo, Janine K, Baggott, Christina R, Merriman, John D, Dodd, Marylin, West, Claudia, Paul, Steven M, and Miaskowski, Christine
Subjects: Humans, Neoplasms, Genetic Predisposition to Disease, Cytokines, Severity of Illness Index, Incidence, Multivariate Analysis, Logistic Models, Cohort Studies, Follow-Up Studies, Depression, Medical Oncology, Comorbidity, Age Distribution, Sex Distribution, Genotype, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Caregivers, California, Female, Male, Genetic Variation, Clinical Research, Breast Cancer, Mind and Body, Genetics, Mental Health, Cancer, Aetiology, 2.1 Biological and endogenous factors, Growth mixture modeling, Family caregivers, Radiation therapy, Nursing, Oncology and Carcinogenesis
Abstract: PurposeDepressive symptoms are common in cancer patients and their family caregivers (FCs). While these symptoms are characterized by substantial interindividual variability, the factors that predict this variability remain largely unknown. This study sought to confirm latent classes of oncology patients and FCs with distinct depressive symptom trajectories and to examine differences in phenotypic and genotypic characteristics among these classes.MethodAmong 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM) was used to identify latent classes of individuals based on Center for Epidemiological Studies-Depression (CES-D) scores obtained prior to, during, and for four months following completion of radiation therapy. One hundred four single nucleotide polymorphisms (SNPs) and haplotypes in 15 candidate cytokine genes were interrogated for differences between the two largest latent classes. Multivariate logistic regression analyses assessed effects of phenotypic and genotypic characteristics on class membership.ResultsFour latent classes were confirmed: Resilient (56.3%), Subsyndromal (32.5%), Delayed (5.2%), and Peak (6.0%). Participants who were younger, female, non-white, and who reported higher baseline trait and state anxiety were more likely to be in the Subsyndromal, Delayed, or Peak groups. Variation in three cytokine genes (i.e., interleukin 1 receptor 2 [IL1R2], IL10, tumor necrosis factor alpha [TNFA]), age, and performance status predicted membership in the Resilient versus Subsyndromal classes.ConclusionsFindings confirm the four latent classes of depressive symptom trajectories previously identified in a sample of breast cancer patients. Variations in cytokine genes may influence variability in depressive symptom trajectories.
Published: 2013

20. Evidence of associations between cytokine genes and subjective reports of sleep disturbance in oncology patients and their family caregivers.

Author: Miaskowski, Christine, Cooper, Bruce A, Dhruva, Anand, Dunn, Laura B, Langford, Dale J, Cataldo, Janine K, Baggott, Christina R, Merriman, John D, Dodd, Marylin, Lee, Kathryn, West, Claudia, Paul, Steven M, and Aouizerat, Bradley E
Subjects: Humans, Neoplasms, Cytokines, Models, Statistical, Regression Analysis, Polymorphism, Single Nucleotide, Middle Aged, Caregivers, Female, Male, Self Report, Sleep Wake Disorders, Sleep Research, Genetics, Cancer, Aetiology, 2.1 Biological and endogenous factors, General Science & Technology
Abstract: The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM) was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS) obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs) and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5%) and higher sleep disturbance (11.5%). Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB) predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories.
Published: 2012

21. Alu Elements and Hominid Phylogenetics

Author: Salem, Abdel-Halim, Ray, David A., Xing, Jinchuan, Callinan, Pauline A., Myers, Jeremy S., Hedges, Dale J., Garber, Randall K., Witherspoon, David J., Jorde, Lynn B., and Batzer, Mark A.
Published: 2003

22. Psychological value theory: The psychological value of human lives and economic goods

Author: Katelyn E. Freda, Dale J. Cohen, Madeline R. White, and Amanda R. Cromley
Subjects: Value (ethics), Linguistics and Language, Databases, Factual, Decision Making, Experimental and Cognitive Psychology, PsycINFO, Multiple methods, Morals, Language and Linguistics, Test (assessment), Value theory, Generalization (learning), Utilitarianism, Humans, Psychological values, Ethical Theory, Psychological Theory, Psychology, Social psychology
Abstract: Here, we present a strong test of the hypothesis that sacrificial moral dilemmas are solved using the same value-based decision mechanism that operates on decisions concerning economic goods. To test this hypothesis, we developed Psychological Value Theory. Psychological Value Theory is an expansion and generalization of Cohen and Ahn's (2016) Theory of Subjective Utilitarianism. Psychological Value Theory defines a new theoretical construct termed Psychological Value, measures Psychological Value using a traditional psychophysics paradigm, and predicts preferential choice from those measurements using a value-based computational model. We evaluate the validity of Psychological Value Theory across six experiments. In Experiment 1, we use Psychological Value Theory to estimate the perceived Psychological Value of human lives and economic goods. The data reveal that perceived Psychological Value of lives is highly influenced by individual differences of people but minimally influenced by the number of people in a group. In Experiments 2-5, we demonstrate that when used as input in a value-based computational model, perceived Psychological Values of human lives accurately predict participants' RT and response choices to sacrificial moral dilemmas. In Experiment 6, we replicate these findings for decisions involving economic goods. We cross-validate our results with multiple data sets using multiple methods. We conclude that the same value-based processes underlying economic decisions also underlie choices involving human lives. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Published: 2022
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23. Initial Content Validation and Roadmap for a New Patient-Reported Outcome Measure of Pain Intensity

Author: Dale J. Langford, Jennifer S. Gewandter, Dagmar Amtmann, Bryce B. Reeve, Amy Corneli, Kevin McKenna, Teresa Swezey, Molly McFatrich, Mark P. Jensen, Dennis C. Turk, and Robert H. Dworkin
Subjects: Clinical Trials as Topic, Anesthesiology and Pain Medicine, Neurology, Humans, Reproducibility of Results, Patient Reported Outcome Measures, Neurology (clinical), Chronic Pain, Acute Pain, Pain Measurement
Abstract: Measures of pain intensity (eg, numeric rating scales [NRS]) are widely used in clinical research and practice. While these measures have evidence for validity and reliability, poor standardization of instructions, and response options limits precision of pain assessment, allows for inconsistency in interpretation, and presents a challenge for comparison and aggregation of study results. Despite these pitfalls, the 0 to 10 NRS remains the most commonly used primary outcome measure in clinical trials of pain treatments and is the core measure recommended by regulatory agencies. The purpose of this study was to describe the first phase in the development of a pain intensity measure that is easily interpretable, psychometrically sound, and that adheres to FDA qualification processes. The Analgesic, Anesthetic, and Addiction Clinical Trial, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership conducted concept elicitation interviews (N = 44; 22 with acute pain; 22 with chronic pain) to understand the patient perspective on rating pain intensity and to identify actionable suggestions for improved clarity and meaningfulness of instructions, recall periods, and response options. This article summarizes interview findings, describes how patient input and FDA feedback informed preliminary candidate measures, and provides an overview of the FDA qualification process. PERSPECTIVE: Concept elicitation interviews informed the development of content-valid candidate measures of acute and chronic pain intensity for planned use in clinical trials of pain treatments, and comprise the initial stage in FDA clinical outcome assessment qualification. Measures will subsequently be evaluated through cognitive interviews and a series of psychometric studies.
Published: 2022
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24. Sex differences in time to primary percutaneous coronary intervention and outcomes in patients presenting with ST‐segment elevation myocardial infarction

Author: Michael L. Savage, Karen Hay, Dale J. Murdoch, Darren L. Walters, Russell Denman, Isuru Ranasinghe, and Christopher Raffel
Subjects: Male, Sex Characteristics, Percutaneous Coronary Intervention, Treatment Outcome, Humans, ST Elevation Myocardial Infarction, Female, Radiology, Nuclear Medicine and imaging, General Medicine, Cardiology and Cardiovascular Medicine, Time-to-Treatment
Abstract: We assessed sex differences in treatment and outcomes in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI).Historically, delays to timely reperfusion and poorer outcomes have been described in women who suffer STEMI. However, whether these sex discrepancies still exist with contemporary STEMI treatment remains to be evaluated.Consecutive STEMI patients treated with primary PCI patients over a 10-year period (January 1, 2010 to December 31, 2019) from a tertiary referral center were assessed. Comparisons were performed between patient's sex. Primary outcomes were 30-day and 1-year mortality. Secondary outcomes were STEMI performance measures.Most patients (n = 950; 76%) were male. Females were on average older (66.8 vs. 61.4 years males; p 0.001). Prehospital treatment delays did not differ between sexes (54 min [IQR: 44-65] females vs. 52 min [IQR: 43-62] males; p = 0.061). STEMI performance measures (door-to-balloon, first medical contact-to-balloon [FMCTB]) differed significantly with longer median durations in females and fewer females achieving FMCTB 90 min (28% females vs. 39% males; p 0.001). Women also experienced greater rates of initial radial arterial access failure (11.3% vs. 3.1%; p 0.001). However, there were no significant sex differences in crude or adjusted mortality between sexes at 30-days (3.6% male vs. 5.1% female; p = 0.241, adjusted OR: 1.1, 95% CI: 0.5-2.2, p = 0.82) or at 1-year (4.8% male vs. 6.8% female; p = 0.190, adjusted OR: 1.0, (95% CI: 0.5-1.8; p = 0.96).Small discrepancies between sexes in measures of timely reperfusion for STEMI still exist. No significant sex differences were observed in either 30-day or 1-year mortality.
Published: 2022
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25. Comparison of PACU length of stay and opioid requirements of patients maintained on buprenorphine or methadone for opioid use disorder

Author: Rebecca C. Dale, DO, Carol L. Metcalf, ARNP, Christina Bockman, PharmD, Dale J. Langford, PhD, Christine T. Fong, MS, and Katherin A. Peperzak, MD
Subjects: Analgesics, Opioid, Anesthesiology and Pain Medicine, Opiate Substitution Treatment, Humans, Pharmacology (medical), General Medicine, Length of Stay, Opioid-Related Disorders, Methadone, Buprenorphine, Retrospective Studies
Abstract: Objectives: Literature supporting best practice of perioperative buprenorphine management for opioid use disorder is evolving with more recent studies trending toward maintenance of home dose. To guide treatment protocols at our institution, we evaluated patients taking medication for opioid use disorder (MOUD) undergoing similar surgeries. Patients were maintained on either their outpatient buprenorphine or methadone.Patients and participants: Data were collected on 46 patients maintained on buprenorphine MOUD who underwent surgery. A subset of these patients (n = 24) was compared with 24 patients maintained on methadone MOUD, matched on surgical procedure, admission date, age, and sex.Design: This is a retrospective matched control study.Setting: An academic, tertiary, Level 1 trauma center.Main outcome measures: Primary outcomes were post-operative opioid use and post-anesthesia care unit (PACU) length of stay.Results: No significant differences in demographic characteristics, physical status, comorbid psychiatric diagnoses, or illicit substance use history were observed between patient groups. A higher proportion of patients taking methadone was admitted due to infection (41.7 percent vs 16.7 percent, p = 0.031) and underwent nonelective surgery (75.0 percent vs 45.8 percent, p = 0.039). No significant differences were observed between patients taking buprenorphine versus methadone with respect to PACU length of stay, post-operative opioid consumption, time-to-transition to oral opioids, or discharge opioid prescriptions. Patients taking buprenorphine were more likely to receive intravenous lidocaine (25.0 percent vs 0.0 percent, p = 0.031) and ketamine (83.3 percent vs 54.2 percent, p = 0.039).Conclusion: Findings from this study support accumulating evidence that patients should be maintained on buprenorphine MOUD throughout the perioperative period.
Published: 2022
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26. Validation and utility of ARDS subphenotypes identified by machine-learning models using clinical data: an observational, multicohort, retrospective analysis

