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1. SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.

Author

Chan, Yi-Hao, Lundberg, Vanja, Le Pen, Jérémie, Yuan, Jiayi, Lee, Danyel, Pinci, Francesca, Volpi, Stefano, Nakajima, Koji, Bondet, Vincent, Åkesson, Sanna, Khobrekar, Noopur, Bodansky, Aaron, Du, Likun, Melander, Tina, Mariaggi, Alice-Andrée, Seeleuthner, Yoann, Saleh, Tariq, Chakravarty, Debanjana, Marits, Per, Dobbs, Kerry, Vonlanthen, Sofie, Hennings, Viktoria, Thörn, Karolina, Rinchai, Darawan, Bizien, Lucy, Chaldebas, Matthieu, Sobh, Ali, Özçelik, Tayfun, Keles, Sevgi, AlKhater, Suzan, Prando, Carolina, Meyts, Isabelle, Wilson, Michael, Rosain, Jérémie, Jouanguy, Emmanuelle, Aubart, Mélodie, Abel, Laurent, Mogensen, Trine, Pan-Hammarström, Qiang, Gao, Daxing, Duffy, Darragh, Cobat, Aurélie, Berg, Stefan, Notarangelo, Luigi, Harschnitz, Oliver, Rice, Charles, Studer, Lorenz, Casanova, Jean-Laurent, Ekwall, Olov, and Zhang, Shen-Ying

Subjects
Humans, Male, SARS-CoV-2, COVID-19, Brain Stem, Adolescent, Neurons, Encephalitis, Viral, Fibroblasts, Rhombencephalon
Abstract

Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.

Published
2024

2. Molecular Transducers of Physical Activity Consortium (MoTrPAC): human studies design and protocol

Author

Group, MoTrPAC Study, Jakicic, John M, Kohrt, Wendy M, Houmard, Joseph A, Miller, Michael E, Radom-Aizik, Shlomit, Rasmussen, Blake B, Ravussin, Eric, Serra, Monica, Stowe, Cynthia L, Trappe, Scott, Abouassi, Hiba, Adkins, Joshua N, Alekel, D Lee, Ashley, Euan, Bamman, Marcas M, Bergman, Bryan C, Bessesen, Daniel H, Broskey, Nicholas T, Buford, Thomas W, Burant, Charles F, Chen, Haiying, Christle, Jeffrey W, Clish, Clary B, Coen, Paul M, Collier, David, Collins, Katherine A, Cooper, Daniel M, Cortes, Tiffany, Cutter, Gary R, Dubis, Gabriel, Fernández, Facundo M, Firnhaber, Jonathon, Forman, Daniel E, Gaul, David A, Gay, Nicole, Gerszten, Robert E, Goodpaster, Bret H, Gritsenko, Marina A, Haddad, Fadia, Huffman, Kim M, Ilkayeva, Olga, Jankowski, Catherine M, Jin, Christopher, Johannsen, Neil M, Johnson, Johanna, Kelly, Leslie, Kershaw, Erin, Kraus, William E, Laughlin, Maren, Lester, Bridget, Lindholm, Malene E, Lowe, Adam, Lu, Ching-Ju, McGowan, Joan, Melanson, Edward L, Montgomery, Stephen, Moore, Samuel G, Moreau, Kerrie L, Muehlbauer, Michael, Musi, Nicolas, Nair, Venugopalan D, Newgard, Christopher B, Newman, Anne B, Nicklas, Barbara, Nindl, Bradley C, Ormond, Kelly, Piehowski, Paul D, Qian, Wei-Jun, Rankinen, Tuomo, Rejeski, W Jack, Robbins, Jeremy, Rogers, Renee J, Rooney, Jessica L, Rushing, Scott, Sanford, James A, Schauer, Irene E, Schwartz, Robert S, Sealfon, Stuart C, Slentz, Cris, Sloan, Ruben, Smith, Kevin S, Snyder, Michael, Spahn, Jessica, Sparks, Lauren M, Stefanovic-Racic, Maja, Tanner, Charles J, Thalacker-Mercer, Anna, Tracy, Russell, Trappe, Todd A, Volpi, Elena, Walsh, Martin J, Wheeler, Matthew T, and Willis, Leslie

Subjects
Biomedical and Clinical Sciences, Health Sciences, Public Health, Sports Science and Exercise, Clinical Sciences, Behavioral and Social Science, Physical Activity, Nutrition, Clinical Research, Obesity, Prevention, Cardiovascular, 6.7 Physical, Generic health relevance, Good Health and Well Being, Humans, Exercise, Adult, Resistance Training, Child, Male, Female, Adolescent, Research Design, Cardiorespiratory Fitness, Muscle Strength, Body Composition, Young Adult, Endurance Training, adipose tissue, biospecimens, molecular transducers, physical activity, skeletal muscle, MoTrPAC Study Group, Biological Sciences, Medical and Health Sciences, Physiology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multicenter study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a preclinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 wk of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 wk. The adult component also includes recruitment of highly active endurance-trained or resistance-trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.NEW & NOTEWORTHY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) will be the first large trial to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. By generating a compendium of the molecular responses to exercise, MoTrPAC will lay the foundation for a new era of biomedical research on Precision Exercise Medicine. Presented here is the design, protocols, and procedures for the MoTrPAC human studies.

Published
2024

3. Optimizing the Design of Clinical Trials to Evaluate the Efficacy of Function-Promoting Therapies.

Author

Bhasin, Shalender, Cawthon, Peggy, Correa-de-Araujo, Rosaly, Storer, Thomas, Volpi, Elena, Newman, Anne, Dioh, Waly, Tourette, Cendrine, Evans, William, and Fielding, Roger

Subjects
Clinical trial design, Function-promoting drugs, Functional decline with aging, Sarcopenia, Skeletal muscle dysfunction, Aged, Humans, Aging, Frailty, Neoplasms, Sarcopenia, Clinical Trials as Topic
Abstract

BACKGROUND: Several candidate molecules that may have application in treating physical limitations associated with aging and chronic diseases are in development. Challenges in the framing of indications, eligibility criteria, and endpoints and the lack of regulatory guidance have hindered the development of function-promoting therapies. METHODS: Experts from academia, pharmaceutical industry, National Institutes of Health (NIH), and Food and Drug Administration (FDA) discussed optimization of trial design including the framing of indications, eligibility criteria, and endpoints. RESULTS: Mobility disability associated with aging and chronic diseases is an attractive indication because it is recognized by geriatricians as a common condition associated with adverse outcomes, and it can be ascertained reliably. Other conditions associated with functional limitation in older adults include hospitalization for acute illnesses, cancer cachexia, and fall injuries. Efforts are underway to harmonize definitions of sarcopenia and frailty. Eligibility criteria should reconcile the goals of selecting participants with the condition and ensuring generalizability and ease of recruitment. An accurate measure of muscle mass (eg, D3 creatine dilution) could be a good biomarker in early-phase trials. Performance-based and patient-reported measures of physical function are needed to demonstrate whether treatment improves how a person lives, functions, or feels. Multicomponent functional training that integrates training in balance, stability, strength, and functional tasks with cognitive and behavioral strategies may be needed to translate drug-induced muscle mass gains into functional improvements. CONCLUSIONS: Collaborations among academic investigators, NIH, FDA, pharmaceutical industry, patients, and professional societies are needed to conduct well-designed trials of function-promoting pharmacological agents with and without multicomponent functional training.

Published
2023

4. Effect of the STRIDE fall injury prevention intervention on falls, fall injuries, and health‐related quality of life

Author

Ganz, David A, Yuan, Anita H, Greene, Erich J, Latham, Nancy K, Araujo, Katy, Siu, Albert L, Magaziner, Jay, Gurwitz, Jerry H, Wu, Albert W, Alexander, Neil B, Wallace, Robert B, Greenspan, Susan L, Rich, Jeremy, Volpi, Elena, Waring, Stephen C, Dykes, Patricia C, Ko, Fred, Resnick, Neil M, McMahon, Siobhan K, Basaria, Shehzad, Wang, Rixin, Lu, Charles, Esserman, Denise, Dziura, James, Miller, Michael E, Travison, Thomas G, Peduzzi, Peter, Bhasin, Shalender, Reuben, David B, and Gill, Thomas M

Subjects
Health Services and Systems, Public Health, Health Sciences, Clinical Research, Rehabilitation, Patient Safety, Prevention, Clinical Trials and Supportive Activities, Aging, Physical Injury - Accidents and Adverse Effects, Injuries and accidents, Good Health and Well Being, Humans, Aged, Quality of Life, Independent Living, Fractures, Bone, Hospitalization, care management, health-related quality of life, older persons, pragmatic trials, falls, Medical and Health Sciences, Geriatrics, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

BackgroundFalls are common in older adults and can lead to severe injuries. The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial cluster-randomized 86 primary care practices across 10 health systems to a multifactorial intervention to prevent fall injuries, delivered by registered nurses trained as falls care managers, or enhanced usual care. STRIDE enrolled 5451 community-dwelling older adults age ≥70 at increased fall injury risk.MethodsWe assessed fall-related outcomes via telephone interviews of participants (or proxies) every 4 months. At baseline, 12 and 24 months, we assessed health-related quality of life (HRQOL) using the EQ-5D-5L and EQ-VAS. We used Poisson models to assess intervention effects on falls, fall-related fractures, fall injuries leading to hospital admission, and fall injuries leading to medical attention. We used hierarchical longitudinal linear models to assess HRQOL.ResultsFor recurrent event models, intervention versus control incidence rate ratios were 0.97 (95% confidence interval [CI], 0.93-1.00; p = 0.048) for falls, 0.93 (95% CI, 0.80-1.08; p = 0.337) for self-reported fractures, 0.89 (95% CI, 0.73-1.07; p = 0.205) for adjudicated fractures, 0.91 (95% CI, 0.77-1.07; p = 0.263) for falls leading to hospital admission, and 0.97 (95% CI, 0.89-1.06; p = 0.477) for falls leading to medical attention. Similar effect sizes (non-significant) were obtained for dichotomous outcomes (e.g., participants with ≥1 events). The difference in least square mean change over time in EQ-5D-5L (intervention minus control) was 0.009 (95% CI, -0.002 to 0.019; p = 0.106) at 12 months and 0.005 (95% CI, -0.006 to 0.015; p = 0.384) at 24 months.ConclusionsAcross a standard set of outcomes typically reported in fall prevention studies, we observed modest improvements, one of which was statistically significant. Future work should focus on patient-, practice-, and organization-level operational strategies to increase the real-world effectiveness of interventions, and improving the ability to detect small but potentially meaningful clinical effects.Clinicaltrialsgov identifier: NCT02475850.

Published
2022

5. Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction JACC State-of-the-Art Review

Author

Pandey, Ambarish, Shah, Sanjiv J, Butler, Javed, Kellogg, Dean L, Lewis, Gregory D, Forman, Daniel E, Mentz, Robert J, Borlaug, Barry A, Simon, Marc A, Chirinos, Julio A, Fielding, Roger A, Volpi, Elena, Molina, Anthony JA, Haykowsky, Mark J, Sam, Flora, Goodpaster, Bret H, Bertoni, Alain G, Justice, Jamie N, White, James P, Ding, Jingzhone, Hummel, Scott L, LeBrasseur, Nathan K, Taffet, George E, Pipinos, Iraklis I, and Kitzman, Dalane

Subjects
Aging, Heart Disease, Cardiovascular, Animals, Exercise Tolerance, Heart Failure, Diastolic, Humans, exercise intolerance, heart failure with preserved ejection fraction, senescence, skeletal muscle, aging, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Published
2021

6. Effect of a Multifactorial Fall Injury Prevention Intervention on Patient Well‐Being: The STRIDE Study

Author

Gill, Thomas M, Bhasin, Shalender, Reuben, David B, Latham, Nancy K, Araujo, Katy, Ganz, David A, Boult, Chad, Wu, Albert W, Magaziner, Jay, Alexander, Neil, Wallace, Robert B, Miller, Michael E, Travison, Thomas G, Greenspan, Susan L, Gurwitz, Jerry H, Rich, Jeremy, Volpi, Elena, Waring, Stephen C, Manini, Todd M, Min, Lillian C, Teresi, Jeanne, Dykes, Patricia C, McMahon, Siobhan, McGloin, Joanne M, Skokos, Eleni A, Charpentier, Peter, Basaria, Shehzad, Duncan, Pamela W, Storer, Thomas W, Gazarian, Priscilla, Allore, Heather G, Dziura, James, Esserman, Denise, Carnie, Martha B, Hanson, Catherine, Ko, Fred, Resnick, Neil M, Wiggins, Jocelyn, Lu, Charles, Meng, Can, Goehring, Lori, Fagan, Maureen, Correa‐de‐Araujo, Rosaly, Casteel, Carri, Peduzzi, Peter, and Greene, Erich J

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Clinical Sciences, Health Sciences, Depression, Clinical Trials and Supportive Activities, Clinical Research, Prevention, Patient Safety, Aging, Physical Injury - Accidents and Adverse Effects, Mental Health, Rehabilitation, Brain Disorders, Cancer, 7.1 Individual care needs, Management of diseases and conditions, Injuries and accidents, Good Health and Well Being, Accidental Falls, Aged, 80 and over, Anxiety, Female, Humans, Independent Living, Male, Nurse's Role, Patient Reported Outcome Measures, Patients, Primary Health Care, Risk Assessment, older persons, fall injury prevention, well-being, pragmatic trials, Medical and Health Sciences, Geriatrics, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Background/objectivesIn the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability.DesignPragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries.SettingA total of 86 primary care practices within 10 U.S. healthcare systems.ParticipantsA random subsample of 743 persons aged 75 and older.MeasurementsThe well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument.ResultsParticipants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference.ConclusionsSTRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being.

Published
2021

7. D‐CARE: The Dementia Care Study: Design of a Pragmatic Trial of the Effectiveness and Cost Effectiveness of Health System–Based Versus Community‐Based Dementia Care Versus Usual Dementia Care

Author

Reuben, David B, Gill, Thomas M, Stevens, Alan, Williamson, Jeff, Volpi, Elena, Lichtenstein, Maya, Jennings, Lee A, Tan, Zaldy, Evertson, Leslie, Bass, David, Weitzman, Lisa, Carnie, Martie, Wilson, Nancy, Araujo, Katy, Charpentier, Peter, Meng, Can, Greene, Erich J, Dziura, James, Liu, Jodi, Unger, Erin, Yang, Mia, Currie, Katherine, Lenoir, Kristin M, Green, Aval‐NaʼRee S, Abraham, Sitara, Vernon, Ashley, Samper‐Ternent, Rafael, Raji, Mukaila, Hirst, Roxana M, Galloway, Rebecca, Finney, Glen R, Ladd, Ilene, Rahm, Alanna Kulchak, Borek, Pamela, and Peduzzi, Peter

Subjects
Health Services and Systems, Nursing, Health Sciences, Neurodegenerative, Comparative Effectiveness Research, Behavioral and Social Science, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Health Services, Clinical Research, Alzheimer's Disease, Acquired Cognitive Impairment, Neurosciences, Aging, Clinical Trials and Supportive Activities, Brain Disorders, Dementia, Cost Effectiveness Research, 7.1 Individual care needs, Management of diseases and conditions, Neurological, Good Health and Well Being, Aged, Alzheimer Disease, Caregiver Burden, Community Health Services, Comprehensive Health Care, Cost-Benefit Analysis, Female, Humans, Male, Multicenter Studies as Topic, Pragmatic Clinical Trials as Topic, Quality Improvement, Quality of Life, Alzheimer's disease, dementia, care coordination, pragmatic trials, Medical and Health Sciences, Geriatrics, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Background/objectivesAlthough several approaches have been developed to provide comprehensive care for persons living with dementia (PWD) and their family or friend caregivers, the relative effectiveness and cost effectiveness of community-based dementia care (CBDC) versus health system-based dementia care (CBDC) and the effectiveness of both approaches compared with usual care (UC) are unknown.DesignPragmatic randomized three-arm superiority trial. The unit of randomization is the PWD/caregiver dyad.SettingFour clinical trial sites (CTSs) based in academic and clinical health systems.ParticipantsA total of 2,150 English- or Spanish-speaking PWD who are not receiving hospice or residing in a nursing home and their caregivers.InterventionsEighteen months of (1) HSDC provided by a nurse practitioner or physician's assistant dementia care specialist who works within the health system, or (2) CBDC provided by a social worker or nurse care consultant who works at a community-based organization, or (3) UC with as needed referral to the Alzheimer's Association Helpline.MeasurementsPrimary outcomes: PWD behavioral symptoms and caregiver distress as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Modified Caregiver Strain Index scales.Secondary outcomesNPI-Q Distress, caregiver unmet needs and confidence, and caregiver depressive symptoms. Tertiary outcomes: PWD long-term nursing home placement rates, caregiver-reported PWD functional status, cognition, goal attainment, "time spent at home," Dementia Burden Scale-Caregiver, a composite measure of clinical benefit, Quality of Life of persons with dementia, Positive Aspects of Caregiving, and cost effectiveness using intervention costs and Medicare claims.ResultsThe results will be reported in the spring of 2024.ConclusionD-CARE will address whether emphasis on clinical support and tighter integration with other medical services has greater benefit than emphasis on social support that is tied more closely to community resources. It will also assess the effectiveness of both interventions compared with UC and will evaluate the cost effectiveness of each intervention.

Published
2020

8. A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries

Author

Bhasin, Shalender, Gill, Thomas M, Reuben, David B, Latham, Nancy K, Ganz, David A, Greene, Erich J, Dziura, James, Basaria, Shehzad, Gurwitz, Jerry H, Dykes, Patricia C, McMahon, Siobhan, Storer, Thomas W, Gazarian, Priscilla, Miller, Michael E, Travison, Thomas G, Esserman, Denise, Carnie, Martha B, Goehring, Lori, Fagan, Maureen, Greenspan, Susan L, Alexander, Neil, Wiggins, Jocelyn, Ko, Fred, Siu, Albert L, Volpi, Elena, Wu, Albert W, Rich, Jeremy, Waring, Stephen C, Wallace, Robert B, Casteel, Carri, Resnick, Neil M, Magaziner, Jay, Charpentier, Peter, Lu, Charles, Araujo, Katy, Rajeevan, Haseena, Meng, Can, Allore, Heather, Brawley, Brooke F, Eder, Rich, McGloin, Joanne M, Skokos, Eleni A, Duncan, Pamela W, Baker, Dorothy, Boult, Chad, Correa-de-Araujo, Rosaly, and Peduzzi, Peter

Subjects
Health Services, Aging, Clinical Trials and Supportive Activities, Comparative Effectiveness Research, Physical Injury - Accidents and Adverse Effects, Patient Safety, Prevention, Clinical Research, Injuries and accidents, Good Health and Well Being, Accidental Falls, Accidental Injuries, Aged, Aged, 80 and over, Female, Hospitalization, Humans, Incidence, Independent Living, Male, Patient Care Management, Precision Medicine, Risk Assessment, Risk Factors, STRIDE Trial Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundInjuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined.MethodsWe conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group.ResultsThe demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups.ConclusionsA multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.).

Published
2020

9. The Role of Chest Imaging in Patient Management During the COVID-19 Pandemic A Multinational Consensus Statement From the Fleischner Society

Author

Rubin, Geoffrey D, Ryerson, Christopher J, Haramati, Linda B, Sverzellati, Nicola, Kanne, Jeffrey P, Raoof, Suhail, Schluger, Neil W, Volpi, Annalisa, Yim, Jae-Joon, Martin, Ian BK, Anderson, Deverick J, Kong, Christina, Altes, Talissa, Bush, Andrew, Desai, Sujal R, Goldin, Jonathan, Goo, Jin Mo, Humbert, Marc, Inoue, Yoshikazu, Kauczor, Hans-Ulrich, Luo, Fengming, Mazzone, Peter J, Prokop, Mathias, Remy-Jardin, Martine, Richeldi, Luca, Schaefer-Prokop, Cornelia M, Tomiyama, Noriyuki, Wells, Athol U, and Leung, Ann N

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Lung, Prevention, Infection, Good Health and Well Being, Betacoronavirus, COVID-19, Coronavirus Infections, Diagnosis, Differential, Disease Progression, Early Diagnosis, Humans, International Cooperation, Pandemics, Patient Care Management, Pneumonia, Viral, Radiography, Thoracic, Respiratory Tract Diseases, SARS-CoV-2, Tomography, X-Ray Computed, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

With more than 900,000 confirmed cases worldwide and nearly 50,000 deaths during the first 3 months of 2020, the coronavirus disease 2019 (COVID-19) pandemic has emerged as an unprecedented health care crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, health care delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and health care workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. Although mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography and CT are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pretest probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing patients with COVID-19 across a spectrum of health care environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based on the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of chest radiography and CT in the management of COVID-19.

Published
2020

10. Quantification of muscle triglyceride synthesis rate requires an adjustment for total triglyceride content

Author

Asghar, Rabia, Chondronikola, Maria, Dillon, Edgar L, Durham, William J, Porter, Craig, Wu, Zhanpin, Camacho-Hughes, Maria, Andersen, Clark R, Spratt, Heidi, Volpi, Elena, Sheffield-Moore, Melinda, Sidossis, Labros, Wolfe, Robert R, Abate, Nicola, and Tuvdendorj, Demidmaa R

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Artifacts, Female, Healthy Volunteers, Humans, Kinetics, Middle Aged, Muscle, Skeletal, Triglycerides, in vivo muscle triglyceride synthesis, stable isotope tracers, skeletal muscle lipid metabolism, Biochemistry and Cell Biology, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Intramyocellular triglyceride (imTG) in skeletal muscle plays a significant role in metabolic health, and an infusion of [13C16]palmitate can be used to quantitate the in vivo fractional synthesis rate (FSR) and absolute synthesis rate (ASR) of imTGs. However, the extramyocellular TG (emTG) pool, unless precisely excised, contaminates the imTG pool, diluting the imTG-bound tracer enrichment and leading to underestimation of FSR. Because of the difficulty of excising the emTGs precisely, it would be advantageous to be able to calculate the imTG synthesis rate without dissecting the emTGs from each sample. Here, we tested the hypothesis that the ASR of total TGs (tTGs), a combination of imTGs and emTGs, calculated as "FSR × tTG pool," reasonably represents the imTG synthesis. Muscle lipid parameters were measured in nine healthy women at 90 and 170 min after the start of [13C16]palmitate infusion. While the measurements of tTG content, enrichment, and FSR did not correlate (P > 0.05), those of the tTG ASR were significantly correlated (r = 0.947, P < 0.05). These results demonstrate that when imTGs and emTGs are pooled, the resulting underestimation of imTG FSR is balanced by the overestimation of the imTG content. We conclude that imTG metabolism is reflected by the measurement of the tTG ASR.

Published
2018

11. Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE): A Cluster-Randomized Pragmatic Trial of a Multifactorial Fall Injury Prevention Strategy: Design and Methods

Author

Bhasin, Shalender, Gill, Thomas M, Reuben, David B, Latham, Nancy K, Gurwitz, Jerry H, Dykes, Patricia, McMahon, Siobhan, Storer, Thomas W, Duncan, Pamela W, Ganz, David A, Basaria, Shehzad, Miller, Michael E, Travison, Thomas G, Greene, Erich J, Dziura, James, Esserman, Denise, Allore, Heather, Carnie, Martha B, Fagan, Maureen, Hanson, Catherine, Baker, Dorothy, Greenspan, Susan L, Alexander, Neil, Ko, Fred, Siu, Albert L, Volpi, Elena, Wu, Albert W, Rich, Jeremy, Waring, Stephen C, Wallace, Robert, Casteel, Carri, Magaziner, Jay, Charpentier, Peter, Lu, Charles, Araujo, Katy, Rajeevan, Haseena, Margolis, Scott, Eder, Richard, McGloin, Joanne M, Skokos, Eleni, Wiggins, Jocelyn, Garber, Lawrence, Clauser, Steven B, Correa-De-Araujo, Rosaly, and Peduzzi, Peter

Subjects
Health Services, Rehabilitation, Clinical Research, Comparative Effectiveness Research, Patient Safety, Aging, Prevention, Physical Injury - Accidents and Adverse Effects, Clinical Trials and Supportive Activities, Prevention of disease and conditions, and promotion of well-being, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Injuries and accidents, Good Health and Well Being, Accidental Falls, Aged, Aged, 80 and over, Female, Humans, Male, Motivational Interviewing, Risk Assessment, Wounds and Injuries, Fall prevention, Clinical effectiveness, Patient and stakeholders in fall injury prevention research, Nurse falls care managers, Clinical Sciences, Gerontology
Abstract

BackgroundFall injuries are a major cause of morbidity and mortality among older adults. We describe the design of a pragmatic trial to compare the effectiveness of an evidence-based, patient-centered multifactorial fall injury prevention strategy to an enhanced usual care.MethodsStrategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) is a 40-month cluster-randomized, parallel-group, superiority, pragmatic trial being conducted at 86 primary care practices in 10 health care systems across United States. The 86 practices were randomized to intervention or control group using covariate-based constrained randomization, stratified by health care system. Participants are community-living persons, ≥70 years, at increased risk for serious fall injuries. The intervention is a comanagement model in which a nurse Falls Care Manager performs multifactorial risk assessments, develops individualized care plans, which include surveillance, follow-up evaluation, and intervention strategies. Control group receives enhanced usual care, with clinicians and patients receiving evidence-based information on falls prevention. Primary outcome is serious fall injuries, operationalized as those leading to medical attention (nonvertebral fractures, joint dislocation, head injury, lacerations, and other major sequelae). Secondary outcomes include all fall injuries, all falls, and well-being (concern for falling; anxiety and depressive symptoms; physical function and disability). Target sample size was 5,322 participants to provide 90% power to detect 20% reduction in primary outcome rate relative to control.ResultsTrial enrolled 5,451 subjects in 20 months. Intervention and follow-up are ongoing.ConclusionsThe findings of the STRIDE study will have important clinical and policy implications for the prevention of fall injuries in older adults.

Published
2018

12. Palmitoyl-carnitine production by blood cells associates with the concentration of circulating acyl-carnitines in healthy overweight women

Author

Chondronikola, Maria, Asghar, Rabia, Zhang, Xiaojun, Dillon, Edgar L, Durham, William J, Wu, Zhanpin, Porter, Craig, Camacho-Hughes, Maria, Zhao, Yingxin, Brasier, Allan R, Volpi, Elena, Sheffield-Moore, Melinda, Abate, Nicola, Sidossis, Labros, and Tuvdendorj, Demidmaa

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Diabetes, Prevention, Obesity, Nutrition, Metabolic and endocrine, Adult, Aged, Blood Cells, Blood Glucose, Body Mass Index, Carnitine, Diabetes Mellitus, Type 2, Female, Humans, Hyperinsulinism, Insulin, Insulin Resistance, Lipid Metabolism, Middle Aged, Overweight, Oxidation-Reduction, Palmitates, Palmitoylcarnitine, Acyl-carnitines, Blood cells, Stable isotope tracer, Plasma palmitate oxidation, Insulin resistance, Nutrition and Dietetics, Nutrition & Dietetics, Nutrition and dietetics
Abstract

BackgroundCirculating acyl-carnitines (acyl-CNTs) are associated with insulin resistance (IR) and type 2 diabetes (T2D) in both rodents and humans. However, the mechanisms whereby circulating acyl-CNTs are increased in these conditions and their role in whole-body metabolism remains unknown. The purpose of this study was to determine if, in humans, blood cells contribute in production of circulating acyl-CNTs and associate with whole-body fat metabolism.Methods and resultsEight non-diabetic healthy women (age: 47 ± 19 y; BMI: 26 ± 1 kg·m-2) underwent stable isotope tracer infusion and hyperinsulinemic-euglycemic clamp study to determine in vivo whole-body fatty acid flux and insulin sensitivity. Blood samples collected at baseline (0 min) and after 3 h of clamp were used to determine the synthesis rate of palmitoyl-carnitine (palmitoyl-CNT) in vitro. The fractional synthesis rate of palmitoyl-CNT was significantly higher during hyperinsulinemia (0.788 ± 0.084 vs. 0.318 ± 0.012%·hr-1, p = 0.001); however, the absolute synthesis rate (ASR) did not differ between the periods (p = 0.809) due to ∼30% decrease in blood palmitoyl-CNT concentration (p = 0.189) during hyperinsulinemia. The ASR of palmitoyl-CNT significantly correlated with the concentration of acyl-CNTs in basal (r = 0.992, p

Published
2017

13. Genetic effects on gene expression across human tissues

Author

Aguet, François, Brown, Andrew A, Castel, Stephane E, Davis, Joe R, He, Yuan, Jo, Brian, Mohammadi, Pejman, Park, YoSon, Parsana, Princy, Segrè, Ayellet V, Strober, Benjamin J, Zappala, Zachary, Cummings, Beryl B, Gelfand, Ellen T, Hadley, Kane, Huang, Katherine H, Lek, Monkol, Li, Xiao, Nedzel, Jared L, Nguyen, Duyen Y, Noble, Michael S, Sullivan, Timothy J, Tukiainen, Taru, MacArthur, Daniel G, Getz, Gad, Addington, Anjene, Guan, Ping, Koester, Susan, Little, A Roger, Lockhart, Nicole C, Moore, Helen M, Rao, Abhi, Struewing, Jeffery P, Volpi, Simona, Brigham, Lori E, Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F, Lonsdale, John T, McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Bryan, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A, Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A, Gillard, Bryan M, Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T, Jewell, Scott D, Montroy, Robert G, Rohrer, Daniel C, Valley, Dana, Mash, Deborah C, Davis, David A, Sobin, Leslie, Barcus, Mary E, Branton, Philip A, Abell, Nathan S, Balliu, Brunilda, Delaneau, Olivier, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Han, Buhm, He, Amy Z, Hormozdiari, Farhad, Li, Xin, Liu, Boxiang, Kang, Eun Yong, McDowell, Ian C, Ongen, Halit, Palowitch, John J, Peterson, Christine B, Quon, Gerald, Ripke, Stephan, Saha, Ashis, Shabalin, Andrey A, Shimko, Tyler C, Sul, Jae Hoon, Teran, Nicole A, Tsang, Emily K, Zhang, Hailei, Zhou, Yi-Hui, Bustamante, Carlos D, Cox, Nancy J, and Guigó, Roderic

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Alleles, Chromosomes, Human, Disease, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Genome, Human, Genotype, Humans, Male, Organ Specificity, Quantitative Trait Loci, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Lead analysts:, Laboratory, Data Analysis &Coordinating Center (LDACC):, NIH program management:, Biospecimen collection:, Pathology:, eQTL manuscript working group:, General Science & Technology
Abstract

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

Published
2017

14. EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay

Author

Volpi, Stefano, Yamazaki, Yasuhiro, Brauer, Patrick M, van Rooijen, Ellen, Hayashida, Atsuko, Slavotinek, Anne, Kuehn, Hye Sun, Di Rocco, Maja, Rivolta, Carlo, Bortolomai, Ileana, Du, Likun, Felgentreff, Kerstin, de Bruin, Lisa Ott, Hayashida, Kazutaka, Freedman, George, Marcovecchio, Genni Enza, Capuder, Kelly, Rath, Prisni, Luche, Nicole, Hagedorn, Elliott J, Buoncompagni, Antonella, Royer-Bertrand, Beryl, Giliani, Silvia, Poliani, Pietro Luigi, Imberti, Luisa, Dobbs, Kerry, Poulain, Fabienne E, Martini, Alberto, Manis, John, Linhardt, Robert J, Bosticardo, Marita, Rosenzweig, Sergio Damian, Lee, Hane, Puck, Jennifer M, Zúñiga-Pflücker, Juan Carlos, Zon, Leonard, Park, Pyong Woo, Superti-Furga, Andrea, and Notarangelo, Luigi D

Subjects
Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research, Pediatric, Rare Diseases, Congenital Structural Anomalies, 2.1 Biological and endogenous factors, Aetiology, Animals, Bone Diseases, Developmental, Child, Preschool, Developmental Disabilities, Female, Heparitin Sulfate, Humans, Immunologic Deficiency Syndromes, Induced Pluripotent Stem Cells, Infant, Lymphocytes, Mutation, N-Acetylglucosaminyltransferases, Zebrafish, Medical and Health Sciences, Immunology
Abstract

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.

Published
2017

15. Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans

Author

Chondronikola, Maria, Volpi, Elena, Børsheim, Elisabet, Porter, Craig, Saraf, Manish K, Annamalai, Palam, Yfanti, Christina, Chao, Tony, Wong, Daniel, Shinoda, Kosaku, Labbė, Sebastien M, Hurren, Nicholas M, Cesani, Fernardo, Kajimura, Shingo, and Sidossis, Labros S

Subjects
Biochemistry and Cell Biology, Biological Sciences, Clinical Research, Obesity, Diabetes, Nutrition, 1.1 Normal biological development and functioning, Underpinning research, Cardiovascular, Metabolic and endocrine, Adipose Tissue, Brown, Cold Temperature, Humans, Insulin, Kinetics, Linear Models, Lipid Metabolism, Lipids, Lipoproteins, Male, Middle Aged, Multivariate Analysis, Oxidation-Reduction, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Recent studies suggest that brown adipose tissue (BAT) plays a role in energy and glucose metabolism in humans. However, the physiological significance of human BAT in lipid metabolism remains unknown. We studied 16 overweight/obese men during prolonged, non-shivering cold and thermoneutral conditions using stable isotopic tracer methodologies in conjunction with hyperinsulinemic-euglycemic clamps and BAT and white adipose tissue (WAT) biopsies. BAT volume was significantly associated with increased whole-body lipolysis, triglyceride-free fatty acid (FFA) cycling, FFA oxidation, and adipose tissue insulin sensitivity. Functional analysis of BAT and WAT demonstrated the greater thermogenic capacity of BAT compared to WAT, while molecular analysis revealed a cold-induced upregulation of genes involved in lipid metabolism only in BAT. The accelerated mobilization and oxidation of lipids upon BAT activation supports a putative role for BAT in the regulation of lipid metabolism in humans.

Published
2016

16. Parma consensus statement on metabolic disruptors

Author

Heindel, Jerrold J, vom Saal, Frederick S, Blumberg, Bruce, Bovolin, Patrizia, Calamandrei, Gemma, Ceresini, Graziano, Cohn, Barbara A, Fabbri, Elena, Gioiosa, Laura, Kassotis, Christopher, Legler, Juliette, La Merrill, Michele, Rizzir, Laura, Machtinger, Ronit, Mantovani, Alberto, Mendez, Michelle A, Montanini, Luisa, Molteni, Laura, Nagel, Susan C, Parmigiani, Stefano, Panzica, Giancarlo, Paterlini, Silvia, Pomatto, Valentina, Ruzzin, Jérôme, Sartor, Giorgio, Schug, Thaddeus T, Street, Maria E, Suvorov, Alexander, Volpi, Riccardo, Zoeller, R Thomas, and Palanza, Paola

Subjects
Epidemiology, Public Health, Health Sciences, Obesity, Nutrition, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Congresses as Topic, Consensus Development Conferences as Topic, Diabetes Mellitus, Environmental Exposure, Environmental Pollutants, Hazardous Substances, Humans, Italy, Metabolic Syndrome, Metabolic disruptor, Obesogen, Diabetes, Metabolic syndrome, Developmental Programming, Public Health and Health Services, Toxicology, Public health
Abstract

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Published
2015

17. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Author

Chondronikola, Maria, Volpi, Elena, Børsheim, Elisabet, Porter, Craig, Annamalai, Palam, Enerbäck, Sven, Lidell, Martin E, Saraf, Manish K, Labbe, Sebastien M, Hurren, Nicholas M, Yfanti, Christina, Chao, Tony, Andersen, Clark R, Cesani, Fernando, Hawkins, Hal, and Sidossis, Labros S

Subjects
Biomedical and Clinical Sciences, Clinical Research, Obesity, Diabetes, Nutrition, Metabolic and endocrine, Adipose Tissue, Brown, Blood Glucose, Calorimetry, Indirect, Cohort Studies, Cold Temperature, Energy Metabolism, Fluorodeoxyglucose F18, Glucose Clamp Technique, Homeostasis, Humans, Insulin Resistance, Male, Multimodal Imaging, Positron-Emission Tomography, Radiopharmaceuticals, Thermogenesis, Tomography, X-Ray Computed, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT(+)) men and five BAT-negative (BAT(-)) men under thermoneutral conditions and after prolonged (5-8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT(+) group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.