Author: Maddali, Manoj V, Churpek, Matthew, Pham, Tai, Rezoagli, Emanuele, Zhuo, Hanjing, Zhao, Wendi, June, He, Delucchi, Kevin L, Wang, Chunxue, Wickersham, Nancy, Mcneil, J Brennan, Jauregui, Alejandra, Serena, Ke, Vessel, Kathryn, Gomez, Antonio, Hendrickson, Carolyn M, Kangelaris, Kirsten N, Sarma, Aartik, Leligdowicz, Aleksandra, Liu, Kathleen D, Matthay, Michael A, Ware, Lorraine B, Laffey, John G, Bellani, Giacomo, Calfee, Carolyn S, Sinha, Pratik, Rios, Fernando, Van Haren, Frank, Sottiaux, T, Lora, Fredy S, Azevedo, Luciano C, Depuydt, P, Fan, Eddy, Bugedo, Guillermo, Qiu, Haibo, Gonzalez, Marcos, Silesky, Juan, Cerny, Vladimir, Nielsen, Jonas, Jibaja, Manuel, Pham, Tài, Wrigge, Hermann, Matamis, Dimitrios, Ranero, Jorge Luis, Hashemian, S. M, Amin, Pravin, Clarkson, Kevin, Kurahashi, Kiyoyasu, Villagomez, Asisclo, Zeggwagh, Amine Ali, Heunks, Leo M, Laake, Jon Henrik, Palo, Jose Emmanuel, do Vale Fernandes, Antero, Sandesc, Dorel, Arabi, Yaasen, Bumbasierevic, Vesna, Nin, Nicolas, Lorente, Jose A, Larsson, Anders, Piquilloud, Lise, Abroug, Fekri, Mcauley, Daniel F, Mcnamee, Lia, Hurtado, Javier, Bajwa, Ed, Démpaire, Gabriel, Francois, Guy M, Sula, Hektor, Nunci, Lordian, Cani, Alma, Zazu, Alan, Dellera, Christian, Insaurralde, Carolina S, Alejandro, Risso V, Daldin, Julio, Vinzio, Mauricio, Fernandez, Ruben O, Cardonnet, Luis P, Bettini, Lisandro R, Bisso, Mariano Carboni, Osman, Emilio M, Setten, Mariano G, Lovazzano, Pablo, Alvarez, Javier, Villar, Veronica, Milstein, Cesar, Pozo, Norberto C, Grubissich, Nicolas, Plotnikow, Gustavo A, Vasquez, Daniela N, Ilutovich, Santiago, Tiribelli, Norberto, Chena, Ariel, Pellegrini, Carlos A, Saenz, María G, Estenssoro, Elisa, Brizuela, Matias, Gianinetto, Hernan, Gomez, Pablo E, Cerrato, Valeria I, Bezzi, Marco G, Borello, Silvina A, Loiacono, Flavia A, Fernandez, Adriana M, Knowles, Serena, Reynolds, Claire, Inskip, Deborah M, Miller, Jennene J, Kong, Jing, Whitehead, Christina, Bihari, Shailesh, Seven, Aylin, Krstevski, Amanda, Rodgers, Helen J, Millar, Rebecca T, Mckenna, Toni E, Bailey, Irene M, Hanlon, Gabrielle C, Aneman, Anders, Lynch, Joan M, Azad, Raman, Neal, John, Woods, Paul W, Roberts, Brigit L, Kol, Mark R, Wong, Helen S, Riss, Katharina C, Staudinger, Thomas, Wittebole, Xavier, Berghe, Caroline, Bulpa, Pierre A, Dive, Alain M, Verstraete, Rik, Lebbinck, Herve, Depuydt, Pieter, Vermassen, Joris, Meersseman, Philippe, Ceunen, Helga, Rosa, Jonas I, Beraldo, Daniel O, Piras, Claudio, Ampinelli, Adenilton M R, Nassar Jr, Antonio P, Mataloun, Sergio, Moock, Marcelo, Thompson, Marlus M, Gonçalves, Claudio H, Antônio, Ana Carolina P, Ascoli, Aline, Biondi, Rodrigo S, Fontenele, Danielle C, Nobrega, Danielle, Sales, Vanessa M, Shindhe, Suresh, Ismail, Dk Maizatul Aiman B Pg Hj, Laffey, John, Beloncle, Francois, Davies, Kyle G, Cirone, Rob, Manoharan, Venika, Ismail, Mehvish, Goligher, Ewan C, Jassal, Mandeep, Nishikawa, Erin, Javeed, Areej, Curley, Gerard, Rittayamai, Nuttapol, Parotto, Matteo, Ferguson, Niall D, Mehta, Sangeeta, Knoll, Jenny, Pronovost, Antoine, Canestrini, Sergio, Bruhn, Alejandro R, Garcia, Patricio H, Aliaga, Felipe A, Farías, Pamela A, Yumha, Jacob S, Ortiz, Claudia A, Salas, Javier E, Saez, Alejandro A, Vega, Luis D, Labarca, Eduardo F, Martinez, Felipe T, Carreño, Nicolás G, Lora, Pilar, Liu, Haitao, Liu, Ling, Tang, Rui, Luo, Xiaoming, Youzhong, An, Zhao, Huiying, Gao, Yan, Zhai, Zhe, Zheng L, Ye, Wang, Wei, Wenwen, Li, Qingdong, Li, Zheng, Ruiqiang, Wenkui, Yu, Shen, Juanhong, Xinyu, Li, Tao, Yu, Weihua, Lu, Ya Q, Wu, Huang, Xiao B, Zhenyang, He, Yuanhua, Lu, Han, Hui, Zhang, Fan, Sun, Renhua, Wang, Hua X, Qin, Shu H, Zhu, Bao H, Zhao, Jun, Liu, Jian, Bin, Li, Liu, Jing L, Zhou, Fa C, Qiong J, Li, Zhang, Xing Y, Li-Xin, Zhou, Xin-Hua, Qiang, Jiang, Liangyan, Gao, Yuan N, Zhao, Xian Y, Yuan Y, Li, Xiao L, Li, Wang, Chunting, Yao, Qingchun, Rongguo, Yu, Chen, Kai, Shao, Huanzhang, Qin, Bingyu, Huang, Qing Q, Zhu, Wei H, Hang, Ai Y, Hua, Ma X, Yimin, Li, Yonghao, Xu, Yu D, Di, Ling, Long L, Qin, Tie H, Wang, Shou H, Qin, Junping, Han, Yi, Zhou, Suming, Vargas, Monica P, Silesky Jimenez, Juan I, González Rojas, Manuel A, Solis-Quesada, Jaime E, Ramirez-Alfaro, Christian M, Máca, Jan, Sklienka, Peter, Gjedsted, Jakob, Christiansen, Aage, Villamagua, Boris G, Llano, Miguel, Burtin, Philippe, Buzancais, Gautier, Beuret, Pascal, Pelletier, Nicolas, Mortaza, Satar, Mercat, Alain, Chelly, Jonathan, Jochmans, Sébastien, Terzi, Nicolas, Daubin, Cédric, Carteaux, Guillaume, de Prost, Nicolas, Chiche, Jean-Daniel, Daviaud, Fabrice, Fartoukh, Muriel, Barberet, Guillaume, Biehler, Jerome, Dellamonica, Jean, Doyen, Denis, Arnal, Jean-Michel, Briquet, Anais, Hraiech, Sami, Papazian, Laurent, Follin, Arnaud, Roux, Damien, Messika, Jonathan, Kalaitzis, Evangelos, Dangers, Laurence, Combes, Alain, Siu-Ming, Au, Béduneau, Gaetan, Carpentier, Dorothée, Zogheib, Elie H, Dupont, Herve, Ricome, Sylvie, Santoli, Francesco L, Besset, Sebastien L, Michel, Philippe, Gelée, Bruno, Danin, Pierre-Eric, Goubaux, Bernard, Crova, Philippe J, Phan, Nga T, Berkelmans, Frantz, Badie, Julio C, Tapponnier, Romain, Gally, Josette, Khebbeb, Samy, Herbrecht, Jean-Etienne, Schneider, Francis, Declercq, Pierre-Louis M, Rigaud, Jean-Philippe, Duranteau, Jacques, Harrois, Anatole, Chabanne, Russell, Marin, Julien, Bigot, Charlene, Thibault, Sandrine, Ghazi, Mohammed, Boukhazna, Messabi, Ould Zein, Salem, Richecoeur, Jack R, Combaux, Daniele M, Grelon, Fabien, Le Moal, Charlene, Sauvadet, Elise P, Robine, Adrien, Lemiale, Virginie, Reuter, Danielle, Dres, Martin, Demoule, Alexandre, Goldgran-Toledano, Dany, Baboi, Loredana, Guérin, Claude, Lohner, Ralph, Kraßler, Jens, Schäfer, Susanne, Zacharowski, Kai D, Meybohm, 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Jarquin-Badiola, Yves D, Sanchez-Hurtado, Luis A, Gomez-Flores, Saira S, Marin, Maria C, Villagomez, Asisclo J, Lemus, Jordana S, Fierro, Jonathan M, Cervantes, Mavy Ramirez, Mejia, Francisco Javier Flore, Gonzalez, Daniel R, Dector, Dulce M, Estrella, Claudia R, Sanchez-Medina, Jorge R, Ramirez-Gutierrez, Alvaro, George, Fernando G, Aguirre, Janet S, Buensuseso, Juan A, Poblano, Manuel, Dendane, Tarek, Balkhi, Hicham, Elkhayari, Mina, Samkaoui, Nacer, Ezzouine, Hanane, Benslama, Abdellatif, Amor, Mourad, Maazouzi, Wajdi, Cimic, Nedim, Beck, Oliver, Bruns, Monique M, Schouten, Jeroen A, Rinia, Myra, Raaijmakers, Monique, Van Wezel, Hellen M, Heines, Serge J, Buise, Marc P, Simonis, Fabienne D, Schultz, Marcus J, Goodson, Jennifer C, rowne, Troy S B, Navarra, Leanlove, Hunt, Anna, Hutchison, Robyn A, Bailey, Mathew B, Newby, Lynette, Mcarthur, Colin, Kalkoff, Michael, Mcleod, Alex, Casement, Jonathan, Hacking, Danielle J, Andersen, Finn H, Dolva, Merete S, Laake, Jon H, Barratt-Due, Andrea, Noremark, Kim Andre L, Søreide, Eldar, Sjøbø, Brit Å, Guttormsen, Anne B, Yoshido, Hector H Leon, Aguilar, Ronald Zumaran, Oscanoa, Fredy A Monte, Alisasis, Alain U, Robles, Joanne B, Pasanting-Lim, Rossini Abbie B, Tan, Beatriz C, Andruszkiewicz, Pawel, Jakubowska, Karina, Cox, Cristina M, Alvarez, António M, Oliveira, Bruno S, Montanha, Gustavo M, Barros, Nelson C, Pereira, Carlos S, Messias, António M, Monteiro, Jorge M, Araujo, Ana M, Catorze, Nuno T, Marum, Susan M, Bouw, Maria J, Gomes, Rui M, Brito, Vania A, Castro, Silvia, Estilita, Joana M, Barros, Filipa M, Serra, Isabel M, Martinho, Aurelia M, Tomescu, Dana R, Marcu, Alexandra, Bedreag, Ovidiu H, Papurica, Mariu, Corneci, Dan E, Negoita, Silvius Ioan, Grigoriev, Evgeny, Gritsan, Alexey I, Gazenkampf, Andrey A, Almekhlafi, Ghaleb, Albarrak, Mohamad M, Mustafa, Ghanem M, Maghrabi, Khalid A, Salahuddin, Nawal, Aisa, Tharwat M, Al Jabbary, Ahmed S, Tabhan, Edgardo, Arabi, Yaseen M, Trinidad, Olivia A, Al Dorzi, Hasan M, Tabhan, Edgardo E, Bolon, Stefan, Smith, Oliver, Mancebo, Jordi, Aguirre-Bermeo, Hernan, Lopez-Delgado, Juan C, Esteve, Francisco, Rialp, Gemma, Forteza, Catalina, De Haro, Candelaria, Artigas, Antonio, Albaiceta, Guillermo M, De Cima-Iglesias, Sara, Seoane-Quiroga, Leticia, Ceniceros-Barros, Alexandra, Ruiz-Aguilar, Antonio L, Claraco-Vega, Luis M, Soler, Juan Alfonso, Lorente, Maria del Carmen, Hermosa, Cecilia, Gordo, Federico, Prieto-González, Miryam, López-Messa, Juan B, Perez, Manuel P, Pere, Cesar P, Allue, Raquel