Published
2014

18. Prevalence and features of delirium in older patients admitted to rehabilitation facilities

Author

Sidoli, Chiara, Zambon, Antonella, Tassistro, Elena, Rossi, Emanuela, Mossello, Enrico, Inzitari, Marco, Cherubini, Antonio, Marengoni, Alessandra, Morandi, Alessandro, Bellelli, Giuseppe, Tarasconi, A, Sella, M, Paternò, G, Faggian, G, Lucarelli, C, De Grazia, N, Alberto, C, Porcella, L, Nardiello, I, Chimenti, E, Zeni, M, Romairone, E, Minaglia, C, Ceccotti, C, Guerra, G, Mantovani, G, Monacelli, F, Candiani, T, Santolini, F, Rosso, M, Bono, V, Sibilla, S, Dal Santo, P, Ceci, M, Barone, P, Schirinzi, T, Formenti, A, Nastasi, G, Isaia, G, Gonella, D, Battuello, A, Casson, S, Calvani, D, Boni, F, Ciaccio, A, Rosa, R, Sanna, G, Manfredini, S, Cortese, L, Rizzo, M, Prestano, R, Greco, A, Lauriola, M, Gelosa, G, Piras, V, Arena, M, Cosenza, D, Bellomo, A, Lamontagna, M, Gabbani, L, Lambertucci, L, Perego, S, Parati, G, Basile, G, Gallina, V, Pilone, G, Giudice, C, Pietrogrande, L, Mosca, M, Corazzin, I, Rossi, P, Nunziata, V, D’Amico, F, Grippa, A, Giardini, S, Barucci, R, Cossu, A, Fiorin, L, Distefano, M, Lunardelli, M, Brunori, M, Ruffini, I, Abraham, E, Varutti, A, Fabbro, E, Catalano, A, Martino, G, Leotta, D, Marchet, A, Dell’Aquila, G, Scrimieri, A, Davoli, M, Casella, M, Cartei, A, Polidori, G, Brischetto, D, Motta, S, Saponara, R, Perrone, P, Russo, G, Del, D, Car, C, Pirina, T, Franzoni, S, Cotroneo, A, Ghiggia, F, Volpi, G, Menichetti, C, Bo, M, Panico, A, Calogero, P, Corvalli, G, Mauri, M, Lupia, E, Manfredini, R, Fabbian, F, March, A, Pedrotti, M, Veronesi, M, Strocchi, E, Borghi, C, Bianchetti, A, Crucitti, A, Difrancesco, V, Fontana, G, Geriatria, A, Bonanni, L, Barbone, F, Serrati, C, Ballardini, G, Simoncelli, M, Ceschia, G, Scarpa, C, Brugiolo, R, Fusco, S, Ciarambino, T, Biagini, C, Tonon, E, Porta, M, Venuti, D, Delsette, M, Poeta, M, Barbagallo, G, Trovato, G, Delitala, A, Arosio, P, Reggiani, F, Zuliani, G, Ortolani, B, Mussio, E, Girardi, A, Coin, A, Ruotolo, G, Castagna, A, Masina, M, Cimino, R, Pinciaroli, A, Tripodi, G, Cassadonte, F, Vatrano, M, Scaglione, L, Fogliacco, P, Muzzuilini, C, Romano, F, Padovani, A, Rozzini, L, Cagnin, A, Fragiacomo, F, Desideri, G, Liberatore, E, Bruni, A, Orsitto, G, Franco, M, Bonfrate, L, Bonetto, M, Pizio, N, Magnani, G, Cecchetti, G, Longo, A, Bubba, V, Marinan, L, Cotelli, M, Turla, M, Sessa, M, Abruzzi, L, Castoldi, G, Lovetere, D, Musacchio, C, Novello, M, Cavarape, A, Bini, A, Leonardi, A, Seneci, F, Grimaldi, W, Fimognari, F, Bambar, V, Saitta, A, Corica, F, Braga, M, Servi, Null, Ettorre, E, Camellini Bellelli, C G, Annoni, G, Marengoni, A, Crescenzo, A, Noro, G, Turco, R, Ponzetto, M, Giuseppe, L, Mazzei, B, Maiuri, G, Costaggiu, D, Damato, R, Formilan, M, Patrizia, G, Santuar, L, Gallucci, M, Paragona, M, Bini, P, Modica, D, Abati, C, Clerici, M, Barbera, I, Nigroimperiale, F, Manni, A, Votino, C, Castiglioni, C, Di, M, Degl’Innocenti, M, Moscatelli, G, Guerini, S, Casini, C, Dini, D, Denotariis, S, Bonometti, F, Paolillo, C, Riccardi, A, Tiozzo, A, Samysalamafahmy, A, Dibari, M, Vanni, S, Scarpa, A, Zara, D, Ranieri, P, Alessandro, M, Di, F, Pezzoni, D, Platto, C, D’Ambrosio, V, Ivaldi, C, Milia, P, Desalvo, F, Solaro, C, Strazzacappa, M, Cazzadori, M, Grasso, M, Troisi, E, Guerini, V, Bernardini, B, Corsini, C, Boffelli, S, Filippi, A, Delpin, K, Faraci, B, Bertoletti, E, Vannucci, M, Crippa, P, Malighetti, A, Caltagirone, C, Disant, S, Bettini, D, Maltese, F, Abruzzese, G, Cosimo, D, Azzini, M, Colombo, M, Procino, G, Fascendini, S, Barocco, F, Del, P, Mazzone, A, Cottino, M, Vezzadini, G, Avanzi, S, Brambilla, C, Orini, S, Sgrilli, F, Mello, A, Lombardi Muti, L E, Dijk, B, Fenu, S, Pes, C, Gareri, P, Passamonte, M, Rigo, R, Locusta, L, Caser, L, Rosso, G, Cesarini, S, Cozzi, R, Santini, C, Carbone, P, Cazzaniga, I, Lovati, R, Cantoni, A, Ranzani, P, Barra, D, Pompilio, G, Dimori, S, Cernesi, S, Riccò, C, Piazzolla, F, Capittini, E, Rota, C, Gottardi, F, Merla, L, Barelli, A, Millul, A, De, G, Morrone, G, Bigolari, M, Macchi, M, Zambon, F, Pizzorni, C, Dicasaleto, G, Menculini, G, Marcacci, M, Catanese, G, Sprini, D, Dicasalet, T, Bocci, M, Borga, S, Caironi, P, Cat, C, Cingolani, E, Avalli, L, Greco, G, Citerio, G, Gandini, L, Cornara, G, Lerda, R, Brazzi, L, Simeone, F, Caciorgna, M, Alampi, D, Francesconi, S, Beck, E, Antonini, B, Vettoretto, K, Meggiolaro, M, Garofalo, E, Notaro, S, Varutti, R, Bassi, F, Mistraletti, G, Marino, A, Rona, R, Rondelli, E, Riva, I, Cortegiani, A, Pistidda, L, D’Andrea, R, Querci, L, Gnesin, P, Todeschini, M, Lugano, M, Castelli, G, Ortolani, M, Cotoia, A, Maggiore, S, Ditizio, L, Graziani, R, Testa, I, Ferretti, E, Castioni, C, Lombardi, F, Caserta, R, Pasqua, M, Simoncini, S, Baccarini, F, Rispoli, M, Grossi, F, Cancelliere, L, Carnelli, M, Puccini, F, Biancofiore, G, Siniscalchi, A, Laici, C, Mossello, E, Torrini, M, Pasetti, G, Palmese, S, Oggioni, R, Mangani, V, Pini, S, Martelli, M, Rigo, E, Zuccalà, F, Cherri, A, Spina, R, Calamai, I, Petrucci, N, Caicedo, A, Ferri, F, Gritti, P, Brienza, N, Fonnesu, R, Dessena, M, Fullin, G, Saggioro, D, Sidoli, Chiara, Zambon, Antonella, Tassistro, Elena, Rossi, Emanuela, Mossello, Enrico, Inzitari, Marco, Cherubini, Antonio, Marengoni, Alessandra, Morandi, Alessandro, Bellelli, Giuseppe, A Tarasconi, M Sella, G Paternò, G Faggian, C Lucarelli, N De Grazia, C Alberto, L Porcella, I Nardiello, E Chimenti, M Zeni, E Romairone, C Minaglia, C Ceccotti, G Guerra, G Mantovani, F Monacelli, C Minaglia, T Candiani, F Santolini, C Minaglia, M Rosso, V Bono, S Sibilla, P Dal Santo, M Ceci, P Barone, T Schirinzi, A Formenti, G Nastasi, G Isaia, D Gonella, A Battuello, S Casson, D Calvani, F Boni, A Ciaccio, R Rosa, G Sanna, S Manfredini, L Cortese, M Rizzo, R Prestano, A Greco, M Lauriola, G Gelosa, V Piras, M Arena, D Cosenza, A Bellomo, M LaMontagna, L Gabbani, L Lambertucci, S Perego, G Parati, G Basile, V Gallina, G Pilone, C Giudice, L Pietrogrande, M Mosca, I Corazzin, P Rossi, V Nunziata, F D’Amico, A Grippa, S Giardini, R Barucci, A Cossu, L Fiorin, M Arena , M Distefano, M Lunardelli, M Brunori, I Ruffini, E Abraham, A Varutti, E Fabbro, A Catalano, G Martino, D Leotta, A Marchet, G Dell’Aquila, A Scrimieri, M Davoli, M Casella, A Cartei, G Polidori, G Basile, D Brischetto, S Motta, R Saponara, P Perrone, G Russo, D Del, C Car, T Pirina, S Franzoni, A Cotroneo, F Ghiggia, G Volpi, C Menichetti, M Bo, A Panico, P Calogero, G Corvalli, M Mauri, E Lupia, R Manfredini, F Fabbian, A March, M Pedrotti, M Veronesi, E Strocchi, C Borghi, A Bianchetti, A Crucitti, V DiFrancesco, G Fontana, A Geriatria, L Bonanni, F Barbone, C Serrati, G Ballardini, M Simoncelli, G Ceschia, C Scarpa, R Brugiolo, S Fusco, T Ciarambino, C Biagini, E Tonon, M Porta , D Venuti, M DelSette, M Poeta, G Barbagallo, G Trovato, A Delitala, P Arosio, F Reggiani, G Zuliani, B Ortolani, E Mussio, A Girardi, A Coin, G Ruotolo, A Castagna, M Masina, R Cimino, A Pinciaroli, G Tripodi, F Cassadonte, M Vatrano, L Scaglione, P Fogliacco, C Muzzuilini, F Romano, A Padovani, L Rozzini, A Cagnin, F Fragiacomo, G Desideri, E Liberatore, A Bruni, G Orsitto, M Franco, L Bonfrate, M Bonetto, N Pizio, G Magnani, G Cecchetti, A Longo, V Bubba, L Marinan, M Cotelli, M Turla, M Brunori, M Sessa, L Abruzzi, G Castoldi, D LoVetere, C Musacchio, M Novello, A Cavarape, A Bini, A Leonardi, F Seneci, W Grimaldi, F Seneci, F Fimognari, V Bambar, A Saitta, F Corica, M Braga, Servi, E Ettorre , C G Camellini Bellelli, G Annoni, A Marengoni, A Bruni, A Crescenzo, G Noro, R Turco, M Ponzetto, L Giuseppe, B Mazzei, G Maiuri, D Costaggiu, R Damato, E Fabbro, M Formilan, G Patrizia, L Santuar , M Gallucci, C Minaglia, M Paragona, P Bini, D Modica, C Abati, M Clerici, I Barbera, F NigroImperiale, A Manni, C Votino, C Castiglioni, M Di, M Degl’Innocenti, G Moscatelli, S Guerini, C Casini, D Dini, S DeNotariis, F Bonometti, C Paolillo, A Riccardi, A Tiozzo, A SamySalamaFahmy, A Riccardi, C Paolillo, M DiBari, S Vanni, A Scarpa, D Zara, P Ranieri, M Alessandro, P Calogero, G Corvalli, F Di, D Pezzoni, C Platto, V D’Ambrosio, C Ivaldi, P Milia, F DeSalvo, C Solaro, M Strazzacappa, M Bo, A Panico, M Cazzadori, M Bonetto, M Grasso, E Troisi, G Magnani, G Cecchetti, V Guerini, B Bernardini, C Corsini, S Boffelli, A Filippi, K Delpin, B Faraci, E Bertoletti, M Vannucci, P Crippa, A Malighetti, C Caltagirone, S DiSant, D Bettini, F Maltese, M Formilan, G Abruzzese, C Minaglia, D Cosimo, M Azzini, M Cazzadori, M Colombo, G Procino, S Fascendini, F Barocco, P Del, F D’Amico, A Grippa , A Mazzone, M Cottino, G Vezzadini, S Avanzi, C Brambilla, S Orini, F Sgrilli, A Mello, L E Lombardi Muti, B Dijk , S Fenu, C Pes, P Gareri, A Castagna, M Passamonte, R Rigo, L Locusta, L Caser, G Rosso, S Cesarini, R Cozzi, C Santini, P Carbone, I Cazzaniga, R Lovati, A Cantoni, P Ranzani, D Barra, G Pompilio, S Dimori, S Cernesi, C Riccò, F Piazzolla, E Capittini, C Rota, F Gottardi, L Merla, A Barelli, A Millul , G De, G Morrone, M Bigolari, C Minaglia, M Macchi, F Zambon, F D’Amico, F D’Amico, C Pizzorni, G DiCasaleto, G Menculini, M Marcacci, G Catanese, D Sprini, T DiCasalet, M Bocci, S Borga, P Caironi, C Cat, E Cingolani, L Avalli, G Greco, G Citerio, L Gandini, G Cornara, R Lerda, L Brazzi, F Simeone, M Caciorgna, D Alampi, S Francesconi, E Beck, B Antonini, K Vettoretto, M Meggiolaro, E Garofalo, A Bruni, S Notaro, R Varutti, F Bassi, G Mistraletti, A Marino, R Rona, E Rondelli, I Riva, A Cortegiani, L Pistidda, R D’Andrea, L Querci, P Gnesin, M Todeschini, M Lugano, G Castelli, M Ortolani, A Cotoia, S Maggiore, L DiTizio, R Graziani, I Testa, E Ferretti, C Castioni, F Lombardi, R Caserta, M Pasqua, S Simoncini, F Baccarini, M Rispoli, F Grossi, L Cancelliere, M Carnelli, F Puccini, G Biancofiore, A Siniscalchi, C Laici, E Mossello, M Torrini, G Pasetti, S Palmese, R Oggioni, V Mangani, S Pini, M Martelli, E Rigo, F Zuccalà , A Cherri, R Spina, I Calamai, N Petrucci, A Caicedo, F Ferri, P Gritti, N Brienza, R Fonnesu, M Dessena, G Fullin & D Saggioro, VU University medical center, Sidoli, C, Zambon, A, Tassistro, E, Rossi, E, Mossello, E, Inzitari, M, Cherubini, A, Marengoni, A, Morandi, A, Bellelli, G, Tarasconi, A, Sella, M, Paterno, G, Faggian, G, Lucarelli, C, De Grazia, N, Alberto, C, Porcella, L, Nardiello, I, Chimenti, E, Zeni, M, Romairone, E, Minaglia, C, Ceccotti, C, Guerra, G, Mantovani, G, Monacelli, F, Candiani, T, Santolini, F, Rosso, M, Bono, V, Sibilla, S, Dal Santo, P, Ceci, M, Barone, P, Schirinzi, T, Formenti, A, Nastasi, G, Isaia, G, Gonella, D, Battuello, A, Casson, S, Calvani, D, Boni, F, Ciaccio, A, Rosa, R, Sanna, G, Manfredini, S, Cortese, L, Rizzo, M, Prestano, R, Greco, A, Lauriola, M, Gelosa, G, Piras, V, Arena, M, Cosenza, D, Bellomo, A, Lamontagna, M, Gabbani, L, Lambertucci, L, Perego, S, Parati, G, Basile, G, Gallina, V, Pilone, G, Giudice, C, Pietrogrande, L, Mosca, M, Corazzin, I, Rossi, P, Nunziata, V, D'Amico, F, Grippa, A, Giardini, S, Barucci, R, Cossu, A, Fiorin, L, Distefano, M, Lunardelli, M, Brunori, M, Ruffini, I, Abraham, E, Varutti, A, Fabbro, E, Catalano, A, Martino, G, Leotta, D, Marchet, A, Dell'Aquila, G, Scrimieri, A, Davoli, M, Casella, M, Cartei, A, Polidori, G, Brischetto, D, Motta, S, Saponara, R, Perrone, P, Russo, G, Del, D, Car, C, Pirina, T, Franzoni, S, Cotroneo, A, Ghiggia, F, Volpi, G, Menichetti, C, Bo, M, Panico, A, Calogero, P, Corvalli, G, Mauri, M, Lupia, E, Manfredini, R, Fabbian, F, March, A, Pedrotti, M, Veronesi, M, Strocchi, E, Borghi, C, Bianchetti, A, Crucitti, A, Difrancesco, V, Fontana, G, Geriatria, A, Bonanni, L, Barbone, F, Serrati, C, Ballardini, G, Simoncelli, M, Ceschia, G, Scarpa, C, Brugiolo, R, Fusco, S, Ciarambino, T, Biagini, C, Tonon, E, Porta, M, Venuti, D, Delsette, M, Poeta, M, Barbagallo, G, Trovato, G, Delitala, A, Arosio, P, Reggiani, F, Zuliani, G, Ortolani, B, Mussio, E, Girardi, A, Coin, A, Ruotolo, G, Castagna, A, Masina, M, Cimino, R, Pinciaroli, A, Tripodi, G, Cassadonte, F, Vatrano, M, Scaglione, L, Fogliacco, P, Muzzuilini, C, Romano, F, Padovani, A, Rozzini, L, Cagnin, A, Fragiacomo, F, Desideri, G, Liberatore, E, Bruni, A, Orsitto, G, Franco, M, Bonfrate, L, Bonetto, M, Pizio, N, Magnani, G, Cecchetti, G, Longo, A, Bubba, V, Marinan, L, Cotelli, M, Turla, M, Sessa, M, Abruzzi, L, Castoldi, G, Lovetere, D, Musacchio, C, Novello, M, Cavarape, A, Bini, A, Leonardi, A, Seneci, F, Grimaldi, W, Fimognari, F, Bambar, V, Saitta, A, Corica, F, Braga, M, Servi, Ettorre, E, Camellini Bellelli, C, Annoni, G, Crescenzo, A, Noro, G, Turco, R, Ponzetto, M, Giuseppe, L, Mazzei, B, Maiuri, G, Costaggiu, D, Damato, R, Formilan, M, Patrizia, G, Santuar, L, Gallucci, M, Paragona, M, Bini, P, Modica, D, Abati, C, Clerici, M, Barbera, I, Nigroimperiale, F, Manni, A, Votino, C, Castiglioni, C, Di, M, Degl'Innocenti, M, Moscatelli, G, Guerini, S, Casini, C, Dini, D, Denotariis, S, Bonometti, F, Paolillo, C, Riccardi, A, Tiozzo, A, Samysalamafahmy, A, Dibari, M, Vanni, S, Scarpa, A, Zara, D, Ranieri, P, Alessandro, M, Di, F, Pezzoni, D, Platto, C, D'Ambrosio, V, Ivaldi, C, Milia, P, Desalvo, F, Solaro, C, Strazzacappa, M, Cazzadori, M, Grasso, M, Troisi, E, Guerini, V, Bernardini, B, Corsini, C, Boffelli, S, Filippi, A, Delpin, K, Faraci, B, Bertoletti, E, Vannucci, M, Crippa, P, Malighetti, A, Caltagirone, C, Disant, S, Bettini, D, Maltese, F, Abruzzese, G, Cosimo, D, Azzini, M, Colombo, M, Procino, G, Fascendini, S, Barocco, F, Del, P, Mazzone, A, Cottino, M, Vezzadini, G, Avanzi, S, Brambilla, C, Orini, S, Sgrilli, F, Mello, A, Lombardi Muti, L, Dijk, B, Fenu, S, Pes, C, Gareri, P, Passamonte, M, Rigo, R, Locusta, L, Caser, L, Rosso, G, Cesarini, S, Cozzi, R, Santini, C, Carbone, P, Cazzaniga, I, Lovati, R, Cantoni, A, Ranzani, P, Barra, D, Pompilio, G, Dimori, S, Cernesi, S, Ricco, C, Piazzolla, F, Capittini, E, Rota, C, Gottardi, F, Merla, L, Barelli, A, Millul, A, De, G, Morrone, G, Bigolari, M, Macchi, M, Zambon, F, Pizzorni, C, Dicasaleto, G, Menculini, G, Marcacci, M, Catanese, G, Sprini, D, Dicasalet, T, Bocci, M, Borga, S, Caironi, P, Cat, C, Cingolani, E, Avalli, L, Greco, G, Citerio, G, Gandini, L, Cornara, G, Lerda, R, Brazzi, L, Simeone, F, Caciorgna, M, Alampi, D, Francesconi, S, Beck, E, Antonini, B, Vettoretto, K, Meggiolaro, M, Garofalo, E, Notaro, S, Varutti, R, Bassi, F, Mistraletti, G, Marino, A, Rona, R, Rondelli, E, Riva, I, Cortegiani, A, Pistidda, L, D'Andrea, R, Querci, L, Gnesin, P, Todeschini, M, Lugano, M, Castelli, G, Ortolani, M, Cotoia, A, Maggiore, S, Ditizio, L, Graziani, R, Testa, I, Ferretti, E, Castioni, C, Lombardi, F, Caserta, R, Pasqua, M, Simoncini, S, Baccarini, F, Rispoli, M, Grossi, F, Cancelliere, L, Carnelli, M, Puccini, F, Biancofiore, G, Siniscalchi, A, Laici, C, Torrini, M, Pasetti, G, Palmese, S, Oggioni, R, Mangani, V, Pini, S, Martelli, M, Rigo, E, Zuccala, F, Cherri, A, Spina, R, Calamai, I, Petrucci, N, Caicedo, A, Ferri, F, Gritti, P, Brienza, N, Fonnesu, R, Dessena, M, Fullin, G, and Saggioro, D

Subjects
Aging, Disability, Rehabilitation, Delirium, Dementia, Physical restraint, Cross-Sectional Studies, Activities of Daily Living, mental disorders, Prevalence, Humans, Geriatrics and Gerontology, Aged
Abstract

Background: Delirium is thought to be common across various settings of care; however, still little research has been conducted in rehabilitation. Aim: We investigated the prevalence of delirium, its features and motor subtypes in older patients admitted to rehabilitation facilities during the three editions of the “Delirium Day project”. Methods: We conducted a cross-sectional study in which 1237 older patients (age ≥ 65 years old) admitted to 50 Italian rehabilitation wards during the three editions of the “Delirium Day project” (2015 to 2017) were included. Delirium was evaluated through the 4AT and its motor subtype with the Delirium Motor Subtype Scale. Results: Delirium was detected in 226 patients (18%), and the most recurrent motor subtype was mixed (37%), followed by hypoactive (26%), hyperactive (21%) and non-motor one (16%). In a multivariate Poisson regression model with robust variance, factors associated with delirium were: disability in basic (PR 1.48, 95%CI: 1.17–1.9, p value 0.001) and instrumental activities of daily living (PR 1.58, 95%CI: 1.08–2.32, p value 0.018), dementia (PR 2.10, 95%CI: 1.62–2.73, p value < 0.0001), typical antipsychotics (PR 1.47, 95%CI: 1.10–1.95, p value 0.008), antidepressants other than selective serotonin reuptake inhibitors (PR 1.3, 95%CI: 1.02–1.66, p value 0.035), and physical restraints (PR 2.37, 95%CI: 1.68–3.36, p value < 0.0001). Conclusion: This multicenter study reports that 2 out 10 patients admitted to rehabilitations had delirium on the index day. Mixed delirium was the most prevalent subtype. Delirium was associated with unmodifiable (dementia, disability) and modifiable (physical restraints, medications) factors. Identification of these factors should prompt specific interventions aimed to prevent or mitigate delirium.

Published
2022
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19. Risk of hospitalization and death for <scp>COVID</scp> ‐19 in persons with epilepsy over a 20‐month period: The <scp>EpiLink</scp> Bologna cohort, Italy

Author

Lorenzo Muccioli, Corrado Zenesini, Lisa Taruffi, Laura Licchetta, Barbara Mostacci, Lidia Di Vito, Elena Pasini, Lilia Volpi, Patrizia Riguzzi, Lorenzo Ferri, Flavia Baccari, Francesco Nonino, Roberto Michelucci, Paolo Tinuper, Luca Vignatelli, Francesca Bisulli, Muccioli L., Zenesini C., Taruffi L., Licchetta L., Mostacci B., Di Vito L., Pasini E., Volpi L., Riguzzi P., Ferri L., Baccari F., Nonino F., Michelucci R., Tinuper P., Vignatelli L., and Bisulli F.

Subjects
Adult, Male, Epilepsy, COVID-19, antiseizure medication (ASM), Comorbidity, Middle Aged, mortality, Cohort Studies, Hospitalization, epileptic encephalopathy, Neurology, outcome, Humans, epidemiology, Female, Neurology (clinical), Cohort Studie, Human
Abstract

Objective: Data on COVID-19 outcomes in persons with epilepsy (PWE) are scarce and inconclusive. We aimed to study the risk of hospitalization and death for COVID-19 in a large cohort of PWE from March 1, 2020 to October 31, 2021. Methods: The historical cohort design (EpiLink Bologna) compared adult PWE grouped into people with focal epilepsy (PFE), idiopathic generalized epilepsy (PIGE), and developmental and/or epileptic encephalopathy (PDEE), and a population cohort matched (ratio 1:10) for age, sex, residence, and comorbidity (assessed with the multisource comorbidity score), living in the local health trust of Bologna (approximately 800 000 residents). Clinical data were linked to health administrative data. Results: In both cohorts (EpiLink: n=1575 subjects, 1128 PFE, 267 PIGE, 148 PDEE, 32 other; controls: n=15 326 subjects), 52% were females, and the mean age was 50 years (SD=18). Hospital admissions for COVID-19 in the whole period were 49 (3.1%) in PWE and 225 (1.5%) in controls. The adjusted hazard ratio (aHR) in PWE was 1.9 (95% confidence interval [CI] = 1.4–2.7). The subgroups at higher risk were PFE (aHR=1.9, 95% CI=1.3–2.8) and PDEE (aHR=3.9, 95% CI=1.7–8.7), whereas PIGE had a risk comparable to the controls (aHR=1.1, 95% CI =.3–3.5). Stratified analyses of the two main epidemic waves (March–May 2020, October 2020–May 2021) disclosed a higher risk of COVID-19-related hospitalization during the first epidemic wave (March–May 2020; aHR=3.8, 95% CI=2.2–6.7). Polytherapy with antiseizure medications contributed to a higher risk of hospital admission. Thirty-day risk of death after hospitalization was 14% in both PWE and controls. Significance: During the first 20 months since the outbreak of COVID-19 in Bologna, PWE had a doubled risk of COVID-19 hospital admission compared to a matched control population. Conversely, epilepsy did not represent a risk factor for COVID-19-related death.

Published
2022
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20. Readmission in patients undergoing percutaneous patent foramen ovale closure in the United States

Author

Chayakrit, Krittanawong, Bing, Yue, Muzamil, Khawaja, Anirudh, Kumar, Hafeez Ul Hassan, Virk, Zhen, Wang, Sana, Hanif, Umair, Khalid, Ali E, Denktas, Clifford J, Kavinsky, John J, Volpi, and Hani, Jneid

Subjects
Stroke, Cardiac Catheterization, Treatment Outcome, Atrial Flutter, Risk Factors, Septal Occluder Device, Recurrence, Atrial Fibrillation, Humans, Foramen Ovale, Patent, Cardiology and Cardiovascular Medicine, United States
Abstract

Current estimates suggest that a patent foramen ovale (PFO) may exist in up to 25% of the general population and is a potential risk factor for embolic, ischemic stroke. PFO closure complications include bleeding, need for procedure-related surgical intervention, pulmonary emboli, device malpositioning, new onset atrial arrhythmias, and transient atrioventricular block. Rates of PFO closure complications at a national level in the Unites States remain unknown. To address this, we performed a contemporary nationwide study using the 2016 and 2017 Nationwide Readmissions Database (NRD) to identify patterns of readmissions after percutaneous PFO closure. In conclusion, our study showed that following PFO closure, the most common complications were atrial fibrillation/atrial flutter followed by acute heart failure syndrome, supraventricular tachycardia and acute myocardial infarction.

Published
2023
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21. Spontaneous NLRP3 inflammasome-driven IL-1-β secretion is induced in severe COVID-19 patients and responds to anakinra treatment

Author

Arinna Bertoni, Federica Penco, Hilaria Mollica, Paola Bocca, Ignazia Prigione, Anna Corcione, Davide Cangelosi, Francesca Schena, Genny Del Zotto, Adriana Amaro, Noemi Paladino, Emanuele Pontali, Marcello Feasi, Sara Signa, Marta Bustaffa, Roberta Caorsi, Serena Palmeri, Paola Contini, Raffaele De Palma, Ulrich Pfeffer, Paolo Uva, Anna Rubartelli, Marco Gattorno, and Stefano Volpi

Subjects
DNA, Complementary, Inflammasomes, SARS-CoV-2, Interleukin-1beta, Immunology, Anti-Inflammatory Agents, Receptors, Interleukin-1, NLR Proteins, COVID-19 Drug Treatment, Interleukin 1 Receptor Antagonist Protein, NLR Family, Pyrin Domain-Containing 3 Protein, Cytokines, Humans, Immunology and Allergy, Cytokine Release Syndrome
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained.To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1β, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes.We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line.We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1β in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation.These results provide further evidence that IL-1β targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.

Published
2022
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22. Efficacy of an iodoform-based filling material for pulpectomy of primary teeth

Author

Renata S P Marques, Anna Carolina Volpi Mello-Moura, Cacio Moura-Netto, Claudio Costa, Juan Sebastian Lara, Fausto Medeiros Mendes, Carmela Rampazzo Bresolin, and Bruna Okamura

Subjects
Population, Pulpectomy, Dentistry, law.invention, Calcium Hydroxide, Root Canal Filling Materials, chemistry.chemical_compound, Non inferiority, Randomized controlled trial, law, Clinical endpoint, Humans, Medicine, Hydrocarbons, Iodinated, Tooth, Deciduous, Zinc Oxide-Eugenol Cement, Child, education, General Dentistry, education.field_of_study, Calcium hydroxide, business.industry, Iodoform, Confidence interval, Primary teeth, chemistry, Endodontic treatment, Iodoform-based pastes, Child, Preschool, Randomized clinical trials, business
Abstract

Aim: The aim of this non-inferiority randomized clinical trial was to compare the efficacy of an iodoform-based paste (Guedes-Pinto –(GP)) as a filling material in pulpectomies of primary teeth, and a standard material composed by calcium hydroxide and iodoform (CaOH/Iodof paste; Vitapex®). Design: A total of 104 teeth from 61 children (3–8 years old) were randomly allocated to two groups according to filling materials. Children were followed up for 24 months. The primary endpoint was the treatment success rate evaluated through clinical and radiographic examinations at follow-up, and the secondary outcome was the analysis of the canal filling quality. Differences in the proportion of treatment success was calculated based on 95% confidence intervals (95% CI) and with the Miettinen and Nurminen method in the intention-to-treat population, considering a −20% of the non-inferiority limit. Results: From 104 randomized teeth, 102 were followed up after 24 months (attrition rate of 1.9%). The success rate of teeth treated with the GP paste was 86.8% (95% CI: 69.9–94.9) and 78.4% (95% CI: 61.8–89.1) with the CaOH/Iodof paste. Consequently, a non-inferiority of the GP paste was observed when compared to the CaOH/Iodof paste (P

Published
2022
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23. Hyperglycemia at admission, comorbidities, and in-hospital mortality in elderly patients hospitalized in internal medicine wards: data from the RePoSI Registry

Author

Salvatore, Corrao, Alessandro, Nobili, Giuseppe, Natoli, Pier Mannuccio Mannucci, Francesco, Perticone, Antonello, Pietrangelo, Christiano, Argano, Giuseppe, Licata, Francesco, Violi, Gino Roberto Corazza, Alessandra, Marengoni, Francesco, Salerno, Matteo, Cesari, Mauro, Tettamanti, Luca, Pasina, Carlotta, Franchi, Laura, Cortesi, Gabriella, Miglio, Ilaria, Ardoino, Alessio, Novella, Domenico, Prisco, Elena, Silvestri, Giacomo, Emmi, Alessandra, Bettiol, Cenci, Caterina, Gianni, Biolo, Michela, Zanetti, Martina, Guadagni, Michele, Zaccari, Massimiliano, Chiuch, Massimo, Vanoli, Giulia, Grignani, Edoardo Alessandro Pulixi, Mauro, Bernardi, Silvia Li Bassi, Luca, Santi, Giacomo, Zaccherini, Graziana, Lupattelli, Elmo, Mannarino, Vanessa, Bianconi, Francesco, Paciullo, Riccardo, Alcidi, Ranuccio, Nuti, Roberto, Valenti, Martina, Ruvio, Silvia, Cappelli, Alberto, Palazzuoli, Domenico, Girelli, Fabiana, Busti, Giacomo, Marchi, Mario, Barbagallo, Ligia, Dominguez, Floriana, Cocita, Vincenza, Beneduce, Lidia, Plances, Salvatore, Mularo, Massimo, Raspanti, Marco, Zoli, Ilaria, Lazzari, Mattia, Brunori, Elisa, Fabbri, Donatella, Magalotti, Raffaella, Arnò, Franco Laghi Pasini, Pier Leopoldo Capecchi, Giuseppe, Palasciano, Maria Ester Modeo, Carla Di Gennaro, Maria Domenica Cappellini, Diletta, Maira, Valeria Di Stefano, Giovanna, Fabio, Sonia, Seghezzi, Marta, Mancarella, Margherita Migone De Amicis, Giacomo De Luca, Natalia, Scaramellini, Paolo Dionigi Rossi, Sarah, Damanti, Marta, Clerici, Federica, Conti, Giulia, Bonini, Barbara Brignolo Ottolini, Antonio Di Sabatino, Emanuela, Miceli, Marco Vincenzo Lenti, Martina, Pisati, Costanza Caccia Dominioni, Giovanni, Murialdo, Alessio, Marra, Federico, Cattaneo, Roberto, Pontremoli, Valentina, Beccati, Giulia, Nobili, Maria Beatrice Secchi, Davide, Ghelfi, Luigi, Anastasio, Lucia, Sofia, Maria, Carbone, Francesco, Cipollone, Maria Teresa Guagnano, Emanuele, Valeriani, Ilaria, Rossi, Gerardo, Mancuso, Daniela, Calipari, Mosè, Bartone, Giuseppe, Delitala, Maria, Berria, Chiara, Pes, Alessandro, Delitala, Maurizio, Muscaritoli, Alessio, Molfino, Enrico, Petrillo, Giuseppe, Zuccalà, Gabriella, D'Aurizio, Giuseppe, Romanelli, Alberto, Zucchelli, Francesca, Manzoni, Andrea, Volpini, Antonio, Picardi, Umberto Vespasiani Gentilucci, Paolo, Gallo, Chiara, Dell'Unto, Giorgio, Annoni, Maurizio, Corsi, Giuseppe, Bellelli, Sara, Zazzetta, Paolo, Mazzola, Hajnalka, Szabo, Alessandra, Bonfanti, Franco, Arturi, Elena, Succurro, Mariangela, Rubino, Bruno, Tassone, Giorgio, Sesti, Maria Grazia Serra, Maria Antonietta Bleve, Laura, Gasbarrone, Maria Rosaria Sajeva, Antonio, Brucato, Silvia, Ghidoni, Fabrizio, Fabris, Irene, Bertozzi, Giulia, Bogoni, Maria Victoria Rabuini, Elisabetta, Cosi, Paolo, Scarinzi, Annalisa, Amabile, Elisabetta, Omenetto, Tancredi, Prandini, Manfredini, Roberto, Fabbian, Fabio, Boari, Benedetta, DE GIORGI, Alfredo, Tiseo, Ruana, DE GIORGIO, Roberto, Giuseppe, Paolisso, Maria Rosaria Rizzo, Claudio, Borghi, Enrico, Strocchi, Eugenia, Ianniello, Mario, Soldati, Carlo, Sabbà, Francesco Saverio Vella, Patrizia, Suppressa, Andrea, Schilardi, Francesca, Loparco, Giovanni Michele De Vincenzo, Alessio, Comitangelo, Emanuele, Amoruso, Luigi, Fenoglio, Andrea, Falcetta, Christian, Bracco, Anna, L Fracanzani Silvia Fargion, Silvia, Tiraboschi, Annalisa, Cespiati, Giovanna, Oberti, Giordano, Sigon, Flora, Peyvandi, Raffaella, Rossio, Barbara, Ferrari, Giulia, Colombo, Pasquale, Agosti, Valter, Monzani, Valeria, Savojardo, Christian, Folli, Giuliana, Ceriani, Giada, Pallini, Franco, Dallegri, Luciano, Ottonello, Luca, Liberale, Lara, Caserza, Kassem, Salam, Nicola Lucio Liberato, Tiziana, Tognin, Giovanni Battista Bianchi, Sabrina, Giaquinto, Francesco, Purrello, Antonino Di Pino, Salvatore, Piro, Renzo, Rozzini, Lina, Falanga, Elena, Spazzini, Camillo, Ferrandina, Giuseppe, Montrucchio, Paolo, Petitti, Paolo, Peasso, Edoardo, Favale, Cesare, Poletto, Raffaella, Salmi, Piergiorgio, Gaudenzi, 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Cittadini, Carlo, Vigorito, Michele, Arcopinto, Andrea, Salzano, Emanuele, Bobbio, Alberto Maria Marra, Domenico, Sirico, Guido, Moreo, Francesca, Gasparini, Silvia, Prolo, Gloria, Pina, Alberto, Ballestrero, Fabio, Ferrando, Sergio, Berra, Simonetta, Dassi, Maria Cristina Nava, Bruno, Graziella, Stefano, Baldassarre, Salvatore, Fragapani, Gabriella, Gruden, Giorgio, Galanti, Gabriele, Mascherini, Cristian, Petri, Laura, Stefani, Margherita, Girino, Valeria, Piccinelli, Francesco, Nasso, Vincenza, Gioffrè, Maria, Pasquale, Giuseppe, Scattolin, Sergio, Martinelli, Mauro, Turrin, Leonardo, Sechi, Cristina, Catena, Gianluca, Colussi, Nicola, Passariello, Luca, Rinaldi, Franco, Berti, Giuseppe, Famularo, Patrizia, Tarsitani, Roberto, Castello, Michela, Pasino, Gian Paolo Ceda, Marcello Giuseppe Maggio, Simonetta, Morganti, Andrea, Artoni, Stefano Del Giacco, Davide, Firinu, Francesca, Losa, Giovanni, Paoletti, Giulia, Costanzo, Giuseppe, Montalto, Anna, Licata, Valentina, Malerba, Filippo Alessandro Montalto, Antonino, Lasco, Giorgio, Basile, Antonino, Catalano, Lorenzo, Malatino, Benedetta, Stancanelli, Valentina, Terranova, Salvatore Di Marca, Rosario Di Quattro, Lara La Malfa, Rossella, Caruso, Patrizia, Mecocci, Carmelinda, Ruggiero, Virginia, Boccardi, Tiziana, Meschi, Fulvio, Lauretani, Andrea, Ticinesi, Antonio, Nouvenne, Pietro, Minuz, Luigi, Fondrieschi, Mario, Pirisi, Gian Paolo Fra, Daniele, Sola, Massimo, Porta, Piero, Riva, Roberto, Quadri, Erica, Larovere, Marco, Novelli, Giorgio, Scanzi, Caterina, Mengoli, Stella, Provini, Laura, Ricevuti, Emilio, Simeone, Rosa, Scurti, Fabio, Tolloso, Roberto, Tarquini, Alice, Valoriani, Silvia, Dolenti, Giulia, Vannini, Alberto, Tedeschi, Lucia, Trotta, Riccardo, Volpi, Pietro, Bocchi, Alessandro, Vignali, Sergio, Harari, Chiara, Lonati, Mara, Cattaneo, Federico, Napoli., Corrao S, Nobili A, Natoli G, Mannucci PM, Perticone F, Pietrangelo A, Argano C, REPOSI Investigator, Borghi C, Corrao S., Nobili A., Natoli G., Mannucci P.M., Perticone F., Pietrangelo A., Argano C., Licata G., Violi F., Corazza G.R., Marengoni A., Salerno F., Cesari M., Tettamanti M., Pasina L., Franchi C., Cortesi L., Miglio G., Ardoino I., Novella A., Prisco D., Silvestri E., Emmi G., Bettiol A., Caterina C., Biolo G., Zanetti M., Guadagni M., Zaccari M., Chiuch M., Vanoli M., Grignani G., Pulixi E.A., Bernardi M., Bassi S.L., Santi L., Zaccherini G., Lupattelli G., Mannarino E., Bianconi V., Paciullo F., Alcidi R., Nuti R., Valenti R., Ruvio M., Cappelli S., Palazzuoli A., Girelli D., Busti F., Marchi G., Barbagallo M., Dominguez L., Cocita F., Beneduce V., Plances L., Mularo S., Raspanti M., Zoli M., Lazzari I., Brunori M., Fabbri E., Magalotti D., Arno R., Pasini F.L., Capecchi P.L., Palasciano G., Modeo M.E., Di Gennaro C., Cappellini M.D., Maira D., Di Stefano V., Fabio G., Seghezzi S., Mancarella M., De Amicis M.M., De Luca G., Scaramellini N., Rossi P.D., Damanti S., Clerici M., Conti F., Bonini G., Ottolini B.B., Di Sabatino A., Miceli E., Lenti M.V., Pisati M., Dominioni C.C., Murialdo G., Marra A., Cattaneo F., Pontremoli R., Beccati V., Nobili G., Secchi M.B., Ghelfi D., Anastasio L., Sofia L., Carbone M., Cipollone F., Guagnano M.T., Valeriani E., Rossi I., Mancuso G., Calipari D., Bartone M., Delitala G., Berria M., Pes C., Delitala A., Muscaritoli M., Molfino A., Petrillo E., Zuccala G., D'Aurizio G., Romanelli G., Zucchelli A., Manzoni F., Volpini A., Picardi A., Gentilucci U.V., Gallo P., Dell'Unto C., Annoni G., Corsi M., Bellelli G., Zazzetta S., Mazzola P., Szabo H., Bonfanti A., Arturi F., Succurro E., Rubino M., Tassone B., Sesti G., Serra M.G., Bleve M.A., Gasbarrone L., Sajeva M.R., Brucato A., Ghidoni S., Fabris F., Bertozzi I., Bogoni G., Rabuini M.V., Cosi E., Scarinzi P., Amabile A., Omenetto E., Prandini T., Manfredini R., Fabbian F., Boari B., De Giorgi A., Tiseo R., De Giorgio R., Paolisso G., Rizzo M.R., Borghi C., Strocchi E., Ianniello E., Soldati M., Sabba C., Vella F.S., Suppressa P., Schilardi A., Loparco F., De Vincenzo G.M., Comitangelo A., Amoruso E., Fenoglio L., Falcetta A., Bracco C., Fargion A.L.F.S., Tiraboschi S., Cespiati A., Oberti G., Sigon G., Peyvandi F., Rossio R., Ferrari B., Colombo G., Agosti P., Monzani V., Savojardo V., Folli C., Ceriani G., Pallini G., Dallegri F., Ottonello L., Liberale L., Caserza L., Salam K., Liberato N.L., Tognin T., Bianchi G.B., Giaquinto S., Purrello F., Di Pino A., Piro S., Rozzini R., Falanga L., Spazzini E., Ferrandina C., Montrucchio G., Petitti P., Peasso P., Favale E., Poletto C., Salmi R., Gaudenzi P., Perri L., Landolfi R., Montalto M., Mirijello A., Guasti L., Castiglioni L., Maresca A., Squizzato A., Campiotti L., Grossi A., Bertolotti M., Mussi C., Lancellotti G., Libbra M.V., Dondi G., Pellegrini E., Carulli L., Galassi M., Grassi Y., Perticone M., Battaglia R., FIlice M., Maio R., Stanghellini V., Ruggeri E., del Vecchio S., Salvi A., Leonardi R., Damiani G., Capeci W., Gabrielli A., Mattioli M., Martino G.P., Biondi L., Pettinari P., Ghio R., Col A.D., Minisola S., Colangelo L., Cilli M., Labbadia G., Afeltra A., Marigliano B., Pipita M.E., Castellino P., Zanoli L., Pignataro S., Gennaro A., Blanco J., Saracco V., Fogliati M., Bussolino C., Mete F., Gino M., Cittadini A., Vigorito C., Arcopinto M., Salzano A., Bobbio E., Marra A.M., Sirico D., Moreo G., Gasparini F., Prolo S., Pina G., Ballestrero A., Ferrando F., Berra S., Dassi S., Nava M.C., Graziella B., Baldassarre S., Fragapani S., Gruden G., Galanti G., Mascherini G., Petri C., Stefani L., Girino M., Piccinelli V., Nasso F., Gioffre V., Pasquale M., Scattolin G., Martinelli S., Turrin M., Sechi L., Catena C., Colussi G., Passariello N., Rinaldi L., Berti F., Famularo G., Tarsitani P., Castello R., Pasino M., Ceda G.P., Maggio M.G., Morganti S., Artoni A., Del Giacco S., Firinu D., Losa F., Paoletti G., Costanzo G., Montalto G., Licata A., Malerba V., Montalto F.A., Lasco A., Basile G., Catalano A., Malatino L., Stancanelli B., Terranova V., Di Marca S., Di Quattro R., La Malfa L., Caruso R., Mecocci P., Ruggiero C., Boccardi V., Meschi T., Lauretani F., Ticinesi A., Nouvenne A., Minuz P., Fondrieschi L., Pirisi M., Fra G.P., Sola D., Porta M., Riva P., Quadri R., Larovere E., Novelli M., Scanzi G., Mengoli C., Provini S., Ricevuti L., Simeone E., Scurti R., Tolloso F., Tarquini R., Valoriani A., Dolenti S., Vannini G., Tedeschi A., Trotta L., Volpi R., Bocchi P., Vignali A., Harari S., Lonati C., Cattaneo M., Napoli F., Corrao, S., Nobili, A., Natoli, G., Mannucci, P. M., Perticone, F., Pietrangelo, A., Argano, C., Licata, G., Violi, F., Corazza, G. R., Marengoni, A., Salerno, F., Cesari, M., Tettamanti, M., Pasina, L., Franchi, C., Cortesi, L., Miglio, G., Ardoino, I., Novella, A., Prisco, D., Silvestri, E., Emmi, G., Bettiol, A., Caterina, C., Biolo, G., Zanetti, M., Guadagni, M., Zaccari, M., Chiuch, M., Vanoli, M., Grignani, G., Pulixi, E. A., Bernardi, M., Bassi, S. L., Santi, L., Zaccherini, G., Lupattelli, G., Mannarino, E., Bianconi, V., Paciullo, F., Alcidi, R., Nuti, R., Valenti, R., Ruvio, M., Cappelli, S., Palazzuoli, A., Girelli, D., Busti, F., Marchi, G., Barbagallo, M., Dominguez, L., Cocita, F., Beneduce, V., Plances, L., Mularo, S., Raspanti, M., Zoli, M., Lazzari, I., Brunori, M., Fabbri, E., Magalotti, D., Arno, R., Pasini, F. L., Capecchi, P. L., Palasciano, G., Modeo, M. E., Di Gennaro, C., Cappellini, M. D., Maira, D., Di Stefano, V., Fabio, G., Seghezzi, S., Mancarella, M., De Amicis, M. M., De Luca, G., Scaramellini, N., Rossi, P. D., Damanti, S., Clerici, M., Conti, F., Bonini, G., Ottolini, B. B., Di Sabatino, A., Miceli, E., Lenti, M. V., Pisati, M., Dominioni, C. C., Murialdo, G., Marra, A., Cattaneo, F., Pontremoli, R., Beccati, V., Nobili, G., Secchi, M. B., Ghelfi, D., Anastasio, L., Sofia, L., Carbone, M., Cipollone, F., Guagnano, M. T., Valeriani, E., Rossi, I., Mancuso, G., Calipari, D., Bartone, M., Delitala, G., Berria, M., Pes, C., Delitala, A., Muscaritoli, M., Molfino, A., Petrillo, E., Zuccala, G., D'Aurizio, G., Romanelli, G., Zucchelli, A., Manzoni, F., Volpini, A., Picardi, A., Gentilucci, U. V., Gallo, P., Dell'Unto, C., Annoni, G., Corsi, M., Bellelli, G., Zazzetta, S., Mazzola, P., Szabo, H., Bonfanti, A., Arturi, F., Succurro, E., Rubino, M., Tassone, B., Sesti, G., Serra, M. G., Bleve, M. A., Gasbarrone, L., Sajeva, M. R., Brucato, A., Ghidoni, S., Fabris, F., Bertozzi, I., Bogoni, G., Rabuini, M. V., Cosi, E., Scarinzi, P., Amabile, A., Omenetto, E., Prandini, T., Manfredini, R., Fabbian, F., Boari, B., De Giorgi, A., Tiseo, R., De Giorgio, R., Paolisso, G., Rizzo, M. R., Borghi, C., Strocchi, E., Ianniello, E., Soldati, M., Sabba, C., Vella, F. S., Suppressa, P., Schilardi, A., Loparco, F., De Vincenzo, G. M., Comitangelo, A., Amoruso, E., Fenoglio, L., Falcetta, A., Bracco, C., Fargion, A. L. F. S., Tiraboschi, S., Cespiati, A., Oberti, G., Sigon, G., Peyvandi, F., Rossio, R., Ferrari, B., Colombo, G., Agosti, P., Monzani, V., Savojardo, V., Folli, C., Ceriani, G., Pallini, G., Dallegri, F., Ottonello, L., Liberale, L., Caserza, L., Salam, K., Liberato, N. L., Tognin, T., Bianchi, G. B., Giaquinto, S., Purrello, F., Di Pino, A., Piro, S., Rozzini, R., Falanga, L., Spazzini, E., Ferrandina, C., Montrucchio, G., Petitti, P., Peasso, P., Favale, E., Poletto, C., Salmi, R., Gaudenzi, P., Perri, L., Landolfi, R., Montalto, M., Mirijello, A., Guasti, L., Castiglioni, L., Maresca, A., Squizzato, A., Campiotti, L., Grossi, A., Bertolotti, M., Mussi, C., Lancellotti, G., Libbra, M. V., Dondi, G., Pellegrini, E., Carulli, L., Galassi, M., Grassi, Y., Perticone, M., Battaglia, R., Filice, M., Maio, R., Stanghellini, V., Ruggeri, E., del Vecchio, S., Salvi, A., Leonardi, R., Damiani, G., Capeci, W., Gabrielli, A., Mattioli, M., Martino, G. P., Biondi, L., Pettinari, P., Ghio, R., Col, A. D., Minisola, S., Colangelo, L., Cilli, M., Labbadia, G., Afeltra, A., Marigliano, B., Pipita, M. E., Castellino, P., Zanoli, L., Pignataro, S., Gennaro, A., Blanco, J., Saracco, V., Fogliati, M., Bussolino, C., Mete, F., Gino, M., Cittadini, A., Vigorito, C., Arcopinto, M., Salzano, A., Bobbio, E., Marra, A. M., Sirico, D., Moreo, G., Gasparini, F., Prolo, S., Pina, G., Ballestrero, A., Ferrando, F., Berra, S., Dassi, S., Nava, M. C., Graziella, B., Baldassarre, S., Fragapani, S., Gruden, G., Galanti, G., Mascherini, G., Petri, C., Stefani, L., Girino, M., Piccinelli, V., Nasso, F., Gioffre, V., Pasquale, M., Scattolin, G., Martinelli, S., Turrin, M., Sechi, L., Catena, C., Colussi, G., Passariello, N., Rinaldi, L., Berti, F., Famularo, G., Tarsitani, P., Castello, R., Pasino, M., Ceda, G. P., Maggio, M. G., Morganti, S., Artoni, A., Del Giacco, S., Firinu, D., Losa, F., Paoletti, G., Costanzo, G., Montalto, G., Licata, A., Malerba, V., Montalto, F. A., Lasco, A., Basile, G., Catalano, A., Malatino, L., Stancanelli, B., Terranova, V., Di Marca, S., Di Quattro, R., La Malfa, L., Caruso, R., Mecocci, P., Ruggiero, C., Boccardi, V., Meschi, T., Lauretani, F., Ticinesi, A., Nouvenne, A., Minuz, P., Fondrieschi, L., Pirisi, M., Fra, G. P., Sola, D., Porta, M., Riva, P., Quadri, R., Larovere, E., Novelli, M., Scanzi, G., Mengoli, C., Provini, S., Ricevuti, L., Simeone, E., Scurti, R., Tolloso, F., Tarquini, R., Valoriani, A., Dolenti, S., Vannini, G., Tedeschi, A., Trotta, L., Volpi, R., Bocchi, P., Vignali, A., Harari, S., Lonati, C., Cattaneo, M., Napoli, F., Corrao, S, Nobili, A, Natoli, G, Mannucci, P, Perticone, F, Pietrangelo, A, Argano, C, Licata, G, Violi, F, Corazza, G, Marengoni, A, Salerno, F, Cesari, M, Tettamanti, M, Pasina, L, Franchi, C, Cortesi, L, Miglio, G, Ardoino, I, Novella, A, Prisco, D, Silvestri, E, Emmi, G, Bettiol, A, Caterina, C, Biolo, G, Zanetti, M, Guadagni, M, Zaccari, M, Chiuch, M, Vanoli, M, Grignani, G, Pulixi, E, Bernardi, M, Bassi, S, Santi, L, Zaccherini, G, Lupattelli, G, Mannarino, E, Bianconi, V, Paciullo, F, Alcidi, R, Nuti, R, Valenti, R, Ruvio, M, Cappelli, S, Palazzuoli, A, Girelli, D, Busti, F, Marchi, G, Barbagallo, M, Dominguez, L, Cocita, F, Beneduce, V, Plances, L, Mularo, S, Raspanti, M, Zoli, M, Lazzari, I, Brunori, M, Fabbri, E, Magalotti, D, Arno, R, Pasini, F, Capecchi, P, Palasciano, G, Modeo, M, Di Gennaro, C, Cappellini, M, Maira, D, Di Stefano, V, Fabio, G, Seghezzi, S, Mancarella, M, De Amicis, M, De Luca, G, Scaramellini, N, Rossi, P, Damanti, S, Clerici, M, Conti, F, Bonini, G, Ottolini, B, Di Sabatino, A, Miceli, E, Lenti, M, Pisati, M, Dominioni, C, Murialdo, G, Marra, A, Cattaneo, F, Pontremoli, R, Beccati, V, Nobili, G, Secchi, M, Ghelfi, D, Anastasio, L, Sofia, L, Carbone, M, Cipollone, F, Guagnano, M, Valeriani, E, Rossi, I, Mancuso, G, Calipari, D, Bartone, M, Delitala, G, Berria, M, Pes, C, Delitala, A, Muscaritoli, M, Molfino, A, Petrillo, E, Zuccala, G, D'Aurizio, G, Romanelli, G, Zucchelli, A, Manzoni, F, Volpini, A, Picardi, A, Gentilucci, U, Gallo, P, Dell'Unto, C, Annoni, G, Corsi, M, Bellelli, G, Zazzetta, S, Mazzola, P, Szabo, H, Bonfanti, A, Arturi, F, Succurro, E, Rubino, M, Tassone, B, Sesti, G, Serra, M, Bleve, M, Gasbarrone, L, Sajeva, M, Brucato, A, Ghidoni, S, Fabris, F, Bertozzi, I, Bogoni, G, Rabuini, M, Cosi, E, Scarinzi, P, Amabile, A, Omenetto, E, Prandini, T, Manfredini, R, Fabbian, F, Boari, B, De Giorgi, A, Tiseo, R, De Giorgio, R, Paolisso, G, Rizzo, M, Borghi, C, Strocchi, E, Ianniello, E, Soldati, M, Sabba, C, Vella, F, Suppressa, P, Schilardi, A, Loparco, F, De Vincenzo, G, Comitangelo, A, Amoruso, E, Fenoglio, L, Falcetta, A, Bracco, C, Fargion, A, Tiraboschi, S, Cespiati, A, Oberti, G, Sigon, G, Peyvandi, F, Rossio, R, Ferrari, B, Colombo, G, Agosti, P, Monzani, V, Savojardo, V, Folli, C, Ceriani, G, Pallini, G, Dallegri, F, Ottonello, L, Liberale, L, Caserza, L, Salam, K, Liberato, N, Tognin, T, Bianchi, G, Giaquinto, S, Purrello, F, Di Pino, A, Piro, S, Rozzini, R, Falanga, L, Spazzini, E, Ferrandina, C, Montrucchio, G, Petitti, P, Peasso, P, Favale, E, Poletto, C, Salmi, R, Gaudenzi, P, Perri, L, Landolfi, R, Montalto, M, Mirijello, A, Guasti, L, Castiglioni, L, Maresca, A, Squizzato, A, Campiotti, L, Grossi, A, Bertolotti, M, Mussi, C, Lancellotti, G, Libbra, M, Dondi, G, Pellegrini, E, Carulli, L, Galassi, M, Grassi, Y, Perticone, M, Battaglia, R, Filice, M, Maio, R, Stanghellini, V, Ruggeri, E, del Vecchio, S, Salvi, A, Leonardi, R, Damiani, G, Capeci, W, Gabrielli, A, Mattioli, M, Martino, G, Biondi, L, Pettinari, P, Ghio, R, Col, A, Minisola, S, Colangelo, L, Cilli, M, Labbadia, G, Afeltra, A, Marigliano, B, Pipita, M, Castellino, P, Zanoli, L, Pignataro, S, Gennaro, A, Blanco, J, Saracco, V, Fogliati, M, Bussolino, C, Mete, F, Gino, M, Cittadini, A, Vigorito, C, Arcopinto, M, Salzano, A, Bobbio, E, Sirico, D, Moreo, G, Gasparini, F, Prolo, S, Pina, G, Ballestrero, A, Ferrando, F, Berra, S, Dassi, S, Nava, M, Graziella, B, Baldassarre, S, Fragapani, S, Gruden, G, Galanti, G, Mascherini, G, Petri, C, Stefani, L, Girino, M, Piccinelli, V, Nasso, F, Gioffre, V, Pasquale, M, Scattolin, G, Martinelli, S, Turrin, M, Sechi, L, Catena, C, Colussi, G, Passariello, N, Rinaldi, L, Berti, F, Famularo, G, Tarsitani, P, Castello, R, Pasino, M, Ceda, G, Maggio, M, Morganti, S, Artoni, A, Del Giacco, S, Firinu, D, Losa, F, Paoletti, G, Costanzo, G, Montalto, G, Licata, A, Malerba, V, Montalto, F, Lasco, A, Basile, G, Catalano, A, Malatino, L, Stancanelli, B, Terranova, V, Di Marca, S, Di Quattro, R, La Malfa, L, Caruso, R, Mecocci, P, Ruggiero, C, Boccardi, V, Meschi, T, Lauretani, F, Ticinesi, A, Nouvenne, A, Minuz, P, Fondrieschi, L, Pirisi, M, Fra, G, Sola, D, Porta, M, Riva, P, Quadri, R, Larovere, E, Novelli, M, Scanzi, G, Mengoli, C, Provini, S, Ricevuti, L, Simeone, E, Scurti, R, Tolloso, F, Tarquini, R, Valoriani, A, Dolenti, S, Vannini, G, Tedeschi, A, Trotta, L, Volpi, R, Bocchi, P, Vignali, A, Harari, S, Lonati, C, Cattaneo, M, and Napoli, F