Montoiro, Roche-Campo, Ferran, Ibañez-Santacruz, Marco, Temprano, Susana, Pintado, Maria C, De Pablo, Raul, Gómez, Pilar Ricart Aroa, Ruiz, Silvia Rodriguez, Moles, Silvia Iglesia, Jurado, Mª Teresa, Arizmendi, Alfon, Piacentini, Enrique A, Franco, Nieve, Honrubia, Teresa, Perez Cheng, Meisy, Perez Losada, Elena, Blanco, Javier, Yuste, Luis J, Carbayo-Gorriz, Cecilia, Cazorla-Barranquero, Francisca G, Alonso, Javier G, Alda, Rosa S, Algaba, Ángela, Navarro, Gonzalo, Cereijo, Enrique, Diaz-Rodriguez, Esther, Marcos, Diego Pastor, Montero, Laura Alvarez, Para, Luis Herrera, Sanchez, Roberto Jimenez, Blasco Navalpotro, Miguel Angel, Abad, Ricardo Diaz, Montiel González, Raquel, Toribio, Dácil Parrilla, Castro, Alejandro G, Artiga, Maria Jose D, Penuelas, Oscar, Roser, Tomas P, Olga, Moreno F, Curto, Elena Gallego, Sánchez, Rocío Manzano, Imma, Vallverdu P, Elisabet, Garcia M, Claverias, Laura, Magret, Monica, Pellicer, Ana M, Rodriguez, Lucia L, Sánchez-Ballesteros, Jesú, González-Salamanca, Ángela, Jimenez, Antonio G, Huerta, Francisco P, Diaz, Juan Carlos J Sotillo, Lopez, Esther Bermejo, Moya, David D Llinare, Alfonso, Alec A Tallet, Eugenio Luis, Palazon Sanchez, Cesar, Palazon Sanchez, Rafael, Sánchez I, Virgilio, Corcoles G, Recio, Noelia N, Adamsson, Richard O, Rylander, Christian C, Holzgraefe, Bernhard, Broman, Lars M, Wessbergh, Joanna, Persson, Linnea, Schiöler, Fredrik, Kedelv, Han, Tibblin, Anna Oscarsson, Appelberg, Henrik, Hedlund, Lar, Helleberg, Johan, Eriksson, Karin E, Glietsch, Rita, Larsson, Nikla, Nygren, Ingela, Nunes, Silvia L, Morin, Anna-Karin, Kander, Thoma, Adolfsson, Anne, Zender, Hervé O., Leemann-Refondini, Corinne, Elatrous, Souheil, Bouchoucha, Slaheddine, Chouchene, Imed, Ouanes, Islem, Ben Souissi, Asma, Kamoun, Salma, Demirkiran, Oktay, Aker, Mustafa, Erbabacan, Emre, Ceylan, Ilkay, Girgin, Nermin Kelebek, Ozcelik, Menekse, Ünal, Necmettin, Meco, Basak Ceyda, Akyol, Onat O, Derman, Suleyman S, Kennedy, Barry, Parhar, Ken, Srinivasa, Latha, McAuley, Danny, Steinberg, Jack, Hopkins, Phil, Mellis, Clare, Stansil, Frank, Kakar, Vivek, Hadfield, Dan, Brown, Christine, Vercueil, Andre, Bhowmick, Kaushik, Humphreys, Sally K, Ferguson, Andrew, Mckee, Raymond, Raj, Ashok S, Fawkes, Danielle A, Watt, Philip, Twohey, Linda, Thomas, Rajeev R Jha Matthew, Morton, Alex, Kadaba, Varsha, Smith, Mark J, Hormis, Anil P, Kannan, Santhana G, Namih, Miriam, Reschreiter, Henrik, Camsooksai, Julie, Kumar, Alek, Rugonfalvi, Szabolc, Nutt, Christopher, Oneill, Orla, Seasman, Colette, Dempsey, Ged, Scott, Christopher J, Ellis, Helen E, Mckechnie, Stuart, Hutton, Paula J, Di Tomasso, Nora N, Vitale, Michela N, Griffin, Ruth O, Dean, Michael N, Cranshaw, Julius H, Willett, Emma L, Ioannou, Nichola, Gillis, Sarah, Csabi, Peter, Macfadyen, Rosaleen, Dawson, Heidi, Preez, Pieter D, Williams, Alexandra J, Boyd, Owen, De Gordoa, Laura Ortiz-Ruiz, Bramall, Jon, Symmonds, Sophie, Chau, Simon K, Wenham, Tim, Szakmany, Tama, Toth-Tarsoly, Piroska, Mccalman, Katie H, Alexander, Peter, Stephenson, Lorraine, Collyer, Thoma, Chapman, Rhiannon, Cooper, Raphael, Allan, Russell M, Sim, Malcolm, Wrathall, David W, Irvine, Donald A, Zantua, Kim S, Adams, John C, Burtenshaw, Andrew J, Sellors, Gareth P, Welters, Ingeborg D, Williams, Karen E, Hessell, Robert J, Oldroyd, Matthew G, Battle, Ceri E, Pillai, Suresh, Kajtor, Istvan, Sivashanmugave, Mageswaran, Okane, Sinead C, Donnelly, Adrian, Frigyik, Aniko D, Careless, Jon P, May, Martin M, Stewart, Richard, Trinder, T John, Hagan, Samantha J, Wise, Matt P, Cole, Jade M, MacFie, Caroline C, Dowling, Anna T, Nuñez, Edgardo, Pittini, Gustavo, Rodriguez, Ruben, Imperio, María C, Santos, Cristina, França, Ana G., Ebeid, Alejandro, Deicas, Alberto, Serra, Carolina, Uppalapati, Aditya, Kamel, Ghassan, Banner-Goodspeed, Valerie M, Beitler, Jeremy R, Mukkera, Satyanarayana Reddy, Kulkarni, Shreedhar, Lee, Jarone, Mesar, Tomaz, Shinn Iii, John O, Gomaa, Dina, Tainter, Christopher, Cowley, R Adam, Yeatts, Dale J, Warren, Jessica, Lanspa, Michael J, Miller, Russel R, Grissom, Colin K, Brown, Samuel M, Bauer, Philippe R, Gosselin, Ryan J, Kitch, Barrett T, Cohen, Jason E, Beegle, Scott H, Gueret, Renaud M, Tulaimat, Aiman, Choudry, Shazia, Stigler, William, Batra, Hitesh, Huff, Nidhi G, Lamb, Keith D, Oetting, Trevor W, Mohr, Nicholas M, Judy, Claine, Saito, Shigeki, Kheir, Fayez M, Schlichting, Adam B, Delsing, Angela, Elmasri, Mary, Crouch, Daniel R, Ismail, Dina, Blakeman, Thomas C, Dreyer, Kyle R, Baron, Rebecca M, Grijalba, Carolina Quintana, Hou, Peter C, Seethala, Raghu, Aisiku, Imo, Henderson, Galen, Frendl, Gyorgy, Hou, Sen-Kuang, Owens, Robert L, Schomer, Ashley, Bumbasirevic, Vesna, Jovanovic, Bojan, Surbatovic, Maja, Veljovic, Milic, Intensive Care Medicine, ACS - Pulmonary hypertension & thrombosis, AII - Inflammatory diseases, ACS - Diabetes & metabolism, ACS - Microcirculation, Maddali, M, Churpek, M, Pham, T, Rezoagli, E, Zhuo, H, Zhao, W, He, J, Delucchi, K, Wang, C, Wickersham, N, Mcneil, J, Jauregui, A, Ke, S, Vessel, K, Gomez, A, Hendrickson, C, Kangelaris, K, Sarma, A, Leligdowicz, A, Liu, K, Matthay, M, Ware, L, Laffey, J, Bellani, G, Calfee, C, and Sinha, P
Subjects: Pulmonary and Respiratory Medicine, Clinical Sciences, Acute Lung Injury, Article, Machine Learning, Positive-Pressure Respiration, Rare Diseases, Clinical Research, Retrospective Studie, Settore MED/41 - ANESTESIOLOGIA, Humans, Lung, Acute Respiratory Distress Syndrome, Retrospective Studies, Respiratory Distress Syndrome, Other Medical and Health Sciences, LUNG SAFE Investigators and the ESICM Trials Group, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Phenotype, Good Health and Well Being, Area Under Curve, ARDS: Phenotype, Respiratory, Public Health and Health Services, ARDS, Human
Abstract: Item does not contain fulltext BACKGROUND: Two acute respiratory distress syndrome (ARDS) subphenotypes (hyperinflammatory and hypoinflammatory) with distinct clinical and biological features and differential treatment responses have been identified using latent class analysis (LCA) in seven individual cohorts. To facilitate bedside identification of subphenotypes, clinical classifier models using readily available clinical variables have been described in four randomised controlled trials. We aimed to assess the performance of these models in observational cohorts of ARDS. METHODS: In this observational, multicohort, retrospective study, we validated two machine-learning clinical classifier models for assigning ARDS subphenotypes in two observational cohorts of patients with ARDS: Early Assessment of Renal and Lung Injury (EARLI; n=335) and Validating Acute Lung Injury Markers for Diagnosis (VALID; n=452), with LCA-derived subphenotypes as the gold standard. The primary model comprised only vital signs and laboratory variables, and the secondary model comprised all predictors in the primary model, with the addition of ventilatory variables and demographics. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC) and calibration plots, and assigning subphenotypes using a probability cutoff value of 0·5 to determine sensitivity, specificity, and accuracy of the assignments. We also assessed the performance of the primary model in EARLI using data automatically extracted from an electronic health record (EHR; EHR-derived EARLI cohort). In Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE; n=2813), a multinational, observational ARDS cohort, we applied a custom classifier model (with fewer variables than the primary model) to determine the prognostic value of the subphenotypes and tested their interaction with the positive end-expiratory pressure (PEEP) strategy, with 90-day mortality as the dependent variable. FINDINGS: The primary clinical classifier model had an area under receiver operating characteristic curve (AUC) of 0·92 (95% CI 0·90-0·95) in EARLI and 0·88 (0·84-0·91) in VALID. Performance of the primary model was similar when using exclusively EHR-derived predictors compared with manually curated predictors (AUC=0·88 [95% CI 0·81-0·94] vs 0·92 [0·88-0·97]). In LUNG SAFE, 90-day mortality was higher in patients assigned the hyperinflammatory subphenotype than in those with the hypoinflammatory phenotype (414 [57%] of 725 vs 694 [33%] of 2088; p
Published: 2022

27. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Author: Michael Pulley, Mikko Kuoppamäki, Carolyn A Young, Jesus S. Mora Pardina, Kumaraswamy Sivakumar, Toni Sarapohja, Michael A. Elliott, Chafic Karam, Sandeep Rana, Orla Hardiman, Nathan P. Staff, Letizia Mazzini, Gabriele Mora, Thomas F. Meyer, Colleen O'Connell, Stéphanie Delstanche, Elham Bayat, Michael D. Weiss, Waqar Waheed, Nenad Mitrovic, Philippe Corcia, Marie-Hélène Soriani, Edward J. Kasarskis, Claudia Caponnetto, Dale J. Lange, Tuan Vu, Leo McCluskey, Berthold Schrank, Angela Genge, Matthew C. Kiernan, Valtteri V Aho, Manu Jokela, Philip Van Damme, Juan F. Vázquez Costa, Maurizio Inghilleri, Wolfgang Löscher, David Schultz, Tero Tapiola, Susanne Petri, Adriano Chiò, Gary L. Pattee, Julian Großkreutz, Ammar Al-Chalabi, Aziz Shaibani, Susan Mathers, Kevin J. Felice, Kimberly Goslin, James Caress, Matthias Boentert, Albert C. Ludolph, Aleksandar Radunovic, Robert D. Henderson, James Wymer, Todd Levine, Jakob Rath, Merrilee Needham, William Camu, Gaurav Guliani, Rune Johansson, Leonard H. van den Berg, Namita Goyal, Mark B. Bromberg, Bjorn Oskarsson, Annie Dionne, Eduardo Locatelli, Brent T. Harris, Suma Babu, Richard Bedlack, John Ravits, Jinsy A. Andrews, Philippe Couratier, Gabriele Siciliano, Hannu Laaksovirta, Kourosh Rezania, Lawrence Korngut, Eduardo Aguera Morales, Peter M Andersen, Eva Farrero Munoz, David Lacomis, Stephen N. Scelsa, Chris Garratt, Matthew Burford, Merit Cudkowicz, Nicholas J. Maragakis, Wendy Johnston, Martin M. Brown, Johannes Prudlo, Justin Y. Kwan, Dominic B. Fee, Senda Ajroud-Driss, Stephen A. Goutman, John Turnbull, Michael H. Rivner, Timothy M. Miller, Jan De Bleecker, Caroline Ingre, Luis Varona, Genevieve Matte, Daragh Heitzman, Robert Untucht, Lorne Zinman, Adam Quick, and Jonathan S. Katz
Subjects: education.field_of_study, medicine.medical_specialty, Supine position, business.industry, Amyotrophic Lateral Sclerosis, Population, Administration, Oral, Levosimendan, Placebo, Treatment Outcome, amyotrophic lateral sclerosis, levosimendan, randomised, double-blind, placebo-controlled trial, Double-Blind Method, Respiratory failure, Internal medicine, Clinical endpoint, Humans, Medicine, Respiratory function, Neurology (clinical), business, Adverse effect, education, Simendan, medicine.drug
Abstract: Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.
Published: 2021
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28. Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Author: Pisani, Luigi, Algera, Anna Geke, Neto, Ary Serpa, Azevedo, Luciano, Pham, Tài, Paulus, Frederique, de Abreu, Marcelo Gama, Pelosi, Paolo, Dondorp, Arjen M, Bellani, Giacomo, Laffey, John G, Schultz, Marcus J, Martinez, Amadeu, Leal, Livia, Jorge Pereira, Antonio, de Oliveira Maia, Marcelo, Neto, Josè Aires, Piras, Claudio, Caser, Eliana Bernadete, Moreira, Cora Lavigne, Braga Gusman, Pablo, Dalcomune, Dyanne Moysés, Ribeiro de Carvalho, Alexandre Guilherme, Gondim, Louise Aline Romão, Castelo Branco Reis, Lívia Mariane, da Cunha Ribeiro, Daniel, de Assis Simões, Leonardo, Campos, Rafaela Siqueira, Fernandez Versiani dos Anjos, José Carlos, Bruzzi Carvalho, Frederico, Alves, Rossine Ambrosio, Nunes, Lilian Batista, Réa-Neto, Álvaro, de Oliveira, Mirella Cristine, Tannous, Luana, Cardoso Gomes, Brenno, Rodriguez, Fernando Borges, Abelha, Priscila, Lugarinho, Marcelo E, Japiassu, Andre, de Melo, Hélder Konrad, Lopes, Elton Afonso, Varaschin, Pedro, de Souza Dantas, Vicente Cés, Freitas Knibel, Marcos, Ponte, Micheli, de Azambuja Rodrigues, Pedro Mendes, Costa Filho, Rubens Carmo, Saddy, Felipe, Wanderley Castellões, Théia Forny, Silva, Suzana Alves, Osorio, Luiz Antonio Gomes, Mannarino, Dora, Espinoza, Rodolfo, Righy, Cassia, Soares, Marcio, Salluh, Jorge, Tanaka, Lilian, Aragão, Daniel, Tavares, Maria Eduarda, Kehdi, Maura Goncalves Pereira, Rezende, Valéria Maria Campos, Carbonell, Roberto Carlos Cruz, Teixeira, Cassiano, de Oliveira, Roselaine Pinheiro, Maccari, Juçara Gasparetto, Castro, Priscylla Souza, Berto, Paula, Schwarz, Patricia, Torelly, André Peretti, Lisboa, Thiago, Moraes, Edison, Dal-Pizzol, Felipe, Tomasi Damiani, Cristiane, Ritter, Cristiane, Ferreira, Juliana Carvalho, Teixeira Costa, Ramon, Caruso, Pedro, Amendola, Cristina Prata, de Oliveira, Amanda Maria R R, Silva, Ulysses V A, Sanches, Luciana Coelho, Almeida, Rosana D S, Azevedo, Luciano Cesar, Park, Marcelo, Schettino, Guilherme, Assunção, Murillo Santucci, Silva, Eliezer, Barboza, Carlos Eduardo, Junior, Antonio Paulo Nassar, Marzocchi Tierno, Paulo Fernando G M, Malbouisson, Luis Marcelo, Oliveira, Lucas, Cristovao, Davi, Neto, Manoel Leitão, Rego, Ênio, Fernandes, Fernanda Eugênia, Romano, Marcelo Luz Pereira, Cavalcanti, Alexandre Biasi, de Souza Barros, Dalton, Suzumura, Érica Aranha, Meira, Karla Loureiro, de Oliveira, Gustavo Affonso, Luciano, Paula Menezes, Pacheco, Evelin Drociunas, Mazza, Bruno Franco, Machado, Flavia Ribeiro, Ferreira, Elaine, dos Santos, Ronaldo Batista, Colombo, Alexandra Siqueira, Nogueira, Antonio Carlos, Fernandes, Juliana Baroni, Nóbrega, Raquel Siqueira, do CS Martins, Barbara, Soriano, Francisco, Morsch, Rafaela Deczka, Nunes, Andre Luiz Baptiston, de Almeida, Juliano Pinheiro, Hajjar, Ludhmila, Moulin, Sílvia, Giannini, Fábio Poianas, Baptiston Nunes, Andre Luiz, Rios, Fernando, Van Haren, Frank, Sottiaux, T, Lora, Fredy S, Azevedo, Luciano C, Depuydt, P, Fan, Eddy, Bugedo, Guillermo, Qiu, Haibo, Gonzalez, Marcos, Silesky, Juan, Cerny, Vladimir, Nielsen, Jonas, Jibaja, Manuel, Wrigge, Hermann, Matamis, Dimitrios, Ranero, Jorge Luis, Hashemian, S M, Amin, Pravin, Clarkson, Kevin, Kurahashi, Kiyoyasu, Villagomez, Asisclo, Zeggwagh, Amine Ali, Heunks, Leo M, Laake, Jon Henrik, Palo, Jose Emmanuel, do Vale Fernandes, Antero, Sandesc, Dorel, Arabi, Yaasen, Bumbasierevic, Vesna, Lorente, Jose A, Larsson, Anders, Piquilloud, Lise, Abroug, Fekri, McAuley, Daniel F, McNamee, Lia, Hurtado, Javier, Bajwa, Ed, Démpaire, Gabriel, Francois, Guy M, Sula, Hektor, Nunci, Lordian, Cani, Alma, Zazu, Alan, Dellera, Christian, Insaurralde, Carolina S, Alejandro, Risso V, Daldin, Julio, Vinzio, Mauricio, Fernandez, Ruben O, Cardonnet, Luis P, Bettini, Lisandro R, Bisso, Mariano Carboni, Osman, Emilio M, Setten, Mariano G, Lovazzano, Pablo, Alvarez, Javier, Villar, Veronica, Milstein, Cesar, Pozo, Norberto C, Grubissich, Nicolas, Plotnikow, Gustavo A, Vasquez, Daniela N, Ilutovich, Santiago, Tiribelli, Norberto, Chena, Ariel, Pellegrini, Carlos A, Saenz, María G, Estenssoro, Elisa, Brizuela, Matias, Gianinetto, Hernan, Gomez, Pablo E, Cerrato, Valeria I, Bezzi, Marco G, Borello, Silvina A, Loiacono, Flavia A, Fernandez, Adriana M, Knowles, Serena, Reynolds, Claire, Inskip, Deborah M, Miller, Jennene J, Kong, Jing, Whitehead, Christina, Bihari, Shailesh, Seven, Aylin, Krstevski, Amanda, Rodgers, Helen J, Millar, Rebecca T, Mckenna, Toni E, Bailey, Irene M, Hanlon, Gabrielle C, Aneman, Anders, Lynch, Joan M, Azad, Raman, Neal, John, Woods, Paul W, Roberts, Brigit L, Kol, Mark R, Wong, Helen S, Riss, Katharina C, Staudinger, Thomas, Wittebole, Xavier, Berghe, Caroline, Bulpa, Pierre A, Dive, Alain M, Verstraete, Rik, Lebbinck, Herve, Depuydt, Pieter, Vermassen, Joris, Meersseman, Philippe, Ceunen, Helga, Rosa, Jonas I, Beraldo, Daniel O, Ampinelli, Adenilton M R, Nassar Jr, Antonio P, Mataloun, Sergio, Moock, Marcelo, Thompson, Marlus M, Gonçalves, Claudio H, Antônio, Ana Carolina P, Ascoli, Aline, Biondi, 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Nicholas M, Judy, Claine, Saito, Shigeki, Kheir, Fayez M, Schlichting, Adam B, Delsing, Angela, Elmasri, Mary, Crouch, Daniel R, Ismail, Dina, Blakeman, Thomas C, Dreyer, Kyle R, Baron, Rebecca M, Grijalba, Carolina Quintana, Hou, Peter C, Seethala, Raghu, Aisiku, Imo, Henderson, Galen, Frendl, Gyorgy, Hou, Sen-Kuang, Owens, Robert L, Schomer, Ashley, Bumbasirevic, Vesna, Jovanovic, Bojan, Surbatovic, Maja, Veljovic, Milic, Rodgers, Helen, Dixon, Barry, Smith, Roger, Kol, Mark, Wong, Helen, Schmid, Werner, Hermans, Greet, Bourgeois, Marc, Anquez, Nathalie, Decruyenaere, Johan, DeCrop, Luc, Souza dos Santos, Rafaella, Beraldo, Daniel, dos Santos, Moreno Calcagnotto, Pellegrini, Jose Augusto Santos, Oliveira, Vanessa, Munhoz, Carlos, Peçanha, Ana Carolina, da Silva Ramos, Fernando José, Maia, Israel, Bahl, Marina, Biondi, Rodrigo, Prado, Daniel, Pinto, Sérgio Felix, Salgado, Jean, Falcão, Luis Fernando, Macruz, Tiago, Ruas, Kessia, Mecatti, Giovana Colozza, Caser, Eliane Bernadete, Gava, 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França, Ana G, Ebeid, Alejandro, Deicas, Alberto, Serra, Carolina, Uppalapati, Aditya, Kamel, Ghassan, Banner-Goodspeed, Valerie M, Beitler, Jeremy R, Mukkera, Satyanarayana Reddy, Kulkarni, Shreedhar, Lee, Jarone, Mesar, Tomaz, Shinn Iii, John O, Gomaa, Dina, Tainter, Christopher, Cowley, R Adam, Yeatts, Dale J, Warren, Jessica, Lanspa, Michael J, Miller, Russel R, Grissom, Colin