Subjects
Registrie, Male, Comorbidity, Diabetes, Disability, Elderly, Hyperglycemia, Mortality, Aged, Aged, 80 and over, Female, Hospital Mortality, Hospitals, Humans, Internal Medicine, Registries, Hospitalization, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Socio-culturale, Renal function, 030204 cardiovascular system & hematology, Diabete, Hospital, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Rating scale, Internal medicine, Diabetes mellitus, 80 and over, medicine, LS4_4, 030212 general & internal medicine, Class III obesity, business.industry, Mortality rate, Comorbidity, Diabetes, Disability, Elderly, Hyperglycemia, Mortality, General Medicine, medicine.disease, Mood disorders, Geriatric Depression Scale, Original Article, business, Human
Abstract

Aims The association between hyperglycemia at hospital admission and relevant short- and long-term outcomes in elderly population is known. We assessed the effects on mortality of hyperglycemia, disability, and multimorbidity at admission in internal medicine ward in patients aged ≥ 65 years. Methods Data were collected from an active register of 102 internal medicine and geriatric wards in Italy (RePoSi project). Patients were recruited during four index weeks of a year. Socio-demographic data, reason for hospitalization, diagnoses, treatment, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), renal function, functional (Barthel Index), and cognitive status (Short Blessed Test) and mood disorders (Geriatric Depression Scale) were recorded. Mortality rates were assessed in hospital 3 and 12 months after discharge. Results Of the 4714 elderly patients hospitalized, 361 had a glycemia level ≥ 250 mg/dL at admission. Compared to subjects with lower glycemia level, patients with glycemia ≥ 250 mg/dL showed higher rates of male sex, smoke and class III obesity. These patients had a significantly lower Barthel Index (p = 0.0249), higher CIRS-SI and CIRS-CI scores (p = 0.0025 and p = 0.0013, respectively), and took more drugs. In-hospital mortality rate was 9.2% and 5.1% in subjects with glycemia ≥ 250 and p = 0.0010). Regression analysis showed a strong association between in-hospital death and glycemia ≥ 250 mg/dL (OR 2.07; [95% CI 1.34–3.19]), Barthel Index ≤ 40 (3.28[2.44–4.42]), CIRS-SI (1.87[1.27–2.77]), and male sex (1.54[1.16–2.03]). Conclusions The stronger predictors of in-hospital mortality for older patients admitted in general wards were glycemia level ≥ 250 mg/dL, Barthel Index ≤ 40, CIRS-SI, and male sex.

Published
2021

24. Activated phosphoinositide 3‐dinase delta syndrome (APDS): An update

Author

Vassilios Lougaris, Caterina Cancrini, Beatrice Rivalta, Riccardo Castagnoli, Giuliana Giardino, Stefano Volpi, Lucia Leonardi, Francesco La Torre, Silvia Federici, Stefania Corrente, Bianca Laura Cinicola, Annarosa Soresina, Gian Luigi Marseglia, Fabio Cardinale, Lougaris, V., Cancrini, C., Rivalta, B., Castagnoli, R., Giardino, G., Volpi, S., Leonardi, L., La Torre, F., Federici, S., Corrente, S., Cinicola, B. L., Soresina, A., Marseglia, G. L., and Cardinale, F.

Subjects
p85, activated phosphoinositide 3-kinase delta syndrome, lymphoproliferation, Class I Phosphatidylinositol 3-Kinases, p110δ, Primary Immunodeficiency Diseases, Immunology, Phosphatidylinositols, clinical research, immune dysregulation, primary combined immune deficiency, Phosphatidylinositol 3-Kinases, Settore MED/02, Humans, Mutation, Quality of Life, Pediatrics, Perinatology and Child Health, Immunology and Allergy
Abstract

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients’ quality of life and prognosis.

Published
2022
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25. Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the <scp>IGNITE ADOPT PGx</scp> investigators

Author

Larisa H, Cavallari, Emily, Cicali, Kristin, Wiisanen, Roger B, Fillingim, Hrishikesh, Chakraborty, Rachel A, Myers, Kathryn V, Blake, Bolanle, Asiyanbola, Jordan F, Baye, Wesley H, Bronson, Kelsey J, Cook, Erica N, Elwood, Chancellor F, Gray, Yan, Gong, Lindsay, Hines, Joseph, Kannry, Natalie, Kucher, Sheryl, Lynch, Khoa A, Nguyen, Aniwaa Owusu, Obeng, Victoria M, Pratt, Hernan A, Prieto, Michelle, Ramos, Azita, Sadeghpour, Rajbir, Singh, Marc, Rosenman, Petr, Starostik, Cameron D, Thomas, Emma, Tillman, Paul R, Dexter, Carol R, Horowitz, Lori A, Orlando, Josh F, Peterson, Todd C, Skaar, Sara L, Van Driest, Simona, Volpi, Deepak, Voora, Hari K, Parvataneni, and Julie A, Johnson

Subjects
Pain, Postoperative, Codeine, General Neuroscience, General Medicine, Acute Pain, General Biochemistry, Genetics and Molecular Biology, Analgesics, Opioid, Cytochrome P-450 CYP2D6, Humans, Hydrocodone, Prospective Studies, Practice Patterns, Physicians', General Pharmacology, Toxicology and Pharmaceutics, Tramadol
Abstract

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Published
2022
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26. Mycophenolate mofetil-induced hypogammaglobulinemia and infectious disease susceptibility in pediatric patients with chronic rheumatic disorders: a monocentric retrospective study

Author

Federica Barbati, Edoardo Marrani, Beatrice Volpi, Giovanna Ferrara, Lorenzo Lodi, Maria Vincenza Mastrolia, Clementina Canessa, Ilaria Maccora, Gabriele Simonini, Chiara Azzari, and Silvia Ricci

Subjects
Agammaglobulinemia, Immunoglobulin G, Pediatrics, Perinatology and Child Health, Humans, Disease Susceptibility, Mycophenolic Acid, Child, Immunosuppressive Agents, Retrospective Studies
Abstract

Mycophenolate mofetil (MMF) is an immunosuppressive drug used for the treatment of autoimmune rheumatological diseases. To test the risk of hypothetical drug-induced hypogammaglobulinemia, the aim of this study was to report the trend of the immunoglobulin (Ig) values and of the infectious diseases in children treated with MMF. This study retrospectively evaluated demographic, clinical, and laboratory data of a cohort of patients affected by a chronic rheumatic disease receiving MMF, followed at the Rheumatology Unit of Meyer Children Hospital, Florence. A total of 29 pediatric patients were enrolled. In patients with normal values of immunoglobulins at the baseline, treatment with MMF resulted in a statistically significant reduction of the IgG levels (p = 0.0058) and in a decrease of IgM levels not reaching statistical significance. The levels of IgA were not affected. During the follow-up, seven patients developed an humoral immune defect. The univariate analysis did not identify any risk factors related to the iatrogenic hypogammaglobulinemia. The infection rate during MMF therapy was significantly higher than the 12-month period before therapy (p = 0.006), while the severe infections did not significantly increase (p = 0.1818), even considering only the patients with hypogammaglobulinemia.In pediatric patients with chronic rheumatic diseases, immunological first level tests and serological analyses to screen the protection against the common childhood pathogens are suggested before starting an immunosuppressive drug. These patients should also complete the vaccination schedule. In patients treated with MMF a strict monitoring of Ig is required during treatment and after discontinuation of the drug.• MMF is an immunosuppressive drug initially used for the treatment of the graft-versus-host disease. • Mycophenolic acid is an inhibitor of inosine-5'-monophosphate dehydrogenase, expressed in lymphocytes; therefore, MMF could impair the immune system function.• MMF resulted in a reduction of IgG and an increase of not severe infection rate. • Immunological first level tests, including Ig, lymphocyte subpopulations, and antibody response to vaccines, are suggested in pediatric patients before starting MMF; a strict monitoring of Ig is important before, during, and after MMF treatment.

Published
2022
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27. Resistance-Trained Individuals Can Underestimate the Intensity of the Resistance Training Session: An Analysis Among Sexes, Training Experience, and Exercises

Author

Julio Wilson dos Santos, Wellington Martins dos Santos, Antonio Carlos Tavares Junior, Charles Ricardo Lopes, Tiago Volpi Braz, and Felipe Alves Brigatto

Subjects
Male, medicine.medical_specialty, Weight Lifting, media_common.quotation_subject, Physical Therapy, Sports Therapy and Rehabilitation, Bench press, Young Adult, Humans, Medicine, Orthopedics and Sports Medicine, Muscle Strength, Muscle, Skeletal, Leg press, Exercise, Normality, Aged, media_common, business.industry, Biceps curl, Resistance Training, General Medicine, Test (assessment), Intensity (physics), Friedman test, Exercise intensity, Physical therapy, Female, business
Abstract

Dos Santos, WM, Tavares Junior, AC, Braz, TV, Lopes, CR, Brigatto, FA, and Dos Santos, JW. Resistance-trained individuals can underestimate the intensity of the resistance training session: An analysis among genders, training experience, and exercises. J Strength Cond Res 36(6): 1506-1510, 2022-Resistance training (RT) promotes improvements in healthy parameters for young to elderly adults and athletes' performance. Strength and muscle mass improvements are dependent on exercise intensity. This study verifies whether 53 healthy young adults underestimate exercise intensity in 3 different exercises, such as bench press (BP), biceps curl (BC), and leg press 45° (LP). Researchers asked the subjects "How much load do you use to perform 10 repetitions in this exercise usually in workout routines?" in each exercise. Individuals warmed up and then performed as many repetitions as possible until they reached the concentric failure. Deviations from data normality were found by using Levene's test; the number of repetitions per exercise within sex was tested by using Friedman's test and Conover's post hoc and Kruskal-Wallis tests to compare the number of repetitions between sex and RT experience. We correlated the number of repetitions and training experience using the Spearman test. The number of repetitions for both groups (male and female) is greater than 8-12 repetitions for BC and LP and BP of the female group, except for men who perform around 8-12 repetitions on BP. Frequency of maximal repetitions reached for 8-12 repetitions for women was 12% for BP, 28% for BC, and 28% for LP. The frequency men reached was 46.5% for BP, 14.3% for BC, and 14.3% for LP. Training experience did not influence the number of repetitions reached. Resistance training practitioners underestimate exercise load (56% of total sample) to be independent of experience. Women underestimate exercise load more than men. Based on the present results, it is possible to state that RT should not be prescribed considering a predefined number of repetitions and a linked percentage of loads, without the guidance for frequent adjustments of loads, according to the exercise performed.

Published
2022
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29. Can Medical Devices Help Mitigate Global Environmental Change Effects on Human and Animal Health? A Pilot Study

Author

Laura Mancini, Stefania Marcheggiani, Mario Figliomeni, Elisabetta Volpi, Luca Avellis, Fabrizio Volpi, Anna Maria D’Angelo, Cristina Romanelli, Pietro Calamea, Lorenzo Tancioni, and Cinzia Ferrari

Subjects
animal health, Settore BIO/07, global environmental change, medical devices, human health, survey, Health, Toxicology and Mutagenesis, Climate Change, Urbanization, Public Health, Environmental and Occupational Health, Pilot Projects, Floods, Animals, Humans, Public Health
Abstract

Globalization and urbanization are new challenges for the ability to protect public health. Indeed, the anthropogenic impact is changing the environment on a global scale. These changes can have direct and indirect health effects on both human and animal populations, introducing new diseases. Heat waves and floods are an example of these changes. Global Environmental Change (GEC) consequences on human health and well-being are stronger in urban areas, which are inhabited by 70% of the European population. In this context, the use of appropriate medical devices can also help mitigate the effects of climate change. Studies into lifestyle, environment quality and potential fields of application can be useful tools to identify possible types of medical device that could help to support the therapeutic needs and the prevention of health both in everyday life, and in the case of environmental alerts. A study was carried out on the potential role of medical devices (MDs) in mitigating the effects of GEC on human and animal health, by issuing two different questionnaires to specific professional clusters: the first to doctors, pharmacists, and veterinarians, the second to MD manufacturers. The data obtained from this study confirm the strong connection between GEC and the increase in the use of some MDs. Results obtained from questionnaires circulated to MD manufacturers confirmed this trend. MD manufacturers also declared that there are no longer any seasonal trends in market demand for some medical devices. This is a pilot study to consider MDs as a mitigation tool for CEGs.

Published
2022

30. Jagged Ends on Multinucleosomal Cell-Free DNA Serve as a Biomarker for Nuclease Activity and Systemic Lupus Erythematosus

Author

Spencer C Ding, Rebecca W Y Chan, Wenlei Peng, Liangbo Huang, Ze Zhou, Xi Hu, Stefano Volpi, Linda T Hiraki, Augusto Vaglio, Paride Fenaroli, Paola Bocca, Lai Shan Tam, Priscilla C H Wong, Lydia H P Tam, Peiyong Jiang, Rossa W K Chiu, K C Allen Chan, and Y M Dennis Lo

Subjects
Deoxyribonucleases, Endodeoxyribonucleases, Biochemistry (medical), Clinical Biochemistry, DNA, Nucleosomes, Mice, Pregnancy, Animals, Humans, Lupus Erythematosus, Systemic, Female, Cell-Free Nucleic Acids, Biomarkers
Abstract

Background Jagged ends of plasma DNA are a recently recognized class of fragmentomic markers for cell-free DNA, reflecting the activity of nucleases. A number of recent studies have also highlighted the importance of jagged ends in the context of pregnancy and oncology. However, knowledge regarding the generation of jagged ends is incomplete. Methods Jaggedness of plasma DNA was analyzed based on Jag-seq, which utilized the differential methylation signals introduced by the DNA end-repair process. We investigated the jagged ends in plasma DNA using mouse models by deleting the deoxyribonuclease 1 (Dnase1), DNA fragmentation factor subunit beta (Dffb), or deoxyribonuclease 1 like 3 (Dnase1l3) gene. Results Aberrations in the profile of plasma DNA jagged ends correlated with the type of nuclease that had been genetically deleted, depending on nucleosomal structures. The deletion of Dnase1l3 led to a significant reduction of jaggedness for those plasma DNA molecules involving more than 1 nucleosome (e.g., size ranges 240-290 bp, 330-380 bp, and 420-470 bp). However, less significant effects of Dnase1 and Dffb deletions were observed regarding different sizes of DNA fragments. Interestingly, the aberration in plasma DNA jagged ends related to multinucleosomes was observed in human subjects with familial systemic lupus erythematosus with Dnase1l3 deficiency and human subjects with sporadic systemic lupus erythematosus. Conclusions Detailed understanding of the relationship between nuclease and plasma DNA jaggedness has opened up avenues for biomarker development.

Published
2022
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31. Performance of the EULAR/ACR 2019 classification criteria for systemic lupus erythematous in monogenic lupus

Author

Sulaiman M Al-Mayouf, Lujayn Akbar, Reem Abdwani, Giulia Ginesi, Stefano Volpi, Marco Gattorno, Reima Bakry, Samia AlHashim, and Alhanouf Alsaleem

Subjects
musculoskeletal diseases, Cohort Studies, Rheumatology, immune system diseases, Humans, Lupus Erythematosus, Systemic, General Medicine, skin and connective tissue diseases, Child, Kidney, Retrospective Studies
Abstract

To evaluate the application of the EULAR/ACR-2019 criteria to monogenic lupus patients and compare its performance against the SLICC-2012 criteria.In a multicenter retrospective cohort study, consecutive patients with monogenic lupus from three tertiary lupus clinics were enrolled. The diagnosis of monogenic lupus was based on the expert physician's opinion or fulfilling the SLICC-2012 criteria. All enrolled patients had genetic variants. A control group of sporadic childhood SLE (cSLE) and non-SLE patients, were included. A descriptive data analysis was conducted, and the EULAR/ACR-2019 and SLICC-2012 criteria were applied to both groups.Forty-nine patients with monogenic lupus with a median age at diagnosis of 6.0 (IQR 3.0-10.8) years and 104 controls (55 patients with cSLE and 49 non-lupus patients with a median age at diagnosis of 10.0 and 5.0 respectively) were included. Forty-four (89.8%) patients with monogenic lupus fulfilled the EULAR/ACR-2019 with a mean score of 22.3±8.9. The most frequent domains were immunologic (93.9%), musculoskeletal and renal (each 57.1%), and mucocutaneous (55.1%). Fifty-four (98.2%) cSLE patients and six (12.2%) non-lupus patients met the EULAR/ACR-2019 criteria with a mean score of 22.5±9.2 and 8.5±5.2, respectively. The sensitivity of the EULAR/ACR-2019 criteria in monogenic lupus was 89.9% (95% CI: 78.3-90.2), while the specificity was 87.6% (95% CI: 75.2-88.7).This is the first and largest cohort of monogenic lupus patients testing the performance of the 2019-EULAR/ACR criteria. It efficiently classifies monogenic lupus patients, irrespective of the underlying genetic variants. Further studies are needed before these criteria are adopted worldwide. Key Points • Typically, patients with monogenic lupus have early onset severe disease, especially with mucocutaneous manifestations and a strong family history of SLE. • Monogenic lupus is a distinctive entity and might differ from the sporadic childhood SLE. • Our study includes a large multinational cohort of monogenic lupus with heterogeneous phenotypic features and underlying genetic variants. • Our study demonstrates that the EULAR/ACR-2019 criteria efficiently classified monogenic lupus patients, irrespective of the diversity of the underlying genetic variants.

Published
2022
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32. Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

Author

Vera G. Volpi, R. Mastrangelo, Cristina Scapin, C. Treins, Yunhong Bai, U. Del Carro, T. Touvier, Cinzia Ferri, Frank Baas, F. Florio, D. Wang, Maurizio D'Antonio, P. Miniou, Michael E. Shy, P. Guedat, and Francesca Bianchi

Subjects
Eukaryotic Initiation Factor-2, Neuroscience (miscellaneous), Biology, medicine.disease_cause, Myelin, Mice, Cellular and Molecular Neuroscience, Charcot-Marie-Tooth Disease, Peripheral myelin protein 22, medicine, Animals, Humans, Myelin Sheath, Mutation, Multiple sclerosis, Myelin protein zero, Wild type, medicine.disease, Disease Models, Animal, medicine.anatomical_structure, Proteostasis, Neurology, Cancer research, Unfolded protein response, Unfolded Protein Response, Schwann Cells
Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modelled by MpzR98C/ + mice that also show ER stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A, we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analysed by behavioural, neurophysiological, morphological and biochemical measures. Both MpzR98C/ + and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild-type values. Taken together, our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in amyotrophic lateral sclerosis and multiple sclerosis animal models, these data demonstrate its potential in managing UPR and ER stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases. Graphical Abstract (Left panel) the accumulation of overexpressed PMP22 or misfolded mutant P0 in the Schwann cell endoplasmic reticulum (ER) leads to overwhelming of the degradative capacity, activation of ER-stress mechanisms, and myelination impairment. (Right panel) by prolonging eIF2α phosphorylation, IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.

Published
2022
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33. Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy

Author

Scott M Ebert, Blake B Rasmussen, Andrew R Judge, Sarah M Judge, Lars Larsson, Ronald C Wek, Tracy G Anthony, George R Marcotte, Matthew J Miller, Mark A Yorek, Adrian Vella, Elena Volpi, Jennifer I Stern, Matthew D Strub, Zachary Ryan, John J Talley, and Christopher M Adams

Subjects
Mammals, Muscular Atrophy, Nutrition and Dietetics, Muscle Fibers, Skeletal, Animals, Humans, Medicine (miscellaneous), Critical Review, Cell Differentiation, Activating Transcription Factor 4, Biology
Abstract

Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper superfamily. ATF4 can be expressed in most if not all mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers.

Published
2022
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34. Evidence for charge-based mimicry in anti dsDNA antibody generation

Author

Maurizio Bruschi, Andrea Angeletti, Xhuliana Kajana, Gabriella Moroni, Renato Alberto Sinico, Micaela Fredi, Augusto Vaglio, Lorenzo Cavagna, Federico Pratesi, Paola Migliorini, Francesco Locatelli, Giulia Pazzola, Giampaola Pesce, Marcello Bagnasco, Angelo Manfredi, Giuseppe Alvise Ramirez, Pasquale Esposito, Simone Negrini, Federica Bui, Barbara Trezzi, Giacomo Emmi, Ilaria Cavazzana, Valentina Binda, Paride Fenaroli, Isabella Pisani, Carlomaurizio Montecucco, Domenico Santoro, Francesco Scolari, Stefano Volpi, Marta Mosca, Angela Tincani, Giovanni Candiano, Enrico Verrina, Franco Franceschini, Angelo Ravelli, Marco Prunotto, Pier Luigi Meroni, Gian Marco Ghiggeri, Bruschi, M, Angeletti, A, Kajana, X, Moroni, G, Sinico, R, Fredi, M, Vaglio, A, Cavagna, L, Pratesi, F, Migliorini, P, Locatelli, F, Pazzola, G, Pesce, G, Bagnasco, M, Manfredi, A, Ramirez, G, Esposito, P, Negrini, S, Bui, F, Trezzi, B, Emmi, G, Cavazzana, I, Binda, V, Fenaroli, P, Pisani, I, Montecucco, C, Santoro, D, Scolari, F, Volpi, S, Mosca, M, Tincani, A, Candiano, G, Verrina, E, Franceschini, F, Ravelli, A, Prunotto, M, Meroni, P, and Ghiggeri, G

Subjects
Immunology, IgG2, DNA, anti-dsDNA antibodie, Lupus Nephritis, Anionic epitope, Antibodies, Antinuclear, Immunoglobulin G, Immunology and Allergy, Humans, Lupus Erythematosus, Systemic, Mimicry, anti-Annexin A1 antibodie, Isotype, Autoantibodies, Annexin A1
Abstract

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Published
2022

35. Autosomal dominant lateral temporal lobe epilepsy associated with a novel reelin mutation

Author

Maria Tappatà, Carlo Alberto Tassinari, Elena Pasini, Anna Federica Marliani, Lilia Volpi, Patrizia Riguzzi, Carlo Nobile, Emanuela Dazzo, Raffaella Minardi, Francesca Bisulli, Roberto Michelucci, Michelucci R., Dazzo E., Volpi L., Pasini E., Riguzzi P., Minardi R., Marliani A.F., Tappata M., Bisulli F., Tassinari C.A., and Nobile C.

Subjects
Adult, Sleep Wake Disorders, Proband, Pathology, medicine.medical_specialty, Cell Adhesion Molecules, Neuronal, Epilepsy, Frontal Lobe, Nerve Tissue Proteins, Grey matter, Electroencephalography, Epilepsy, reelin, medicine, Humans, Missense mutation, Reelin, autosomal dominant lateral temporal lobe epilepsy, Aged, Genetic testing, Extracellular Matrix Proteins, biology, medicine.diagnostic_test, business.industry, Serine Endopeptidases, General Medicine, medicine.disease, Magnetic Resonance Imaging, Hyperintensity, Pedigree, Reelin Protein, medicine.anatomical_structure, Neurology, lateral temporal lobe seizure, biology.protein, Female, autosomal dominant epilepsy with auditory feature, Neurology (clinical), business
Abstract

Aims. Reelin mutations are responsible for a minority of families with autosomal dominant lateral temporal lobe epilepsy. Here, we report a novel nuclear family with distinct clinical and neuroradiological findings. Methods. We studied the proband and her mother by means of EEG, video-EEG, 3T MRI, FDG-PET and genetic testing. Results. Both patients had a focal drug-resistant epilepsy with onset at the age of 16 and focal seizures with typical auditory features combined with fear, followed by loss of contact or evolving to bilateral tonic-clonic seizures. The proband's ictal EEG showed clear left temporal seizure onset, and cerebral MRI revealed subtle left temporal changes (mild hypotrophy, slight blurring of the white and grey matter and hyperintensity) with corresponding left temporal mesial focal hypometabolism on FDG-PET. Genetic testing identified a missense variant, c.6631C>T (p.Arg2211Cys), in reelin repeat #5 in both patients, which markedly affected the secretion of the protein. Conclusion. The data from this family support previous findings indicating that reelin mutations are a cause of autosomal dominant lateral temporal lobe epilepsy which has a clinical spectrum that may also encompass drug-resistant epilepsy associated with mild MRI temporal changes.

Published
2020
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36. Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Author

Maria Chiriaco, Giorgiana Madalina Ursu, Donato Amodio, Nicola Cotugno, Stefano Volpi, Francesco Berardinelli, Simone Pizzi, Cristina Cifaldi, Matteo Zoccolillo, Ignazia Prigione, Silvia Di Cesare, Carmela Giancotta, Elisa Anastasio, Beatrice Rivalta, Lucia Pacillo, Paola Zangari, Alessandro G. Fiocchi, Andrea Diociaiuti, Alessandro Bruselles, Francesca Pantaleoni, Andrea Ciolfi, Valentina D’Oria, Giuseppe Palumbo, Marco Gattorno, Maya El Hachem, Jean-Pierre de Villartay, Andrea Finocchi, Paolo Palma, Paolo Rossi, Marco Tartaglia, Alessandro Aiuti, Antonio Antoccia, Gigliola Di Matteo, Caterina Cancrini, Chiriaco, Maria, Madalina Ursu, Giorgiana, Amodio, Donato, Cotugno, Nicola, Volpi, Stefano, Berardinelli, Francesco, Pizzi, Simone, Cifaldi, Cristina, Zoccolillo, Matteo, Prigione, Ignazia, Di Cesare, Silvia, Giancotta, Carmela, Anastasio, Elisa, Zangari, Paola, G Fiocchi, Alessandro, Diociaiuti, Andrea, Bruselles, Alessandro, Pantaleoni, Francesca, Ciolfi, Andrea, D’Oria, Valentina, Palumbo, Giuseppe, Gattorno, Marco, Elachem, Maya, de Villartay, Jean-Pierre, Finocchi, Andrea, Palma, Paolo, Rossi, Paolo, Tartaglia MSc, Marco, Aiuti, Alessandro, Antoccia, Antonio, Di Matteo, Gigliola, and Caterina Cancrini, And

Subjects
immune dysregulation, radiosensitivity, ARPC1B, Immunology, Actin-Related Protein 2, Immunology and Allergy, combined immunodeficiency, Humans, Settore MED/38, Radiation Tolerance, DNA damage response (DDR), Actin-Related Protein 2-3 Complex, Cytoskeleton
Abstract

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions.

Published
2022

37. Nuclease deficiencies alter plasma cell-free DNA methylation profiles

Author

Peiyong Jiang, Meng Ni, Y.M. Dennis Lo, Danny K L Wong, Diana S.C. Han, K.C. Allen Chan, Rossa W.K. Chiu, Rebecca W.Y. Chan, Kathy O. Lui, Linda T. Hiraki, and Stefano Volpi

Subjects
Animals, Chromatin, CpG Islands, DNA Methylation, Humans, Mice, Cell-Free Nucleic Acids, DNA Fragmentation, Endodeoxyribonucleases, Plasma cell, Free dna, chemistry.chemical_compound, Genetics, medicine, Fragmentation (cell biology), Genetics (clinical), Nuclease, biology, Research, Methylation, Molecular biology, medicine.anatomical_structure, CpG site, chemistry, biology.protein, DNA
Abstract

The effects of DNASE1L3 or DNASE1 deficiency on cell-free DNA (cfDNA) methylation were explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wild-type cfDNA, cfDNA in DNASE1L3-deficient mice was significantly hypomethylated, while cfDNA in DNASE1-deficient mice was hypermethylated. The cfDNA hypomethylation in DNASE1L3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in DNASE1-deficient mice, demonstrating the preference of DNASE1 to cleave in hypomethylated OCRs and CGIs. We also observed a substantial decrease of fragment ends at methylated CpGs in the absence of DNASE1L3, thereby demonstrating that DNASE1L3 prefers to cleave at methylated CpGs. Furthermore, we found that methylation levels of cfDNA varied by fragment size in a periodic pattern, with cfDNA of specific sizes being more hypomethylated and enriched for OCRs and CGIs. These findings were confirmed in DNASE1L3-deficient human cfDNA. Thus, we have found that nuclease-mediated cfDNA fragmentation markedly affects cfDNA methylation level on a genome-wide scale. This work provides a foundational understanding of the relationship between methylation, nuclease biology, and cfDNA fragmentation.