K, Brown, Samuel M, Bauer, Philippe R, Gosselin, Ryan J, Kitch, Barrett T, Cohen, Jason E, Beegle, Scott H, Gueret, Renaud M, Tulaimat, Aiman, Choudry, Shazia, Stigler, William, Batra, Hitesh, Huff, Nidhi G, Lamb, Keith D, Oetting, Trevor W, Mohr, Nicholas M, Judy, Claine, Saito, Shigeki, Kheir, Fayez M, Schlichting, Adam B, Delsing, Angela, Elmasri, Mary, Crouch, Daniel R, Ismail, Dina, Blakeman, Thomas C, Dreyer, Kyle R, Baron, Rebecca M, Grijalba, Carolina Quintana, Hou, Peter C, Seethala, Raghu, Aisiku, Imo, Henderson, Galen, Frendl, Gyorgy, Hou, Sen-Kuang, Owens, Robert L, Schomer, Ashley, Bumbasirevic, Vesna, Jovanovic, Bojan, Surbatovic, Maja, Veljovic, Milic, Rodgers, Helen, Dixon, Barry, Smith, Roger, Kol, Mark, Wong, Helen, Schmid, Werner, Hermans, Greet, Bourgeois, Marc, Anquez, Nathalie, Decruyenaere, Johan, DeCrop, Luc, Souza dos Santos, Rafaella, Beraldo, Daniel, dos Santos, Moreno Calcagnotto, Pellegrini, Jose Augusto Santo, Oliveira, Vanessa, Munhoz, Carlo, Peçanha, Ana Carolina, da Silva Ramos, Fernando José, Maia, Israel, Bahl, Marina, Biondi, Rodrigo, Prado, Daniel, Pinto, Sérgio Felix, Salgado, Jean, Falcão, Luis Fernando, Macruz, Tiago, Ruas, Kessia, Mecatti, Giovana Colozza, Caser, Eliane Bernadete, Gava, Isabela Ambrósio, Carreño, Nicolá, Morales, Mauricio, Avendaño, Rossana, Aguirre, Stefania, Sribar, Andrej, Klaric, Vlasta, Skilijic, Sonja, Dvorscak, Matea Bogdanovic, Krkusek, Marijana, Jurjevic, Matija, Karanovic, Nenad, Simurina, Tatjana, Stourac, Petr, Kratochvil, Milan, Schlegel, Christian, Treschan, Tanja A, Schaefer, Maximilian, Aytulun, Akut, Kienbaum, Peter, Jaafar, Rola, Collins, Daniel, Plant, Robert, Melchionda, Giuseppe, Di Lauro, Eduardo, Russotto, Vincenzo, Caione, Raffaele, Mestria, Donatella, Volta, Carlo Alberto, Seghelini, Elisa, Sales, Gabriele, D'Antini, Davide, Severgnini, Paolo, Bacuzzi, Alessandro, Peluso, Lorenzo, Verrastro, Pasquale, Raimondo, Pasquale, Gecaj-Gashi, Agreta, Tuinman, Pieter Roel, Alberts, Erna, van den Hul, Ingrid, Kuiper, Michael, de Wilde, Robert BP, Koopmans, Matty, Kose, Isil, Zincircioglu, Çiler, Dogan, Nazim, Aydin, Demet, Denker, Ahmet Sukru, Buyukkocak, Unase, Akgun, Nur, Turan, Güldem, Senturk, Evren, Demirtürk, Zerrin, Özcan, Perihan Ergin, Ekinci, Osman, Saylan, Sedat, Eren, Gulay, Ulger, Fatma, Dilek, Ahmet, Ulusoy, Hulya, Goktas, Ugur, Soyoral, Lokman, Toman, Huseyin, Orak, Yavuz, Kahveci, Feda, Mills, Gary H, Pinder, Angela, Walker, Rachel, Harrison, Jonathan, Snell, Jane, Pearson, Rachel, Sharman, Michael, Kaloo, Claire, Bynorth, Natalie, Matthews, Kelly, Hughes, Chloe, Rose, Alastair, Simeson, Karen, Niska, Lotta, Huneke, Nathan, Adderly, Jane, Padilla-Harris, Cheryl, Oliver, Rebecca, Brohi, Farooq, Wilson, Natalie, Talbot, Helen, Wilson, Deborah, Smith, Deborah, Dark, Paulo, Evans, Tracey, Fisher, Nicola, Montgomery, Jane, Fitzell, Pauline, Muench, Christoph, Hugill, Keith, Cirstea, Emanuel, Bentley, Andrew, Lynch, Katie, White, Ian, Cooper, Jonathan, Brazier, Melinda, Devile, Michael, Parris, Michael, Gill, Pardeep, Patel, Tasmin, Criswell, John, Trodd, Dawn, Griffin, Denise, Martin, Jane, Wreybrown, Caroline, Bewley, Jeremy, Sweet, Katie, Grimmer, Lisa, Kozlowski, Marta, James, Shanaz, Limb, Jame, Cowton, Amanda, Rogerson, David, Downes, Charlotte, Melbourne, Susan, Humphries, Ryan, Pulletz, Mark, Moreton, Sarah, Janes, Stephanie, Corner, Andrew, Linnett, Vanessa, Ritzema, Jenny, Watters, Malcolm, Windebank, Steve, Chenna, Shailaja, Howard-Griffin, Richard, Turner, Kate, Suresh, Sheeba, Blaylock, Heather, Bell, Stephanie, Blenk, Karl, Everett, Lynn, Hadfield, Daniel, Harris, Clair, Chan, Alexandre, Birch, Sian, Pegg, Claire, Plowright, Catherine, Cooper, Lucy, Hatton, Tom, McCullagh, Iain, Wright, Stephen, Scott, Carmen, Boyd, Christine, Holliday, Mark, Poultney, Una, Crowther, Hannah, Thornthwaite, Sarah, Hollister, Nigel, Hunt, Jane, Skinner, Amanda, Matsa, Ramprasad, Salt, Ruth, Matthews, Claire, Venner, Nicola, Barcraft-Barnes, Helena, Tbaily, Lee, Pogson, David, Mouland, Johanna, Rose, Steve, Lamb, Nicola, Tarmey, Nichola, Knighton, John, Giles, Julian, Weller, Debbie, Reed, Isabelle, Hormis, Anil, Pearson, Sallyane, Harris, Meredith, Howe, Joanne, Paddle, Jonathan, Burt, Karen, Welters, Ingeborg, Walker, Anna, Youds, Laura, Hendry, Sam, Shaw, David, Williams, Karen, Hollands, Robin, Carnahan, Mandy, Stickley, Johanna, Miller, Claire, Donaldson, Denise, Tonks, Louise, Creagh-Brown, Ben, Hull, Daniel, Ortiz-Ruiz, Laura, Gopal, Shammer, Metherell, Stella, Spencer, Hazel, Frey, Christian, Brown, Carly, Clifford, Gayle, Leaver, Susannah, Ryan, Christine, Mellinghoff, Johannes Mellinghoff, Prudden, Sarah Prudden, Green, Helen Green, Roy, Alistair Roy, Furneval, Julie Furneval, Bell, Adam Bell, Lakhani, Sandeep Lakhani, Fasting, Lousie Fasting, Murray, Lorna Murray, Preller, Kobu, McInerney, Amy, Beavis, Sarah, Whileman, Amanda, Toms, Julie, Glenn, Sue, Ramali, Mohamed, Ghosh, Alison, Bullock, Clare, Barrell, Lisa, Young, Eoin, Robertson, Helen, Faulkner, Maria, MacNaughton, Peter, Tyson, Susan, Pulak, Paul, Sewell, Terri-Ann, Smalley, Christopher, Jacob, Reni, Alzugaray, Pedro, Vidal Melo, Marcos F, Joyce, Kristen, Needleman, Joseph, Ahsan, Areef, Faiz, Abul, Alam, AKM Shamsul, Khatoon, Syeda Nafisa, Nath, Ranjan Kumer, Rahman Chowdhury, Mohammed Abdur, Banik, Debabrata, Mondol, Montosh Kumar, Bhuiyan, Sakibur Rahman, Nazneed, Suraiya, Sultana, Rozina, Hamid, Tarikul, Hossain, Mozaffer, Reza, Syed Tariq, Asaduzzaman, Muhammad, Salim, Mohammad, Mostafa Kamal, Abu Hena, Taher, Sheikh Mohammed, Taohid, Taohidul Majid, Karmaker, Pranab, Roy, Sabyasachi, Das, Shantanu, Sarkar, Sohel Ahmed, Dutta, Monju Lal, Roy, Poulomi, Iyer, Shivakumar, Krishna, Bhuvana, Sampath, Sriram, Pattnaik, Rajyabardhan, Kasi, Chinni Krishna, Shah, Jignesh, Dongre, Anand, Reza Hashemian, Seyed Mohammad, Nooraei, Navid, Raessi Estabragh, Reza, Malekmohammad, Majid, Khoundabi, Batoul, Mobasher, Maziar, Mohd Yunos, Nor'azim, Kassim, Mahazir, Voon, Chern Min, Das, Stanis Sutharsa, Azauddin, Siti Nur Suhaila, Dorasamy, Dharshinie, Tai, Li Ling, Mat Nor, Mohd Basri, Zarudin, Nurhafizah, Hasan, Mohd Shahnaz, Jamaluddin, Mohamad Fadhil Hadi, Othman Jailani, Mohamad Irfan, Kayashta, Gyan, Adhikari, Aaradhana, Pangeni, Raju, Hashmi, Madiha, Joseph, Sonia, Akhtar, Aftab, Qadeer, Aayesha, Memon, Iqbal, Ali, Syed Muneeb, Idrees, Farah, Kamal, Saima, Hanif, Sadaf, Rehman, Atta Ur, Taqi, Arshad, Hussain, Tanveer, Farooq, Ahmed, Khaskheli, Saleh, Hayat, Muhammad, Indraratna, Kanishka, Beane, Abigail, Haniffa, Rashan, Samaranayake, Upeka, Mathanalagan, Sathiyamoorthy, Gunaratne, Asoka, Mithraratne, Nimangee, Thilakasiri, Kaushila, Pilimatalawwe, Chamila, Dilhani, Y A Hasitha, Fernando, Marie, Ranatunge, Kumudini, Samarasinghe, Loranthi, Vaas, Manori, Edirisooriya, Manoj, Sigera, Chathurani, Arumoli, Janaki, De Silva, Kesharie, Kudavidanage, Bimal, Pinto, Visanthi, Dissanayake, Lakshman, Chittawatanarat, Kaweesak, Kongpolprom, Napplika, Silachamroon, Udomsak, Pornsuriyasak, Prapaporn, Petnak, Tananchai, Singhatas, Pongsasit, Tangsujaritvijit, Viratch, Rungruanghiranya, Suthat, Piriyapatsom, Annop, Juntaping, Kanokkarn, Trongtrakul, Konlawij, Thungtitigul, Poungrat, Tajarernmuang, Pattraporn, Chatmongkolchart, Sunisa, Bhurayanontachai, Rungsun, Akaraborworn, Osaree, Navasakulpong, Asma, Surasit, Karjbundid, Thwaites, Louise, Nadjm, Behzad, Vu Quoc, Dat, Nguyen Thi Thanh, Ha, Nguyen Van, Kinh, Duong Bich, Thuy, Lam Minh, Yen, Anesthesiology, Intensive care medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Diabetes & metabolism, Graduate School, Intensive Care Medicine, AII - Inflammatory diseases, Nursing, and ACS - Microcirculation
Subjects: Male, Sociodemographic Factors, Respiration, Artificial/methods, ARDS, mechanical ventilation, Severity of Illness Index, NO, Settore MED/41 - ANESTESIOLOGIA, 80 and over, Tidal Volume, Humans, Hospital Mortality, Prospective Studies, ddc:610, Developing Countries, Aged, Hospital Mortality/trends, Aged, 80 and over, Developed Countries/statistics & numerical data, Developing Countries/statistics & numerical data, Respiration, Developed Countries, Articles, General Medicine, acute respiratory distress syndrome, Length of Stay, Middle Aged, Respiration, Artificial, Intensive Care Units, Observational Studies as Topic, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Length of Stay/statistics & numerical data, Artificial, Intensive Care Units/statistics & numerical data, Income, Female
Abstract: Contains fulltext : 252214.pdf (Publisher’s version ) (Open Access) BACKGROUND: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. METHODS: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. FINDINGS: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H(2)O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p
Published: 2022
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29. Cultural selection drives the evolution of human communication systems