Published
2021
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38. Percutaneous puncture during PCNL: new perspective for the future with virtual imaging guidance

Author

Enrico Checcucci, Francesco Porpiglia, Gabriele Volpi, P. Alessio, D. Zamengo, S. De Luca, Beatrice Carbonaro, Federico Piramide, Giovanni Cacciamani, Matteo Manfredi, Arman Tsaturyan, S. De Cillis, Juan Gómez Rivas, J. Meziere, Alberto Piana, Daniele Amparore, P. Verri, S. Piscitello, Carla Fiori, and Evangelos Liatsikos

Subjects
Nephrolithotomy, Artificial intelligence, medicine.medical_specialty, Percutaneous, Kidney stones, Urology, medicine.medical_treatment, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, MEDLINE, Punctures, PCNL, Surgical planning, Kidney Calculi, medicine, Humans, Medical physics, Percutaneous nephrolithotomy, Augmented Reality, Modalities, business.industry, Perspective (graphical), Mixed reality, 3D, Augmented reality, Virtual imaging, Artificial Intelligence, Nephrolithotomy, Percutaneous, business
Abstract

Large and complex renal stones are usually treated with percutaneous nephrolithotomy (PCNL). One of the crucial steps in this procedure is the access to the collecting system with the percutaneous puncture and this maneuver leads to a risk of vascular and neighboring organs’ injury. In the last years, the application of virtual image-guided surgery has gained wide diffusion even in this specific field. To provide a short overview of the most recent evidence on current applications of virtual imaging guidance for PCNL. A non-systematic review of the literature was performed. Medline, PubMed, the Cochrane Database and Embase were screened for studies regarding the use virtual imaging guidance for PCNL. 3D virtual navigation technology for PCNL was first used in urology with the purpose of surgical training and surgical planning; subsequently, the field of surgical navigation with different modalities (from cognitive to augmented reality or mixed reality) had been explored. Finally, anecdotal preliminary experiences explored the potential application of artificial intelligence guidance for percutaneous puncture. Nowadays, many experiences proved the potential benefit of virtual guidance for surgical simulation and training. Focusing on surgery, this tool revealed to be useful both for surgical planning, allowed to achieve a better surgical performance, and for surgical navigation by using augmented reality and mixed reality systems aimed to assist the surgeon in real time during the intervention.

Published
2021
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39. Effect of the STRIDE fall injury prevention intervention on falls, fall injuries, and health-related quality of life

Author

David A. Ganz, Anita H. Yuan, Erich J. Greene, Nancy K. Latham, Katy Araujo, Albert L. Siu, Jay Magaziner, Jerry H. Gurwitz, Albert W. Wu, Neil B. Alexander, Robert B. Wallace, Susan L. Greenspan, Jeremy Rich, Elena Volpi, Stephen C. Waring, Patricia C. Dykes, Fred Ko, Neil M. Resnick, Siobhan K. McMahon, Shehzad Basaria, Rixin Wang, Charles Lu, Denise Esserman, James Dziura, Michael E. Miller, Thomas G. Travison, Peter Peduzzi, Shalender Bhasin, David B. Reuben, and Thomas M. Gill

Subjects
Aging, care management, Clinical Trials and Supportive Activities, Medical and Health Sciences, Fractures, Bone, Clinical Research, falls, Humans, Bone, Aged, Prevention, Rehabilitation, Injuries and accidents, Hospitalization, health-related quality of life, Good Health and Well Being, pragmatic trials, Geriatrics, Quality of Life, older persons, Injury (total) Accidents/Adverse Effects, Independent Living, Patient Safety, Geriatrics and Gerontology, Fractures
Abstract

BackgroundFalls are common in older adults and can lead to severe injuries. The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial cluster-randomized 86 primary care practices across 10 health systems to a multifactorial intervention to prevent fall injuries, delivered by registered nurses trained as falls care managers, or enhanced usual care. STRIDE enrolled 5451 community-dwelling older adults age ≥70 at increased fall injury risk.MethodsWe assessed fall-related outcomes via telephone interviews of participants (or proxies) every 4 months. At baseline, 12 and 24 months, we assessed health-related quality of life (HRQOL) using the EQ-5D-5L and EQ-VAS. We used Poisson models to assess intervention effects on falls, fall-related fractures, fall injuries leading to hospital admission, and fall injuries leading to medical attention. We used hierarchical longitudinal linear models to assess HRQOL.ResultsFor recurrent event models, intervention versus control incidence rate ratios were 0.97 (95% confidence interval [CI], 0.93-1.00; p= 0.048) for falls, 0.93 (95% CI, 0.80-1.08; p= 0.337) for self-reported fractures, 0.89 (95% CI, 0.73-1.07; p= 0.205) for adjudicated fractures, 0.91 (95% CI, 0.77-1.07; p= 0.263) for falls leading to hospital admission, and 0.97 (95% CI, 0.89-1.06; p= 0.477) for falls leading to medical attention. Similar effect sizes (non-significant) were obtained for dichotomous outcomes (e.g., participants with ≥1 events). The difference in least square mean change over time in EQ-5D-5L (intervention minus control) was 0.009 (95% CI, -0.002 to 0.019; p= 0.106) at 12 months and 0.005 (95% CI, -0.006 to 0.015; p= 0.384) at 24 months.ConclusionsAcross a standard set of outcomes typically reported in fall prevention studies, we observed modest improvements, one of which was statistically significant. Future work should focus on patient-, practice-, and organization-level operational strategies to increase the real-world effectiveness of interventions, and improving the ability to detect small but potentially meaningful clinical effects.Clinicaltrialsgov identifier: NCT02475850.

Published
2022

40. Epigenetic analysis of cell-free DNA by fragmentomic profiling

Author

Qing Zhou, Guannan Kang, Peiyong Jiang, Rong Qiao, W. K. Jacky Lam, Stephanie C. Y. Yu, Mary-Jane L. Ma, Lu Ji, Suk Hang Cheng, Wanxia Gai, Wenlei Peng, Huimin Shang, Rebecca W. Y. Chan, Stephen L. Chan, Grace L. H. Wong, Linda T. Hiraki, Stefano Volpi, Vincent W. S. Wong, John Wong, Rossa W. K. Chiu, K. C. Allen Chan, and Y. M. Dennis Lo

Subjects
Guanine, Multidisciplinary, Nucleotides, Liver Neoplasms, DNA, DNA Methylation, Epigenesis, Genetic, Phosphates, Cytosine, Pregnancy, Biomarkers, Tumor, Humans, Female, Cell-Free Nucleic Acids
Abstract

Cell-free DNA (cfDNA) fragmentation patterns contain important molecular information linked to tissues of origin. We explored the possibility of using fragmentation patterns to predict cytosine-phosphate-guanine (CpG) methylation of cfDNA, obviating the use of bisulfite treatment and associated risks of DNA degradation. This study investigated the cfDNA cleavage profile surrounding a CpG (i.e., within an 11-nucleotide [nt] window) to analyze cfDNA methylation. The cfDNA cleavage proportion across positions within the window appeared nonrandom and exhibited correlation with methylation status. The mean cleavage proportion was ∼twofold higher at the cytosine of methylated CpGs than unmethylated ones in healthy controls. In contrast, the mean cleavage proportion rapidly decreased at the 1-nt position immediately preceding methylated CpGs. Such differential cleavages resulted in a characteristic change in relative presentations of CGN and NCG motifs at 5′ ends, where N represented any nucleotide. CGN/NCG motif ratios were correlated with methylation levels at tissue-specific methylated CpGs (e.g., placenta or liver) (Pearson’s absolute r > 0.86). cfDNA cleavage profiles were thus informative for cfDNA methylation and tissue-of-origin analyses. Using CG-containing end motifs, we achieved an area under a receiver operating characteristic curve (AUC) of 0.98 in differentiating patients with and without hepatocellular carcinoma and enhanced the positive predictive value of nasopharyngeal carcinoma screening (from 19.6 to 26.8%). Furthermore, we elucidated the feasibility of using cfDNA cleavage patterns to deduce CpG methylation at single CpG resolution using a deep learning algorithm and achieved an AUC of 0.93. FRAGmentomics-based Methylation Analysis (FRAGMA) presents many possibilities for noninvasive prenatal, cancer, and organ transplantation assessment.

Published
2022
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41. Modeling venous plasma samples in [

Author

Tommaso, Volpi, John J, Lee, Erica, Silvestri, Tony, Durbin, Maurizio, Corbetta, Manu S, Goyal, Andrei G, Vlassenko, and Alessandra, Bertoldo

Subjects
Kinetics, Fluorodeoxyglucose F18, Positron-Emission Tomography, Humans, Arteries, Algorithms
Abstract

The gold-standard approach to quantifying dynamic PET images relies on using invasive measures of the arterial plasma tracer concentration. An attractive alternative is to employ an image-derived input function (IDIF), corrected for spillover effects and rescaled with venous plasma samples. However, venous samples are not always available for every participant. In this work, we used the nonlinear mixed-effects modeling approach to develop a model which infers venous tracer kinetics by using venous samples obtained from a population of healthy individuals and integrating subject-specific covariates. Population parameters (fixed effects), their between-subject variability (random effects), and the effects of covariates were estimated. The selected model will allow to reliably infer venous tracer kinetics in subjects with missing measurements. Clinical relevance - The derived model will be relevant for fully noninvasive dynamic FDG PET quantification using image-derived input functions in both healthy and patient populations when hemodynamics is not impaired.

Published
2022

42. Image-derived Input Function in brain [

Author

Erica, Silvestri, Tommaso, Volpi, Andrea, Bettinelli, Mattia, De Francisci, Judson, Jones, Maurizio, Corbetta, Diego, Cecchin, and Alessandra, Bertoldo

Subjects
Fluorodeoxyglucose F18, Positron-Emission Tomography, Brain, Humans, Algorithms, Carotid Artery, Internal
Abstract

Quantification of brain [

Published
2022

43. Associations between Maternal Dietary Patterns, Biomarkers and Delivery Outcomes in Healthy Singleton Pregnancies: Multicenter Italian GIFt Study

Author

Gaia Maria Anelli, Francesca Parisi, Laura Sarno, Ottavia Fornaciari, Annunziata Carlea, Chiara Coco, Matteo Della Porta, Nunzia Mollo, Paola Maria Villa, Maurizio Guida, Roberta Cazzola, Ersilia Troiano, Monica Pasotti, Graziella Volpi, Laura Vetrani, Manuela Maione, and Irene Cetin

Subjects
Nutrition and Dietetics, Placenta, Pregnancy Outcome, GIFt study, Vitamins, maternal nutrition, maternal dietary patterns, RBCs folate, vitamin D, hepcidin, Biomarkers, Female, Folic Acid, Humans, Pregnancy, Prospective Studies, Vitamin D, Hepcidins, Settore BIO/10 - Biochimica, Settore MED/40 - Ginecologia e Ostetricia, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, Food Science
Abstract

Background: Maternal nutrition represents a critical risk factor for adverse health outcomes in both mother and offspring. We aimed to investigate associations between maternal nutritional habits, biomarker status, and pregnancy outcome among Italian healthy normal-weight pregnancies. Methods: Multicenter prospective cohort study recruiting Italian healthy normal-weight women with singleton spontaneous pregnancies at 20 ± 2 weeks (T1) in Milan and Naples. All patients underwent nutritional evaluations by our collecting a 7-day weighed dietary record at 25 ± 1 weeks (T2) and a Food Frequency Questionnaire at 29 ± 2 weeks (T3). Maternal venous blood samples were collected at T3 to assess nutritional, inflammatory and oxidative biomarker concentrations (RBCs folate, vitamin D, hepcidin, total antioxidant capacity). Pregnancy outcomes were collected at delivery (T4). General linear models adjusted for confounding factors were estimated to investigate associations between maternal dietary pattern adherence, nutrient intakes, biomarker concentrations and delivery outcomes. Results: 219 healthy normal-weight pregnant women were enrolled. Vitamin D and RBCs folate concentrations, as well as micronutrient intakes, were consistently below the recommended range. In a multi-adjusted model, maternal adherence to the most prevalent ‘high meat, animal fats, grains’ dietary pattern was positively associated with hepcidin concentrations and negatively associated with gestational age at delivery in pregnancies carrying female fetuses. Hepcidin plasma levels were further negatively associated to placental weight, whereas vitamin D concentrations were positively associated to neonatal weight. Conclusions: A high adherence to an unbalanced ‘high meat, animal fats, grains’ pattern was detected among Italian normal-weight low-risk pregnancies, further associated with maternal pro-inflammatory status and gestational age at delivery. This evidence underlines the need for a dedicated nutritional counseling even among low-risk pregnancies.

Published
2022
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44. The association between low skeletal muscle mass and delirium: results from the nationwide multi-centre Italian Delirium Day 2017

Author

Zucchelli, A, Manzoni, F, Morandi, A, Di Santo, S, Rossi, E, Valsecchi, Mg, Inzitari, M, Cherubini, A, Bo, M, Mossello, E, Marengoni, A, Bellelli, G, Tarasconi, A, Sella, M, Auriemma, S, Paternò, G, Faggian, G, Lucarelli, C, De Grazia, N, Alberto, C, Margola, A, Porcella, L, Nardiello, I, Chimenti, E, Zeni, M, Giani, A, Famularo, S, Romairone, E, Minaglia, C, Ceccotti, C, Guerra, G, Mantovani, G, Monacelli, F, Candiani, T, Ballestrero, A, Santolini, F, Rosso, M, Bono, V, Sibilla, S, Dal Santo, P, Ceci, M, Barone, P, Schirinzi, T, Formenti, A, Nastasi, G, Isaia, G, Gonella, D, Battuello, A, Casson, S, Calvani, D, Boni, F, Ciaccio, A, Rosa, R, Sanna, G, Manfredini, S, Cortese, L, Rizzo, M, Prestano, R, Greco, A, Lauriola, M, Gelosa, G, Piras, V, Arena, M, Cosenza, D, Bellomo, A, Lamontagna, M, Gabbani, L, Lambertucci, L, Perego, S, Parati, G, Basile, G, Gallina, V, Pilone, G, Giudice, C, De, F, Pietrogrande, L, De, B, Mosca, M, Corazzin, I, Rossi, P, Nunziata, V, D'Amico, F, Grippa, A, Giardini, S, Barucci, R, Cossu, A, Fiorin, L, Distefano, M, Lunardelli, M, Brunori, M, Ruffini, I, Abraham, E, Varutti, A, Fabbro, E, Catalano, A, Martino, G, Leotta, D, Marchet, A, Dell'Aquila, G, Scrimieri, A, Davoli, M, Casella, M, Cartei, A, Polidori, G, Brischetto, D, Motta, S, Saponara, R, Perrone, P, Russo, G, Del, D, Car, C, Pirina, T, Franzoni, S, Cotroneo, A, Ghiggia, F, Volpi, G, Menichetti, C, Panico, A, Calogero, P, Corvalli, G, Mauri, M, Lupia, E, Manfredini, R, Fabbian, F, March, A, Pedrotti, M, Veronesi, M, Strocchi, E, Bianchetti, A, Crucitti, A, Di Francesco, V, Fontana, G, Bonanni, L, Barbone, F, Serrati, C, Ballardini, G, Simoncelli, M, Ceschia, G, Scarpa, C, Brugiolo, R, Fusco, S, Ciarambino, T, Biagini, C, Tonon, E, Porta, M, Venuti, D, Delsette, M, Poeta, M, Barbagallo, G, Trovato, G, Delitala, A, Arosio, P, Reggiani, F, Zuliani, G, Ortolani, B, Mussio, E, Girardi, A, Coin, A, Ruotolo, G, Castagna, A, Masina, M, Cimino, R, Pinciaroli, A, Tripodi, G, Cannistrà, U, Cassadonte, F, Vatrano, M, Scaglione, L, Fogliacco, P, Muzzuilini, C, Romano, F, Padovani, A, Rozzini, L, Cagnin, A, Fragiacomo, F, Desideri, G, Liberatore, E, Bruni, A, Orsitto, G, Franco, M, Bonfrate, L, Bonetto, M, Pizio, N, Magnani, G, Cecchetti, G, Longo, A, Bubba, V, Marinan, L, Cotelli, M, Turla, M, Sessa, M, Abruzzi, L, Castoldi, G, Lovetere, D, Musacchio, C, Novello, M, Cavarape, A, Bini, A, Leonardi, A, Seneci, F, Grimaldi, W, Fimognari, F, Bambara, V, Saitta, A, Corica, F, Braga, M, Ettorre, E, Camellini, C, Crescenzo, A, Noro, G, Turco, R, Ponzetto, M, Giuseppe, L, Mazzei, B, Maiuri, G, Costaggiu, D, Damato, R, Formilan, M, Patrizia, G, Santuari, L, Gallucci, M, Paragona, M, Bini, P, Modica, D, Abati, C, Clerici, M, Barbera, I, Nigroimperiale, F, Manni, A, Votino, C, Castiglioni, C, Di, M, Degl'Innocenti, M, Moscatelli, G, Guerini, S, Casini, C, Dini, D, D'Imporzano, E, Denotariis, S, Bonometti, F, Paolillo, C, Riccardi, A, Tiozzo, A, Samy Salama Fahmy, A, Dibari, M, Vanni, S, Scarpa, A, Zara, D, Ranieri, P, Pezzoni, D, Gentile, S, Platto, C, D'Ambrosio, V, Faraci, B, Brambilla, C, Ivaldi, C, Milia, P, Desalvo, F, Solaro, C, Strazzacappa, M, Cazzadori, M, Confente, S, Grasso, M, Troisi, E, Guerini, V, Bernardini, B, C Boffelli S, Corsini, Filippi, A, Delpin, K, Bertoletti, E, Vannucci, M, Tesi, F, Crippa, P, Malighetti, A, Caltagirone, C, Disant, S, Bettini, D, Maltese, F, Abruzzese, G, Cosimo, D, Azzini, M, Colombo, M, Procino, G, Fascendini, S, Barocco, F, Del, P, Mazzone, A, Riva, E, Dell'Acqua, D, Cottino, M, Vezzadini, G, Avanzi, S, Orini, S, Sgrilli, F, Mello, A, Lombardi, L, Muti, E, Dijk, B, Fenu, S, Pes, C, Gareri, P, Passamonte, M, Rigo, R, Locusta, L, Caser, L, Rosso, G, Cesarini, S, Cozzi, R, Santini, C, Carbone, P, Cazzaniga, I, Lovati, R, Cantoni, A, Ranzani, P, Barra, D, Pompilio, G, Dimori, S, Cernesi, S, Riccò, C, Piazzolla, F, Capittini, E, Rota, C, Gottardi, F, Merla, L, A Millul A, Barelli, De, G, Morrone, G, Bigolari, M, Macchi, M, Zambon, F, Pizzorni, C, Dicasaleto, G, Menculini, G, Marcacci, M, Catanese, G, Sprini, D, Dicasalet, T, Bocci, M, Borga, S, Caironi, P, Cat, C, Cingolani, E, Avalli, L, Greco, G, Citerio, G, Gandini, L, Cornara, G, Lerda, R, Brazzi, L, Simeone, F, Caciorgna, M, Alampi, D, Francesconi, S, Beck, E, Antonini, B, Vettoretto, K, Meggiolaro, M, Garofalo, E, Notaro, S, Varutti, R, Bassi, F, Mistraletti, G, Marino, A, Rona, R, Rondelli, E, Riva, I, Scapigliati, A, Cortegiani, A, Vitale, F, Pistidda, L, D'Andrea, R, Querci, L, Gnesin, P, Todeschini, M, Lugano, M, Castelli, G, Ortolani, M, Cotoia, A, Maggiore, S, Ditizio, L, Graziani, R, Testa, I, Ferretti, E, Castioni, C, Lombardi, F, Caserta, R, Pasqua, M, Simoncini, S, Baccarini, F, Rispoli, M, Grossi, F, Cancelliere, L, Carnelli, M, Puccini, F, Biancofiore, G, Siniscalchi, A, Laici, C, Torrini, M, Pasetti, G, Palmese, S, Oggioni, R, Mangani, V, Pini, S, Martelli, M, Rigo, E, Zuccalà, F, Cherri, A, Spina, R, Calamai, I, Petrucci, N, Caicedo, A, Ferri, F, Gritti, P, Brienza, N, Fonnesu, R, Dessena, M, Fullin, G, Saggioro, D., Zucchelli, A, Manzoni, F, Morandi, A, Di Santo, S, Rossi, E, Valsecchi, M, Inzitari, M, Cherubini, A, Bo, M, Mossello, E, Marengoni, A, Bellelli, G, Citerio, G, Zucchelli, Alberto, Valsecchi, M G, and A Tarasconi, M Sella, S Auriemma, G Paternò, G Faggian, C Lucarelli, N De Grazia, C Alberto, A Margola, L Porcella, I Nardiello, E Chimenti, M Zeni, A Giani, S Famularo, E Romairone, C Minaglia, C Ceccotti, G Guerra, G Mantovani, F Monacelli, C Minaglia, T Candiani, A Ballestrero, C Minaglia, F Santolini, C Minaglia, M Rosso, V Bono, S Sibilla, P Dal Santo, M Ceci, P Barone, T Schirinzi, A Formenti, G Nastasi, G Isaia, D Gonella, A Battuello, S Casson, D Calvani, F Boni, A Ciaccio, R Rosa, G Sanna, S Manfredini, L Cortese, M Rizzo, R Prestano, A Greco, M Lauriola, G Gelosa, V Piras, M Arena, D Cosenza, A Bellomo, M LaMontagna, L Gabbani, L Lambertucci, S Perego, G Parati, G Basile, V Gallina, G Pilone, C Giudice, F De, L Pietrogrande, B De, M Mosca, I Corazzin, P Rossi, V Nunziata, F D'Amico, A Grippa, S Giardini, R Barucci, A Cossu, L Fiorin, M Arena, M Distefano, M Lunardelli, M Brunori, I Ruffini, E Abraham, A Varutti, E Fabbro, A Catalano, G Martino, D Leotta, A Marchet, G Dell'Aquila, A Scrimieri, M Davoli, M Casella, A Cartei, G Polidori, G Basile, D Brischetto, S Motta, R Saponara, P Perrone, G Russo, D Del, C Car, T Pirina, S Franzoni, A Cotroneo, F Ghiggia, G Volpi, C Menichetti, M Bo, A Panico, P Calogero, G Corvalli, M Mauri, E Lupia, R Manfredini, F Fabbian, A March, M Pedrotti, M Veronesi, E Strocchi, A Bianchetti, A Crucitti, V Di Francesco, G Fontana, L Bonanni, F Barbone, C Serrati, G Ballardini, M Simoncelli, G Ceschia, C Scarpa, R Brugiolo, S Fusco, T Ciarambino, C Biagini, E Tonon, M Porta, D Venuti, M DelSette, M Poeta, G Barbagallo, G Trovato, A Delitala, P Arosio, F Reggiani, G Zuliani, B Ortolani, E Mussio, A Girardi, A Coin, G Ruotolo, A Castagna, M Masina, R Cimino, A Pinciaroli, G Tripodi, U Cannistrà, F Cassadonte, M Vatrano, F Cassandonte, L Scaglione, P Fogliacco, C Muzzuilini, F Romano, A Padovani, L Rozzini, A Cagnin, F Fragiacomo, G Desideri, E Liberatore, A Bruni, G Orsitto, M Franco, L Bonfrate, M Bonetto, N Pizio, G Magnani, G Cecchetti, A Longo, V Bubba, L Marinan, M Cotelli, M Turla, M Brunori, M Sessa, L Abruzzi, G Castoldi, D LoVetere, C Musacchio, M Novello, A Cavarape, A Bini, A Leonardi, F Seneci, W Grimaldi, F Fimognari, V Bambara, A Saitta, F Corica, M Braga, E Ettorre, C Camellini, A Marengoni, A Bruni, A Crescenzo, G Noro, R Turco, M Ponzetto, L Giuseppe, B Mazzei, G Maiuri, D Costaggiu, R Damato, E Fabbro, G Patrizia, L Santuari, M Gallucci, C Minaglia, M Paragona, P Bini, D Modica, C Abati, M Clerici, I Barbera, F NigroImperiale, A Manni, C Votino, C Castiglioni, M Di, M Degl'Innocenti, G Moscatelli, S Guerini, C Casini, D Dini, S DeNotariis, F Bonometti, C Paolillo, A Riccardi, A Tiozzo, A SamySalamaFahmy, A Riccardi, C Paolillo, M DiBari, S Vanni, A Scarpa, D Zara, P Ranieri, P Calogero, G Corvalli, D Pezzoni, S Gentile, A Morandi, C Platto, V D'Ambrosio, B Faraci, C Ivaldi, P Milia, F DeSalvo, C Solaro, M Strazzacappa, M Bo, A Panico, M Cazzadori, S Confente, M Bonetto, G Magnani, G Cecchetti, V Guerini, B Bernardini, C Corsini, S Boffelli, A Filippi, K Delpin, E Bertoletti, M Vannucci, F Tesi, P Crippa, A Malighetti, C Caltagirone, S DiSant, D Bettini, F Maltese, M Formilan, G Abruzzese, C Minaglia, D Cosimo, M Azzini, M Cazzadori, M Colombo, G Procino, S Fascendini, F Barocco, P Del, F D'Amico, A Grippa, A Mazzone, E Riva, D Dell'Acqua, M Cottino, G Vezzadini, S Avanzi, S Orini, F Sgrilli, A Mello, L Lombardi, E Muti, B Dijk, S Fenu, C Pes, P Gareri, A Castagna, M Passamonte, F De, R Rigo, L Locusta, L Caser, G Rosso, S Cesarini, R Cozzi, C Santini, P Carbone, I Cazzaniga, R Lovati, A Cantoni, P Ranzani, D Barra, G Pompilio, S Dimori, S Cernesi, C Riccò, F Piazzolla, E Capittini, C Rota, F Gottardi, L Merla, A Barelli, A Millul, G De, G Morrone, M Bigolari, C Minaglia, M Macchi, F Zambon, F D'Amico, F D'Amico, C Pizzorni, G DiCasaleto, G Menculini, M Marcacci, G Catanese, D Sprini, T DiCasalet, M Bocci, S Borga, P Caironi, C Cat, E Cingolani, L Avalli, G Greco, G Citerio, L Gandini, G Cornara, R Lerda, L Brazzi, F Simeone, M Caciorgna, D Alampi, S Francesconi, E Beck, B Antonini, K Vettoretto, M Meggiolaro, E Garofalo, A Bruni, S Notaro, R Varutti, F Bassi, G Mistraletti, A Marino, R Rona, E Rondelli, I Riva, A Scapigliati, A Cortegiani, F Vitale, L Pistidda, R D'Andrea, L Querci, P Gnesin, M Todeschini, M Lugano, G Castelli, M Ortolani, A Cotoia, S Maggiore, L DiTizio, R Graziani, I Testa, E Ferretti, C Castioni, F Lombardi, R Caserta, M Pasqua, S Simoncini, F Baccarini, M Rispoli, F Grossi, L Cancelliere, M Carnelli, F Puccini, G Biancofiore, A Siniscalchi, C Laici, E Mossello, M Torrini, G Pasetti, S Palmese, R Oggioni, V Mangani, S Pini, M Martelli, E Rigo, F Zuccalà, A Cherri, R Spina, I Calamai, N Petrucci, A Caicedo, F Ferri, P Gritti, N Brienza, R Fonnesu, M Dessena, G Fullin, D Saggioro