Author: Tamariz, Monica, Ellison, T. Mark, Barr, Dale J., and Fay, Nicolas
Published: 2014

30. Imaging Evaluation of Plexiform Neurofibromas in Neurofibromatosis Type 1

Author: Johannes Salamon, Dale J. Berg, Shivani Ahlawat, Michael Fisher, Dusica Babovic-Vuksanovic, Jaishri O. Blakeley, K. Ina Ly, Gordon J. Harris, Andrés J. Lessing, Laura M. Fayad, Scott R. Plotkin, Eva Dombi, and Victor-Felix Mautner
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Neurofibromatosis 1, Skin Neoplasms, Adolescent, Neurofibromatoses, MEDLINE, Asymptomatic, Imaging, Young Adult, Surveys and Questionnaires, Humans, Medicine, Clinical care, Neurofibromatosis, Child, Schwannomatosis, Neurofibroma, Plexiform, High prevalence, business.industry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Patient population, Neurology (clinical), medicine.symptom, business, Neurilemmoma
Abstract: ObjectiveTo assess imaging utilization practices across clinical specialists in neurofibromatosis type 1 (NF1) for the evaluation of symptomatic and asymptomatic children and adults with or without plexiform neurofibromas (PN).MethodsAn institutional review board–exempt survey was administered to medical practitioners caring for individuals with NF1 at the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) meeting in September 2019. The survey included questions on respondent demographic data (9 questions), type of imaging obtained for asymptomatic (4 questions) and symptomatic (4 questions) people with and without PN, and utilization of diffusion-weighted imaging (2 questions).ResultsThirty practitioners participated in the survey. Most were academic neuro-oncologists at high-volume (>10 patients/week) NF1 centers. Of 30 respondents, 26 had access to whole-body MRI (WB-MRI). The most common approach to an asymptomatic person without PN was no imaging (adults: 57% [17/30]; children: 50% [15/30]), followed by a screening WB-MRI (adults: 20% [6/30]; children: 26.7% [8/30]). The most common approach to a person with symptoms or known PN was regional MRI (adults: 90% [27/30]; children: 93% [28/30]), followed by WB-MRI (adults: 20% [6/30]; children: 36.7% [11/30]). WB-MRI was most often obtained to evaluate a symptomatic child with PN (37% [11/30]).ConclusionsMore than 90% of practitioners indicated they would obtain a regional MRI in a symptomatic patient without known or visible PN. Otherwise, there was little consensus on imaging practices. Given the high prevalence of PN and risk of malignant conversion in this patient population, there is a need to define imaging-based guidelines for optimal clinical care and the design of future clinical trials.
Published: 2021
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31. Realist analysis of whether emergency departments with primary care services generate ‘provider-induced demand’

Author: McFadzean, I. J., Edwards, M., Davies, F., Cooper, A., Price, D., Carson-Stevens, A., Dale, J., Hughes, T., Porter, A., Harrington, B., Evans, B., Siriwardena, N., Anderson, P., and Edwards, A.
Subjects: A300 Clinical Medicine, England, Primary Health Care, General Practitioners, Emergency Medicine, Humans, Emergency Service, Hospital, RA, Induced Demand
Abstract: Background It is not known whether emergency departments (EDs) with primary care services influence demand for non-urgent care (‘provider-induced demand’). We proposed that distinct primary care services in EDs encourages primary care demand, whereas primary care integrated within EDs may be less likely to cause additional demand. We aimed to explore this and explain contexts (C), mechanisms (M) and outcomes (O) influencing demand. Methods We used realist evaluation methodology and observed ED service delivery. Twenty-four patients and 106 staff members (including Clinical Directors and General Practitioners) were interviewed at 13 EDs in England and Wales (240 hours of observations across 30 days). Field notes from observations and interviews were analysed by creating ‘CMO’ configurations to develop and refine theories relating to drivers of demand. Results EDs with distinct primary care services were perceived to attract demand for primary care because services were visible, known or enabled direct access to health care services. Other influencing factors included patients’ experiences of accessing primary care, community care capacity, service design and population characteristics. Conclusions Patient, local-system and wider-system factors can contribute to additional demand at EDs that include primary care services. Our findings can inform service providers and policymakers in developing strategies to limit the effect of potential influences on additional demand when demand exceeds capacity.
Published: 2022

32. Outcome of acute hypoxaemic respiratory failure: insights from the LUNG SAFE Study

Author: Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andres, Gattinoni, Luciano, Larsson, Anders, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andre, Gattinoni, Luciano, Larsson, Ander, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Intensive Care Medicine, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Pham, T, Pesenti, A, Bellani, G, Rubenfeld, G, Fan, E, Bugedo, G, Lorente, J, Fernandes, A, Van Haren, F, Bruhn, A, Rios, F, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Thompson, B, Wrigge, H, Brochard, L, Laffey, J, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), St. Michael's Hospital, University of Toronto, Groupe de recherche clinique CARMAS, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano [Milano] (UNIMI), University of Milan, San Gerardo Hospital, Sunnybrook Health Sciences Center, Mount Sinai Hospital [Toronto, Canada] (MSH), Pontificia Universidad Católica de Chile (UC), University Hospital of Getafe, CIBER Enfermedades Respiratorias (CIBERES), Universidad Europea de Madrid, Hospital Garcia de Orta (EPE), Canberra Hospital, Medical School [Australian National University - ANU], Australian National University (ANU), University of Canberra, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Göttingen - Georg-August-Universität Göttingen, Uppsala University, Queen's University [Belfast] (QUB), Royal Victoria Hospital, McGill University Health Center [Montreal] (MUHC), Università degli Studi di Bologna, Massachusetts General Hospital [Boston], University Hospital Leipzig, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, 06112, Halle, National University of Ireland [Galway] (NUI Galway), Bayer GlaxoSmithKline, GSK Baxter International Boehringer Ingelheim Wellcome Trust, WT National Institute for Health Research, NIHR Queen's University Belfast, QUB Medical Research Council Canada, MRC European Society of Intensive Care Medicine, ESICM, Support statement: This work was supported by the European Society of Intensive Care Medicine. Funding information for this article has been deposited with the Crossref Funder Registry., Conflict of interest: T. Pham has nothing to disclose. A. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, Gilead and Boehringer Ingelheim, outside the submitted work. G. Bellani reports grants and personal fees from Draeger Medical, personal fees from Getinge, Hamilton, GE Healthcare, Dimar SRL, Intersurgical and Flowmeter SPA, outside the submitted work. G. Rubenfeld has nothing to disclose. E. Fan reports personal fees from ALung Technologies, Getinge and MC3 Cardiopulmonary, grants, personal fees and non-financial support from Fresenius Medical Care, outside the submitted work. G. Bugedo has nothing to disclose. J.A. Lorente has nothing to disclose. A.D. V. Fernandes has nothing to disclose. F. Van Haren has nothing to disclose. A. Bruhn has nothing to disclose. F. Rios has nothing to disclose. A. Esteban has nothing to disclose. L. Gattinoni has nothing to disclose. A. Larsson reports grants from the Swedish Heart and Lung Foundation, during the conduct of the study. D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work, in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, NI HSC R&D Division, NI Chest Heart and Stroke, and MRC, is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen’s University of Belfast (http://www.google.com/patents/US8962032), and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. M. Ranieri has nothing to disclose. B.T. Thompson reports personal fees from Bayer, Thetis and Novartis, outside the submitted work. H. Wrigge reports personal fees for consultancy from Dräger Medical, personal fees for advisory board work from Liberate Medical, grants and personal fees for lectures from InfectoPharm, personal fees for lectures from MSD and GE, outside the submitted work. L.J. Brochard reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec and Philips, other (patent) from General Electric, outside the submitted work. J.G. Laffey reports grants and personal fees from Baxter, grants and non-financial support from Aerogen and Factor Biosciences, outside the submitted work., LUNG SAFE Investigators and the European Society of Intensive Care Medicine Trials Group: Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J 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Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, and UCL - (SLuc) Service de soins intensifs
Subjects: Pulmonary and Respiratory Medicine, ARDS, Unidades de cuidados intensivos, [SDV]Life Sciences [q-bio], medicine.medical_treatment, mechanical ventilation, NO, law.invention, 03 medical and health sciences, Tratamiento médico, 0302 clinical medicine, law, Settore MED/41 - ANESTESIOLOGIA, Insuficiencia respiratoria, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Lung, Mechanical ventilation, Respiratory Distress Syndrome, business.industry, Respiration, Incidence (epidemiology), medicine.disease, Intensive care unit, Respiration, Artificial, 3. Good health, Intensive Care Units, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], medicine.anatomical_structure, 030228 respiratory system, Respiratory failure, Heart failure, Anesthesia, Artificial, ards, business, Respiratory Insufficiency, Enfermedad
Abstract: BackgroundCurrent incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).MethodsAn international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared.Findings12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved.InterpretationMore than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.
Published: 2021
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33. Structure-Based Design of a Selective Class I Histone Deacetylase (HDAC) Near-Infrared (NIR) Probe for Epigenetic Regulation Detection in Triple-Negative Breast Cancer (TNBC)

Author: Dale J. Hamilton, Zhiyi Liu, Sheng Jiang, Dong Chen, Yatao Qiu, Kuojun Zhang, Yiwu Yao, Feng Li, and Zheng Li
Subjects: Poor prognosis, Lung Neoplasms, Mice, Nude, Triple Negative Breast Neoplasms, Cyclic depsipeptide, 01 natural sciences, Histone Deacetylases, Epigenesis, Genetic, Malignant transformation, 03 medical and health sciences, Breast cancer, Cell Line, Tumor, Depsipeptides, Drug Discovery, Biomarkers, Tumor, medicine, Animals, Humans, Fluorometry, Epigenetics, Triple-negative breast cancer, 030304 developmental biology, Vorinostat, 0303 health sciences, Chemistry, Carbocyanines, medicine.disease, 0104 chemical sciences, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, 010404 medicinal & biomolecular chemistry, Cancer research, Heterografts, Molecular Medicine, Structure based, Female, Histone deacetylase
Abstract: Abnormally high levels of class I histone deacetylases (HDACs) are associated with triple-negative breast cancer (TNBC) proliferation, malignant transformation, and poor prognosis of patients. Herein, we report a near-infrared imaging probe for TNBC detection via visualizing class I HDACs. Conjugating Cy5.5 to a cyclic depsipeptide inhibitor, we obtained the probe (20-Cy5.5) that retained desirable class I HDAC affinity and selectivity. Then, this probe could visualize epigenetic changes by class I HDACs in TNBC MDA-MB-231 cells and in xenograft tumor models in real time. Treatment with suberoylanilide hydroxamic acid (SAHA) significantly reduced the uptake of the probe in tumors, suggesting its potential use in evaluation of therapeutic responses of HDACi-mediated therapy. Moreover, 20-Cy5.5 could detect class I HDAC expression in TNBC lung metastasis. This novel NIR probe that achieves tumor class I HDAC imaging not only leads to a better understanding of epigenetic regulation in tumors but also has great potential for improving the TNBC diagnosis and treatment.
Published: 2021
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34. Relationship Between Post-Traumatic Stress Disorder Symptoms and Chronic Pain-Related Symptom Domains Among Military Active Duty Service Members

Author: Ardith Z. Doorenbos, Dale J. Langford, Hongjin Li, Diane M Flynn, Krista B. Highland, and Patricia K Barr
Subjects: Active duty, media_common.quotation_subject, Anxiety, Anger, Stress Disorders, Post-Traumatic, mental disorders, medicine, Humans, Special Populations Section, Depression (differential diagnoses), Pain Measurement, Social functioning, media_common, business.industry, Traumatic stress, Chronic pain, General Medicine, Service member, medicine.disease, Military Personnel, Anesthesiology and Pain Medicine, Neurology (clinical), Chronic Pain, medicine.symptom, business, Clinical psychology
Abstract: Objective This study examined the relationships between symptom domains relevant to post-traumatic stress disorder (PTSD) diagnosis, PTSD screening, and chronic pain-related symptoms (pain intensity, pain interference, physical function, fatigue, depression, anxiety, anger, satisfaction with social roles) experienced by active duty military service members with chronic pain. Design ross-sectional study. Setting This study was conducted at the Interdisciplinary Pain Management Center (IPMC) at Madigan Army Medical Center between 2014 and 2018. Subjects Active duty service members receiving care at IPMC (n = 2745) were included in this study. Methods Independent sample t test was conducted to compare pain intensity and pain-related measures of physical, emotional, and social functioning among patients with and without a PTSD diagnosis or PTSD positive screen (≥3 symptoms). Relative weight analysis was used to identify the relative importance of each PTSD symptom cluster (e.g., intrusion, avoidance, hyperarousal, emotional numbness) to pain and related domains. Results Approximately 27.9% of the patients had a positive screen for PTSD, and 30.5% of the patients had a PTSD diagnosis. Patients with PTSD diagnosis and positive screening had higher pain interference and lower physical function and social satisfaction scores (P Conclusion To improve treatment effectiveness and overall functioning for active duty military patients, integrated treatment and therapies targeted to reducing chronic pain and PTSD symptoms (focus on emotional numbness and avoidance) are recommended.
Published: 2021
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35. Pain Intensity as a Lagging Indicator of Patient Improvement: Longitudinal Relationships With Sleep, Psychiatric Distress, and Function in Multidisciplinary Care

Author: John A. Sturgeon, Dale J. Langford, David J. Tauben, and Mark Sullivan
Subjects: Adult, Sleep Wake Disorders, medicine.medical_specialty, Comorbidity, Anxiety, Severity of Illness Index, Stress Disorders, Post-Traumatic, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Outcome Assessment, Health Care, medicine, Numeric Rating Scale, Humans, Pain Management, Longitudinal Studies, Prospective cohort study, Depression (differential diagnoses), Retrospective Studies, Sleep disorder, Depression, business.industry, Chronic pain, Models, Theoretical, medicine.disease, Psychosocial Functioning, Distress, Anesthesiology and Pain Medicine, Neurology, Physical therapy, Neurology (clinical), Chronic Pain, medicine.symptom, business, Psychosocial, 030217 neurology & neurosurgery
Abstract: Despite a common assumption that reductions in chronic pain intensity must precede improvements in other pain-relevant domains, there has been limited empirical inquiry into the temporal ordering of improvements in chronic pain treatment. Cross-lagged models using retrospective clinical data examined relationships between average pain intensity and symptoms of psychological distress, difficulties with sleep initiation and maintenance, and disability in 666 treatment-seeking patients with chronic pain who demonstrated improvement in pain intensity (≥1-point reduction on 0-10 numeric rating scale) over a 1-year span. Results indicated that decreased difficulties with sleep initiation, depressive and anxious symptoms, and disability predicted later improvement in pain intensity, whereas greater pain intensity predicted only later difficulties in sleep initiation and maintenance. A combined lagged model highlighted fewer baseline symptoms of post-traumatic stress disorder and lower levels of baseline disability as significant predictors of later improvements in pain. Overall, our results indicate that reductions in pain intensity may not be the first factors to change in effective chronic pain management. The current findings should be replicated using prospective studies utilizing structured approaches to maximize data capture, as well as uniform interventional approaches to permit greater inferences regarding causal and temporal aspects of the model. Perspective This study demonstrates that pain intensity scores are not robust predictors of psychosocial outcomes longitudinally. Instead, other factors such as sleep initiation, psychological distress and disability appear to be important targets for intervention that may promote effective pain reduction.
Published: 2021
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36. Prior aerobic exercise mitigates the decrease in serum osteoglycin and lipocalin-2 following high-glucose mixed-nutrient meal ingestion in young men

Author: Lewan Parker, Teddy Ang, Dale J. Morrison, Nicola J. Lee, Itamar Levinger, and Michelle A. Keske
Subjects: Adult, Blood Glucose, Male, Physiology, Endocrinology, Diabetes and Metabolism, Nutrients, Postprandial Period, Hormones, Eating, Glucose, Lipocalin-2, Physiology (medical), Humans, Insulin, Exercise
Abstract: We provide novel evidence that OGN and LCN2 decrease 120 min after ingesting a high-glucose mixed-nutrient meal in healthy adults. Acute aerobic exercise increases circulating LCN2 for up to 3-h postexercise, whereas circulating OGN remains similar to baseline. Despite differing postexercise responses, postprandial LCN2 and OGN are elevated when the high-glucose meal is ingested 3-h and 24-h postexercise. Findings support that OGN and LCN2 are dynamically linked to energy homeostasis in humans.
Published: 2022

37. Patient-Reported Chronic Pain Intensity: More Than Meets the Eye

Author: Dale J, Langford, Jennifer S, Gewandter, Dagmar, Amtmann, Bryce B, Reeve, Sharon, Hertz, John D, Loeser, Christin, Veasley, Dennis C, Turk, and Robert H, Dworkin
Subjects: Quality of Life, Humans, Patient Reported Outcome Measures, Chronic Pain, Pain Measurement
Published: 2022

38. Tobacco and cigarette butt consumption in humans and animals

Author: Novotny, Thomas E, Hardin, Sarah N, Hovda, Lynn R, Novotny, Dale J, McLean, Mary Kay, and Khan, Safdar
Published: 2011

39. Prior exercise enhances skeletal muscle microvascular blood flow and mitigates microvascular flow impairments induced by a high‐glucose mixed meal in healthy young men

Author: Glenn D. Wadley, Katherine Roberts-Thomson, Lewan Parker, Michelle A. Keske, Christopher S. Shaw, Gunveen Kaur, Dale J. Morrison, and Andrew C. Betik
Subjects: Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, Physiology, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Endurance training, Internal medicine, medicine, Humans, Insulin, Ingestion, Muscle, Skeletal, Meal, business.industry, Microcirculation, digestive, oral, and skin physiology, Skeletal muscle, Blood flow, Postprandial Period, medicine.disease, Glucose, 030104 developmental biology, Postprandial, medicine.anatomical_structure, Endocrinology, Heart failure, business, 030217 neurology & neurosurgery
Abstract: KEY POINTS Exercise, insulin-infusion and low-glucose mixed-nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high-glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism. We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high-glucose mixed-nutrient meal ingested 3 and 24 h post-exercise. Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high-glucose mixed meal ingested 3 h post-exercise, and to a lesser extent 24 h post-exercise. High-glucose ingestion 3 h post-exercise leads to greater postprandial blood glucose, non-esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control. Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. ABSTRACT Exercise, insulin-infusion and low-glucose mixed-nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high-glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high-glucose mixed-nutrient meal ingestion. In a randomized cross-over design, eight healthy young men ingested a high-glucose mixed-nutrient meal (1.1 g glucose/kg body weight; 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no-exercise control) and 3 h and 24 h after moderate-intensity cycling exercise (1 h at 70-75% VO2peak ). Skeletal muscle MBF, measured directly by contrast-enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions (P
Published: 2020
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40. Clinical care and therapeutic trials in PLS

Author: Sabrina Paganoni, Hiroshi Mitsumoto, James Wymer, Mary Kay Floeter, Deborah L. Warden, and Dale J. Lange
Subjects: medicine.medical_specialty, Degenerative Disorder, Article, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary approach, Humans, Medicine, Spasticity, Motor Neuron Disease, Amyotrophic lateral sclerosis, Intensive care medicine, Disease burden, Primary Lateral Sclerosis, Motor Neurons, business.industry, Upper motor neuron, Amyotrophic Lateral Sclerosis, medicine.disease, Clinical trial, medicine.anatomical_structure, Neurology, Muscle Spasticity, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Primary lateral sclerosis (PLS) is an extremely rare central nervous system degenerative disorder characterized by slowly progressive upper motor neuron loss leading to severe limb and bulbar dysfunction and disability. Although not necessarily life-shortening, PLS disease burden is substantial and improved symptomatic treatments are a major unmet need, especially for the often refractory spasticity that is a core feature of the syndrome. In Section 1, we describe clinical care needs and emphasize a highly personalized approach that can be best attained through multidisciplinary management. In Section 2, we describe progress in clinical trials in PLS that includes advances in symptomatic treatment, disease-modifying therapy, and emerging innovative trials.
Published: 2020
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41. Mitochondria and chronic effects of cancer therapeutics: The clinical implications

Author: Dale J. Hamilton, Jun Ichi Abe, and Abishai Dominic
Subjects: Senescence, Cell cycle checkpoint, DNA damage, 030204 cardiovascular system & hematology, Mitochondrion, DNA, Mitochondrial, Article, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Neoplasms, Humans, Medicine, 030212 general & internal medicine, Cellular Senescence, business.industry, Cancer, Hematology, Cell cycle, medicine.disease, Mitochondria, Cancer research, Reactive Oxygen Species, Cardiology and Cardiovascular Medicine, business, Reprogramming
Abstract: One of the major mechanisms of action of chemo-radiation is to induce cellular senescence, which exerts crucial roles in age-related pathology. The concept of senescence is evolved, and the novel understanding of senescence-associated reprogramming/stemness has emerged. This new concept emphasizes senescence as not only cell cycle arrest but describes that subsets of senescent cells induced by chemotherapy can re-enter cell cycles, proliferate rapidly, and acquire “stemness” status. Cancer therapeutics, including chemo-radiation triggers toxicity effects through damaging mitochondria, primarily through the upregulation of mtROS production leading to subsequent mtDNA and telomeric DNA damage elicitng DNA damage responses (DDR). . The ultimate goal of this review is to highlight the new concept of senescence-associated stemnessthat is induced by cancer treatment and its adverse effects on the vascular system. . We will describe how chemo-radiation exerts toxicity effects by simultaneously producing reactive oxygen species in mitochondria and promoting DDR in the nucleus. We discuss the potential of clinical targeting poly (ADP-ribose) polymerase which might prevent downstream mitochondrial dysfunction and confer protection to cancer survivors. Overall we emphasize the importance of recognizing the consequences of cardio-toxic effects of several cancer treatments and therefore developing personalized therapeutic approaches to screen for inflammatory and cardiac testing for better patient survival.
Published: 2020
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42. Risk of Breast Cancer Associated with Estrogen DNA Adduct Biomarker

Author: Dale Whittington, Eleanor G. Rogan, Dale J. Langford, Wendy E. Barrington, Lesley F. Tinker, Thomas E. Rohan, Tongguang Cheng, Kerryn W. Reding, Rowan T. Chlebowski, Muhammad Zahid, and Claire J. Han
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, medicine.drug_class, Estrogen receptor, Breast Neoplasms, Urine, Logistic regression, Article, DNA Adducts, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, DNA adduct, Biomarkers, Tumor, Humans, Medicine, business.industry, Estrogens, Odds ratio, Middle Aged, medicine.disease, 030104 developmental biology, Estrogen, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, business
Abstract: Background: It is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women. Methods: In postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs. Results: EDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71–1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer. Conclusions: Despite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC. Impact: This analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.
Published: 2020
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43. Optimizing telehealth pain care after COVID-19

Author: Cara Towle, David J. Tauben, Dale J. Langford, Sean D. Rundell, Michael K. Nicholas, C. Bockman, and John A. Sturgeon
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, Clinical Neurology, Pain, Telehealth, medicine.disease_cause, Betacoronavirus, Behavior Therapy, Pandemic, medicine, Humans, Pain Management, Topical Review, Pandemics, Physical Therapy Modalities, Coronavirus, biology, SARS-CoV-2, Viral Epidemiology, business.industry, COVID-19, medicine.disease, biology.organism_classification, Virology, Telemedicine, Pneumonia, Anesthesiology and Pain Medicine, Neurology, Neurology (clinical), Coronavirus Infections, business
Published: 2020
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44. Postdiagnosis Physical Activity: Association With Long-Term Fatigue and Sleep Disturbance in Older Adult Breast Cancer Survivors