Subjects
Male, Aging, medicine.medical_specialty, Sarcopenia, medicine.medical_treatment, Socio-culturale, Older person, Logistic regression, Delirium, Older persons, Sarcopenia, Internal medicine, mental disorders, Delirium, Older persons, medicine, Dementia, Humans, LS4_4, Muscle, Skeletal, Pathological, Aged, Rehabilitation, business.industry, Area under the curve, Settore MED/23 - Chirurgia Cardiaca, Skeletal, medicine.disease, Skeletal muscle mass, Cross-Sectional Studies, Italy, Muscle, Female, Geriatrics and Gerontology, medicine.symptom, business
Abstract

Introduction Delirium and sarcopenia are common, although underdiagnosed, geriatric syndromes. Several pathological mechanisms can link delirium and low skeletal muscle mass, but few studies have investigated their association. We aimed to investigate (1) the association between delirium and low skeletal muscle mass and (2) the possible role of calf circumference mass in finding cases with delirium. Methods The analyses were conducted employing the cross-sectional “Delirium Day” initiative, on patient 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes and hospices in Italy in 2017. Delirium was diagnosed as a 4 + score at the 4-AT scale. Low skeletal muscle mass was operationally defined as calf circumference ≤ 34 cm in males and ≤ 33 cm in females. Logistic regression models were used to investigate the association between low skeletal muscle mass and delirium. The discriminative ability of calf circumference was evaluated using non-parametric ROC analyses. Results A sample of 1675 patients was analyzed. In total, 73.6% of participants had low skeletal muscle mass and 24.1% exhibited delirium. Low skeletal muscle mass and delirium showed an independent association (OR: 1.50; 95% CI 1.09–2.08). In the subsample of patients without a diagnosis of dementia, the inclusion of calf circumference in a model based on age and sex significantly improved its discriminative accuracy [area under the curve (AUC) 0.69 vs 0.57, p Discussion and conclusion Low muscle mass is independently associated with delirium. In patients without a previous diagnosis of dementia, calf circumference may help to better identify those who develop delirium.

Published
2022

45. Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator

Author

Cristina Mussini, Alessandro Cozzi-Lepri, Marianna Menozzi, Marianna Meschiari, Erica Franceschini, Carlotta Rogati, Gianluca Cuomo, Andrea Bedini, Vittorio Iadisernia, Sara Volpi, Jovana Milic, Roberto Tonelli, Lucio Brugioni, Antonello Pietrangelo, Massimo Girardis, Andrea Cossarizza, Enrico Clini, Giovanni Guaraldi, Erica Bacca, Vanni Borghi, Giulia Burastero, Federica Carli, Giacomo Ciusa, Luca Corradi, Margherita Di Gaetano, Matteo Faltoni, Giacomo Franceschi, Gabriella Orlando, Francesco Pellegrino, Cinzia Puzzolante, Alessandro Raimondi, Antonella Santoro, Marco Tutone, Dina Yaacoub, Alberto Andreotti, Emanuela Biagioni, Filippo Bondi, Stefano Busani, Giovanni Chierego, Marzia Scotti, Lucia Serio, Caterina Bellinazzi, Rebecca Borella, Sara De Biasi, Anna De Gaetano, Lucia Fidanza, Lara Gibellini, Anna Iannone, Domenico Lo Tartaro, Marco Mattioli, Annamaria Paolini, Rossella Fogliani, Grazia Righini, and Mario Lugli

Subjects
Male, sex differences, 0301 basic medicine, Microbiology (medical), Mediation (statistics), medicine.medical_specialty, medicine.medical_treatment, 030106 microbiology, Context (language use), Pathogenesis, Cohort Studies, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Risk Factors, Internal medicine, Humans, Medicine, 030212 general & internal medicine, Respiratory system, female sex, Survival analysis, Aged, Retrospective Studies, Inflammation, Mechanical ventilation, SARS-CoV-2, business.industry, Absolute risk reduction, COVID-19, General Medicine, Middle Aged, Prognosis, medicine.disease, Respiration, Artificial, Hospitalization, Pneumonia, Infectious Diseases, SARS-CoV-2, COVID-19, female sex, prognosis, inflammation, inflammation, Commentary, Female, prognosis, CRP, business, Cohort study
Abstract

Objectives Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference. Methods This was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death by sex. Interaction was formally tested to compare the risk difference by sex in subsets. Mediation analysis with a binary endpoint IMV or death (yes/no) by end of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted. Results Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO2/FiO2 (254 mmHg vs 191 mmHg; p=0.023). By 28 days from admission, 49.2% (95% CI: 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank p-value Conclusions Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. CRP showed a predominant role to mediate the difference in risk by sex.

Published
2021
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46. Elite professional goalkeepers report high rate of sport resumption after shoulder surgery

Author

Riccardo Ranieri, E. Ceccarelli, Piero Volpi, Alessandro Castagna, Marco Conti, and Raffaele Garofalo

Subjects
Adult, Joint Instability, Male, Shoulder, medicine.medical_specialty, Shoulder surgery, Sports medicine, Shoulders, medicine.medical_treatment, Context (language use), Biceps, Arthroscopy, Rotator Cuff, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Orthopedics and Sports Medicine, Rotator cuff, Retrospective Studies, 030222 orthopedics, Rehabilitation, Shoulder Joint, business.industry, 030229 sport sciences, Return to Sport, medicine.anatomical_structure, Orthopedic surgery, Physical therapy, Surgery, Shoulder Injuries, business
Abstract

The aim of this study is to evaluate the return to sport after surgical treatment of shoulder injuries in professional goalkeepers in relationship with the mechanism of injury and the pattern of related shoulder lesions. Twenty-six shoulders in nineteen elite male professional soccer goalkeepers were retrospectively analyzed considering multiple diseases (instability, rotator cuff, biceps or other tendon injuries). Data was collected for injury modality and context, pathological findings, surgical procedures, time, level of return to sport, and complications. The mechanism of injury was “mild trauma without contact” in 46% of the cases and 54% of injuries happened during training. 11 patients (42%) reported multiple pattern lesions and 9 patients (35%) classic anterior instability lesions. The mean time for return to differentiated training and unrestricted sport activity was 14 and 20.2 weeks, respectively. 15 athletes (62.5%) reported 100% return to sport, 4 (16.7%) to 90%, 1 (4.2%) to 85%, 3 (12.5%) to 80% and 1 athlete to 50%, stopping professional activity. 21% of the cases reported the persistence of some shoulder symptoms. 3 cases experienced a new injury. Patients with classic anterior instability had significantly lower age (30.7 vs 19.8 years, P = 0.001), experienced injury in different context and reported symptoms more frequently compared to multiple lesion patients (4/8 vs 0/10, P = 0.011). Professional elite goalkeepers which required shoulder surgery for different causes demonstrated high-rate level of return to play despite the persistence of mild symptoms. The high frequency of multiple lesions, patients’ characteristics, injury context and mechanism, increase the concern for injuries in overstressed shoulder for this category of sport. IV.

Published
2021
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47. The double life of serotonin metabolites: in the mood for joining neuronal and immune systems

Author

Claudia Volpi and Giada Mondanelli

Subjects
Neurons, 0301 basic medicine, Serotonin, Immunology, Biology, Tryptophan Metabolism, Serotonin pathway, 03 medical and health sciences, Metabolic pathway, Molecular network, 030104 developmental biology, 0302 clinical medicine, Mood, Immune system, Neuroimmune system, Animals, Humans, Immunology and Allergy, Neuroscience, 030215 immunology
Abstract

Neuroimmune system is nowadays considered as one complex, but unique example of coordination between cellular and molecular networks, only apparently segregated, but strictly collaborating for the maintenance of body integrity. Too often, serotonin and its metabolites have been considered merely as neurotransmitters, when they have multiple effects spreading from the modulation of mood and behavioral processes to the regulation of a wide range of physiologic and pathophysiologic processes in most human organs, not least the immune response. The purpose of this review is to highlight the importance of metabolites generated along the serotonin pathway in the constant dialogue between neuroendocrine and immune systems; moreover, we would like to point out that the molecules produced in the two main routes of tryptophan metabolism are involved in a loop of self-regulation aimed at maintaining the equilibrium between these two metabolic pathways in the neuroimmune system, in both physiologic and pathologic conditions.

Published
2021
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48. Expanding the clinical and neuroimaging features of post-varicella arteriopathy of childhood

Author

Bertamino, M., Signa, S., Veneruso, M., Prato, G., Caorsi, R., Losurdo, G., Teutonico, F., Esposito, S., Formica, F., Tovaglieri, N., Nagel, M. A., Amico, G., Zanetti, A., Tortora, D., Rossi, A., Moretti, P., Gattorno, M., Ravelli, A., Severino, M., Di Rocco, M., Cornaglia, S., Tacchino, C., Ceccherini, I., Banov, L., Nobili, L., Palmieri, A., Pavanello, M., Ramenghi, L., Ronchetti, A., Uccella, S., and Volpi, S.

Subjects
Male, Pediatrics, medicine.medical_specialty, Neurology, Post varicella stroke, Late recurrence, Vasculopathy, Neuroimaging, Disease, 03 medical and health sciences, symbols.namesake, Chickenpox, 0302 clinical medicine, Recurrence, Risk Factors, Vessel wall imaging, medicine, Humans, Pediatric stroke, 030212 general & internal medicine, Preschool, Child, Children, Stroke, Fisher's exact test, Neuroradiology, First episode, Arterial ischemic stroke, Child, Preschool, Infant, business.industry, medicine.disease, Rash, symbols, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Post-varicella arterial ischemic stroke (AIS) is considered an uncommon cause of pediatric stroke that is considered a self-limiting, monophasic disease. However, in a subset of patients, disease recurs; the prevalence of vasculopathy or AIS recurrence, severity of clinical outcomes, and standardized therapies have not been well characterized. Herein, we determined the clinical-neuroradiological features, long-term evolution, and relationship between acute phase treatment and vasculopathy recurrence in a pediatric population with post-varicella AIS. Clinical, laboratory, and neuroradiological features of 22 children with post-varicella AIS between 2010 and 2019 (16 males, mean age at stroke 4 years, range 1.7–10) were reviewed. Statistical analyses were performed using χ2 and Fisher exact tests. Of the 22 cases, mean time from varicella to stroke was 4.5 months with 3 cases presenting more than 12 months after rash; 21 (95%) were not vaccinated for varicella; 3 (13.6%) had posterior circulation involvement; and 5 (22.7%) had AIS or vasculopathy recurrence, of which 4 recurred 6.1 months to 2.8 years after initial clinical onset. Recurrence was associated with lack of antiviral treatment during the first episode (p = 0.02). Post-varicella AIS can occur months after rash making diagnosis challenging. Because recurrent vasculopathy was seen predominantly in cases not treated with antiviral therapy during initial presentation, it is important to rapidly diagnose post-varicella AIS through clinical criteria and/or virological testing then treat with antivirals to prevent recurrence.

Published
2021
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49. Detection of Tumor DNA in Human Plasma with a Functional PLL-Based Surface Layer and Plasmonic Biosensing

Author

Stefano Volpi, Andrea Rozzi, Patrizio Giacomini, Almudena Martí, Matteo Allegretti, Giuseppe Spoto, Noemi Bellassai, Jurriaan Huskens, Roberto Corradini, Roberta D'Agata, Molecular Nanofabrication, and MESA+ Institute

Subjects
Analyte, UT-Hybrid-D, Bioengineering, 02 engineering and technology, 01 natural sciences, Article, plasmonics, law.invention, chemistry.chemical_compound, law, Neoplasms, cancer diagnosis, Humans, Surface plasmon resonance, Liquid biopsy, Instrumentation, Polymerase chain reaction, Plasmon, poly-l-lysine, Fluid Flow and Transfer Processes, peptide nucleic acids, Peptide nucleic acid, Lysine, Process Chemistry and Technology, 010401 analytical chemistry, DNA, 021001 nanoscience & nanotechnology, 3. Good health, 0104 chemical sciences, chemistry, poly- l -lysine, Biophysics, 0210 nano-technology, Biosensor, surface plasmon resonance
Abstract

Standard protocols for the analysis of circulating tumor DNA (ctDNA) include the isolation of DNA from the patient's plasma and its amplification and analysis in buffered solutions. The application of such protocols is hampered by several factors, including the complexity and time-constrained preanalytical procedures, risks for sample contamination, extended analysis time, and assay costs. A recently introduced nanoparticle-enhanced surface plasmon resonance imaging-based assay has been shown to simplify procedures for the direct detection of tumor DNA in the patient's plasma, greatly simplifying the cumbersome preanalytical phase. To further simplify the protocol, a new dual-functional low-fouling poly-l-lysine (PLL)-based surface layer has been introduced that is described herein. The new PLL-based layer includes a densely immobilized CEEEEE oligopeptide to create a charge-balanced system preventing the nonspecific adsorption of plasma components on the sensor surface. The layer also comprises sparsely attached peptide nucleic acid probes complementary to the sequence of circulating DNA, e.g., the analyte that has to be captured in the plasma from cancer patients. We thoroughly investigated the contribution of each component of the dual-functional polymer to the antifouling properties of the surface layer. The low-fouling property of the new surface layer allowed us to detect wild-type and KRAS p.G12D-mutated DNA in human plasma at the attomolar level (∼2.5 aM) and KRAS p.G13D-mutated tumor DNA in liquid biopsy from a cancer patient with almost no preanalytical treatment of the patient's plasma, no need to isolate DNA from plasma, and without PCR amplification of the target sequence.

Published
2021
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50. The real-time intraoperative guidance of the new HIFU Focal-One® platform allows to minimize the perioperative adverse events in salvage setting

Author

Enrico Checcucci, Francesco Porpiglia, Gabriele Volpi, Federico Piramide, G. Belli, Cristian Fiori, Stefano De Luca, Alessandra Mosca, Pasquale Rescigno, Andrea Galla, P. Verri, Daniele Amparore, Matteo Manfredi, Diletta Garrou, Filippo Russo, and Carlo Poti

Subjects
medicine.medical_specialty, Urinary system, media_common.quotation_subject, 030232 urology & nephrology, Salvage therapy, Urination, Article, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Quality of life, Internal Medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Adverse effect, media_common, Intraoperative guidance, Salvage Therapy, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, General Medicine, Perioperative, Surgery, Treatment Outcome, 030220 oncology & carcinogenesis, Quality of Life, High-Intensity Focused Ultrasound Ablation, Neoplasm Recurrence, Local, business
Abstract

PURPOSE: To assess the use of the new Focal-One(®) HIFU platform in salvage setting to evaluate the occurrence of postoperative complications. METHODS: Patients who underwent salvage HIFU (sHIFU) with Focal-One(®) platform were enrolled prospectively (Candiolo cancer institute—FPO IRCCS; registry number: 258/2018). Perioperative and postoperative outcomes (in terms of oncological and functional ones) were recorded during the first year of follow-up. In particular postoperative complications were classified according to Clavien–Dindo system. RESULTS: 20 patients were enrolled. No grade 3 complications were recorded. Referring to grade 2 complications, eight patients reported urgency after 3 months of follow-up, and in 4 cases, a low urinary tract infection occurred. Evaluating the impact of sHIFU on patients’ sexual potency, micturition and quality of life, no significant deterioration was recorded during the follow-up as proven using the ANOVA analysis for repeated measurements. Only two patient had a biochemical failure after 12 months of follow-up. CONCLUSIONS: The real-time intraoperative guidance with Focal-One(®) platform, allows a continuous monitoring and tailoring of the treatment, with a minimization of the adverse events even in a salvage setting. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40477-021-00594-8.

Published
2021
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