Author: Dale J. Langford, Di Wang, Oleg Zaslavsky, Elizabeth M. Cespedes Feliciano, Alexi Vasbinder, Wendy E. Barrington, Electra D. Paskett, Claire J. Han, and Kerryn W. Reding
Subjects: Gerontology, Breast Neoplasms, Logistic regression, Article, Breast cancer, Cancer Survivors, Surveys and Questionnaires, Intervention (counseling), Humans, Medicine, Prospective Studies, Association (psychology), Prospective cohort study, Exercise, Fatigue, Aged, General Environmental Science, Sleep disorder, Cancer survivor, business.industry, Cancer, medicine.disease, General Earth and Planetary Sciences, Female, Sleep, business
Abstract: Background Physical activity is frequently proposed as an intervention to reduce fatigue and sleep disturbance in cancer survivors; however, the long-term effects of physical activity are often not reported, and older adults are typically excluded from these intervention studies. Objectives This article aimed to examine if postdiagnosis physical activity is associated with lower long-term fatigue and sleep disturbance in older adult breast cancer survivors. Methods Data were analyzed of a prospective cohort of 440 breast cancer survivors aged 65 years or older from the Women's Health Initiative study. Multiple linear and logistic regression models were used to examine associations of physical activity with fatigue and sleep disturbance. Findings Higher postdiagnosis physical activity was associated with lower long-term fatigue but was not associated with lower sleep disturbance after adjusting for demographics, cancer characteristics, and baseline measures.
Published: 2020
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45. Further insights into the operation of the Chinese number system: Competing effects of Arabic and Mandarin number formats

Author: Xingyu Liu, Dale J. Cohen, and Philip T. Quinlan
Subjects: China, Carry (arithmetic), Numerical cognition, Experimental and Cognitive Psychology, computer.software_genre, Mandarin Chinese, 050105 experimental psychology, Arabic numerals, Article, Task (project management), Numeral system, 03 medical and health sciences, 0302 clinical medicine, Chinese number system, Arts and Humanities (miscellaneous), Mathematical cognition, Similarity (psychology), Humans, 0501 psychology and cognitive sciences, Problem Solving, business.industry, 05 social sciences, language.human_language, Chinese numerals, Neuropsychology and Physiological Psychology, language, Artificial intelligence, Psychology, business, computer, Number processing, 030217 neurology & neurosurgery, Natural language processing
Abstract: Here we report the results of a speeded relative quantity task with Chinese participants. On each trial a single numeral (the probe) was presented and the instructions were to respond as to whether it signified a quantity less than or greater than five (the standard). In separate blocks of trials, the numerals were presented either in Mandarin or in Arabic number formats. In addition to the standard influence of numerical distance, a significant predictor of performance was the degree of physical similarity between the probe and the standard as depicted in Mandarin. Additionally, competing effects of physical similarity, defined in terms of the Arabic number format, were also found. Critically the size of these different effects of physical similarity varied systematically across individuals such that larger effects of one compensated for smaller effects of the other. It is argued that the data favor accounts of processing that assume that different number formats access different format-specific representations of quantities. Moreover, for Chinese participants the default is to translate numerals into a Mandarin format prior to accessing quantity information. The efficacy of this translation process is itself influenced by a competing tendency to carry out a translation into Arabic format.
Published: 2020

46. Distinct Stress Profiles Among Oncology Patients Undergoing Chemotherapy

Author: Bruce A. Cooper, Dale J. Langford, Janice Humphreys, Fay Wright, Laura B. Dunn, Marilyn J. Hammer, Steven M. Paul, Christine Miaskowski, Yvette P. Conley, and Jon D. Levine
Subjects: Male, media_common.quotation_subject, Perceived Stress Scale, Context (language use), Comorbidity, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Humans, Medicine, 030212 general & internal medicine, Socioeconomic status, General Nursing, media_common, business.industry, Stressor, Resilience, Psychological, medicine.disease, Anesthesiology and Pain Medicine, 030220 oncology & carcinogenesis, Normative, Female, Neurology (clinical), Psychological resilience, business, Psychosocial, Stress, Psychological, Clinical psychology
Abstract: Context Cancer and its treatment are inherently stressful and stress impacts important patient outcomes. Patients vary considerably in their response to stress. Understanding this variability requires a patient-centered multidimensional approach. Objectives The objectives of this study were to identify and characterize patient subgroups with distinct multidimensional stress profiles (stress appraisal, exposure, and adaptation) during cancer treatment. Methods Among 957 patients undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer, latent profile analysis was performed to identify patient subgroups using concurrent evaluations of global (Perceived Stress Scale) and cancer-specific (Impact of Events Scale–Revised) stress, lifetime stress exposure (Life Stressor Checklist–Revised), and resilience (Connor-Davidson Resilience Scale-10). Results Three latent classes were identified: “Normative” (54.3%; intermediate global stress and resilience, lower cancer-related stress, lowest life stress); “Stressed” (39.9%; highest global and cancer-specific stress scores, lowest resilience, most life stress); and “Resilient” (5.7%; lowest global stress, cancer-specific stress comparable to Normative class, highest resilience, intermediate life stress). Characteristics that distinguished the Stressed from the Normative class included the following: younger age, female gender, lower socioeconomic status, unmarried/partnered, living alone, poorer functional status, and higher comorbidity burden. Compared to Stressed patients, Resilient patients were more likely to be partnered, to not live alone, and had a higher functional status. No demographic or clinical characteristics differentiated Normative from Resilient patients. Exposure to specific life stressors differed significantly among the classes. Conclusion A subset of patients warrants intensive psychosocial intervention to reduce stress and improve adaptation to cancer. Intervention efforts may be informed by further study of Resilient patients.
Published: 2020
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47. RNA-seq Fusion Detection in Clinical Oncology

Author: Dale J, Hedges
Subjects: Sequence Analysis, RNA, Neoplasms, Exome Sequencing, High-Throughput Nucleotide Sequencing, Humans, RNA-Seq, Gene Fusion, Precision Medicine, Medical Oncology, Ecosystem, Software
Abstract: Gene fusions play a prominent role in the oncogenesis of many cancers and have been extensively targeted as biomarkers for diagnostic, prognostic, and therapeutic purposes. Detection methods span a number of platforms, including cytogenetics (e.g., FISH), targeted qPCR, and sequencing-based assays. Before the advent of next-generation sequencing (NGS), fusion testing was primarily targeted to specific genome loci, with assays tailored for previously characterized fusion events. The availability of whole genome sequencing (WGS) and whole transcriptome sequencing (RNA-seq) allows for genome-wide screening for the simultaneous detection of both known and novel fusions. RNA-seq, in particular, offers the possibility of rapid turn-around testing with less dedicated sequencing than WGS. This makes it an attractive target for clinical oncology testing, particularly when transcriptome data can be multi-purposed for tumor classification and additional analyses. Despite considerable efforts and substantial progress, however, genome-wide screening for fusions solely based on RNA-seq data remains an ongoing challenge. A host of technical artifacts adversely impact the sensitivity and specificity of existing software tools. In this chapter, the general strategies employed by current fusion software are discussed, and a selection of available fusion detection tools are surveyed. Despite its current limitations, RNA-seq-based fusion detection offers a more comprehensive and efficient strategy as compared to multiple targeted fusion assays. When thoughtfully employed within a wider ecosystem of diagnostic assays and clinical information, RNA-seq fusion detection represents a powerful tool for precision oncology.
Published: 2022

48. Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24

Author: Sophia Davidson, Chien-Hsiung Yu, Annemarie Steiner, Frédéric Ebstein, Paul J. Baker, Valentina Jarur-Chamy, Katja Hrovat Schaale, Pawat Laohamonthonkul, Klara Kong, Dale J. Calleja, Cassandra R. Harapas, Katherine R. Balka, Jacob Mitchell, Jacob T. Jackson, Niall D. Geoghegan, Fiona Moghaddas, Kelly L. Rogers, Katrin D. Mayer-Barber, Adriana A. De Jesus, Dominic De Nardo, Benjamin T. Kile, Anthony J. Sadler, M. Cecilia Poli, Elke Krüger, Raphaela Goldbach Mansky, and Seth L. Masters
Subjects: Mice, Inbred C57BL, Mice, Knockout, Mice, eIF-2 Kinase, Interleukins, Immunology, Animals, Humans, General Medicine, Cells, Cultured, Immunity, Innate
Abstract: Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor–induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum–associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.
Published: 2022
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49. SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations

Author: Joy Mitra, Manohar Kodavati, Vincent E. Provasek, K.S. Rao, Sankar Mitra, Dale J. Hamilton, Philip J. Horner, Farhaan S. Vahidy, Gavin W. Britz, Thomas A. Kent, and Muralidhar L. Hegde
Subjects: Aging, Neurology, SARS-CoV-2, Brain, COVID-19, Humans, Hemorrhage, Nervous System Diseases, Molecular Biology, Biochemistry, Biotechnology, Aged
Abstract: Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods. However, prognostic investigations suggest that both acute and long-term neurological complications, including predisposition to irreversible neurodegenerative diseases, can be a serious concern for COVID-19 survivors, especially the elderly population. As emerging studies reveal sites of SARS-CoV-2 infection in different parts of the brain, potential causes of chronic lesions including cerebral and deep-brain microbleeds and the likelihood of developing stroke-like pathologies increases, with critical long-term consequences, particularly for individuals with neuropathological and/or age-associated comorbid conditions. Our recent studies linking the blood degradation products to genome instability, leading to cellular senescence and ferroptosis, raise the possibility of similar neurovascular events as a result of SARS-CoV-2 infection. In this review, we discuss the neuropathological consequences of SARS-CoV-2 infection in COVID survivors, focusing on possible hemorrhagic damage in brain cells, its association to aging, and the future directions in developing mechanism-guided therapeutic strategies.
Published: 2022

50. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Author: Brown, Anna-Leigh, Wilkins, Oscar G., Keuss, Matthew J., Hill, Sarah E., Zanovello, Matteo, Lee, Weaverly Colleen, Bampton, Alexander, Lee, Flora C. Y., Masino, Laura, Qi, Yue A., Bryce-Smith, Sam, Gatt, Ariana, Hallegger, Martina, Fagegaltier, Delphine, Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R., Simmons, Zachary, Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Shneider, Neil A., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos. A., Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Bowser, Robert, Harms, Matthew, Aronica, Eleonora, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J., Adams, Darius J., Stefanis, Leonidas, Gotkine, Marc, Baloh, Robert H., Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, Wu, Lani, Altschuler, Steven, Lerner, Yossef, Sattler, Rita, Van Keuren-Jensen, Kendall, Rozenblatt-Rosen, Orit, Lindblad-Toh, Kerstin, Nicholson, Katharine, Gregersen, Peter, Lee, Jeong-Ho, Kokos, Sulev, Muljo, Stephen, Newcombe, Jia, Gustavsson, Emil K., Seddighi, Sahba, Reyes, Joel F., Coon, Steven L., Ramos, Daniel, Schiavo, Giampietro, Fisher, Elizabeth M. C., Secrier, Maria, Lashley, Tammaryn, Ule, Jernej, Buratti, Emanuele, Humphrey, Jack, Ward, Michael E., Human Genetics, ARD - Amsterdam Reproduction and Development, Pathology, and ANS - Cellular & Molecular Mechanisms
Subjects: General Science & Technology, Gene Expression, Nerve Tissue Proteins, Neurodegenerative, Biochemistry & Proteomics, Rare Diseases, Ecology,Evolution & Ethology, Clinical Research, mental disorders, Acquired Cognitive Impairment, Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Aetiology, Codon, Medicinsk genetik, NYGC ALS Consortium, Computational & Systems Biology, Chemical Biology & High Throughput, Multidisciplinary, Prevention, FOS: Clinical medicine, Stem Cells, Amyotrophic Lateral Sclerosis, Neurosciences, nutritional and metabolic diseases, Single Nucleotide, Brain Disorders, nervous system diseases, DNA-Binding Proteins, Alternative Splicing, Nonsense, TDP-43 Proteinopathies, Frontotemporal Dementia, Neurological, Dementia, ALS, Medical Genetics, Genetics & Genomics, Neurovetenskaper, Structural Biology & Biophysics
Abstract: Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.
Published: 2022
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