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  1. Article ; Online: Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C.

    Giryes, Sami / McGonagle, Dennis

    Autoimmunity reviews

    2022  Volume 22, Issue 2, Page(s) 103240

    Abstract: The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we ... ...

    Abstract The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we highlight common age-related extravascular epicardial microanatomical and immunological factors that might culminate in CAA expression in both MIS-C and KD. Specifically, the coronary vasa vasorum originates outside the major coronary arteries. Widespread inflammation in the epicardial interstitial compartment in shared between KD and MIS-C. Age-related changes in the neonatal and immature coronary vasculature including the impact of coronary artery biomechanical factors including coronary vessel calibre, age-related vessel distensibility, flow, and vessel neurovascular innervation may explain the decreasing CAA frequency from neonates to older children and the virtual absence of CAA in young adults with the MIS-C phenotype. Other KD and MIS-C features including mucocutaneous disease with keratinocyte-related immunopathology corroborate that disease phenotypes are centrally influenced by inflammation originating outside vessel walls but a potential role for primary coronary artery vascular wall inflammation cannot be excluded. Hence, common extravascular originating tissue-specific responses to aetiologically diverse triggers including superantigens may lead to widespread interstitial tissue inflammation characteristically manifesting as CAA development, especially in younger subjects. Given that CAA is virtually absent in adults, further studies are needed to ascertain whether epicardial interstitial inflammation may impact on both coronary artery physiology and cardiac conduction tissue and contribute to cardiovascular disease- a hitherto unappreciated consideration.
    MeSH term(s) Humans ; Mucocutaneous Lymph Node Syndrome/complications ; Coronary Vessels/pathology ; Coronary Aneurysm/complications ; Coronary Aneurysm/pathology ; Inflammation/pathology
    Language English
    Publishing date 2022-12-07
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 2144145-5
    ISSN 1873-0183 ; 1568-9972
    ISSN (online) 1873-0183
    ISSN 1568-9972
    DOI 10.1016/j.autrev.2022.103240
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  2. Article ; Online: Clinical Images: The appearance of scurvy on magnetic resonance imaging.

    Giryes, Sami / Militianu, Daniela / Braun-Moscovici, Yolanda

    Arthritis & rheumatology (Hoboken, N.J.)

    2021  Volume 74, Issue 2, Page(s) 222

    MeSH term(s) Adult ; Female ; Humans ; Magnetic Resonance Imaging ; Scurvy/diagnostic imaging
    Language English
    Publishing date 2021-12-21
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 2756371-6
    ISSN 2326-5205 ; 2326-5191
    ISSN (online) 2326-5205
    ISSN 2326-5191
    DOI 10.1002/art.41932
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  3. Article: Neuropathic Arthropathy of a Knee Joint: A Case Report.

    Giryes, Sami / Militianu, Daniella / Balbir-Gurman, Alexandra

    The Israel Medical Association journal : IMAJ

    2020  Volume 22, Issue 10, Page(s) 650–651

    MeSH term(s) Arthropathy, Neurogenic/diagnosis ; Arthropathy, Neurogenic/etiology ; Diabetes Mellitus, Type 1/complications ; Female ; Humans ; Knee Joint/physiopathology ; Young Adult
    Language English
    Publishing date 2020-10-03
    Publishing country Israel
    Document type Case Reports ; Journal Article
    ZDB-ID 2008291-5
    ISSN 1565-1088 ; 0021-2180
    ISSN 1565-1088 ; 0021-2180
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  4. Article ; Online: COVID-19 Vasculitis and vasculopathy-Distinct immunopathology emerging from the close juxtaposition of Type II Pneumocytes and Pulmonary Endothelial Cells.

    Giryes, Sami / Bragazzi, Nicola Luigi / Bridgewood, Charles / De Marco, Gabriele / McGonagle, Dennis

    Seminars in immunopathology

    2022  Volume 44, Issue 3, Page(s) 375–390

    Abstract: The SARS-CoV-2 virus ACE-2 receptor utilization for cellular entry and the defined ACE-2 receptor role in cardiovascular medicine hinted at dysregulated endothelial function or even direct viral endotheliitis as the key driver of severe COVID-19 vascular ...

    Abstract The SARS-CoV-2 virus ACE-2 receptor utilization for cellular entry and the defined ACE-2 receptor role in cardiovascular medicine hinted at dysregulated endothelial function or even direct viral endotheliitis as the key driver of severe COVID-19 vascular immunopathology including reports of vasculitis. In this article, we critically review COVID-19 immunopathology from the vasculitis perspective and highlight the non-infectious nature of vascular endothelial involvement in severe COVID-19. Whilst COVID-19 lung disease pathological changes included juxta-capillary and vascular macrophage and lymphocytic infiltration typical of vasculitis, we review the evidence reflecting that such "vasculitis" reflects an extension of pneumonic inflammatory pathology to encompass these thin-walled vessels. Definitive, extrapulmonary clinically discernible vasculitis including cutaneous and cardiac vasculitis also emerged- namely a dysregulated interferon expression or "COVID toes" and an ill-defined systemic Kawasaki-like disease. These two latter genuine vasculitis pathologies were not associated with severe COVID-19 pneumonia. This was distinct from cutaneous vasculitis in severe COVID-19 that demonstrated pauci-immune infiltrates and prominent immunothrombosis that appears to represent a novel immunothrombotic vasculitis mimic contributed to by RNAaemia or potentially diffuse pulmonary venous tree thrombosis with systemic embolization with small arteriolar territory occlusion, although the latter remains unproven. Herein, we also performed a systematic literature review of COVID-19 vasculitis and reports of post-SARS-CoV-2 vaccination related vasculitis with respect to the commonly classified pre-COVID vasculitis groupings. Across the vasculitis spectrum, we noted that Goodpasture's syndrome was rarely linked to natural SARS-CoV-2 infection but not vaccines. Both the genuine vasculitis in the COVID-19 era and the proposed vasculitis mimic should advance the understanding of both pulmonary and systemic vascular immunopathology.
    MeSH term(s) Alveolar Epithelial Cells ; COVID-19 ; COVID-19 Vaccines ; Endothelial Cells/pathology ; Endothelium, Vascular ; Humans ; SARS-CoV-2 ; Vasculitis/etiology ; Vasculitis/pathology
    Chemical Substances COVID-19 Vaccines
    Language English
    Publishing date 2022-04-12
    Publishing country Germany
    Document type Journal Article ; Review ; Systematic Review
    ZDB-ID 2316828-6
    ISSN 1863-2300 ; 1863-2297
    ISSN (online) 1863-2300
    ISSN 1863-2297
    DOI 10.1007/s00281-022-00928-6
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  5. Article: Prediction of Chemotherapy-Induced Peripheral Neuropathy in Patients with Lymphoma and Myeloma: the Roles of Brain-Derived Neurotropic Factor Protein Levels and A Gene Polymorphism.

    Azoulay, David / Giryes, Sami / Nasser, Roni / Sharon, Rivka / Horowitz, Netanel A

    Journal of clinical neurology (Seoul, Korea)

    2019  Volume 15, Issue 4, Page(s) 511–516

    Abstract: Background and purpose: Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that plays an essential role in the maintenance of the nervous system. We have evaluated the peripheral blood protein levels of BDNF and the valine-to- ... ...

    Abstract Background and purpose: Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that plays an essential role in the maintenance of the nervous system. We have evaluated the peripheral blood protein levels of BDNF and the valine-to-methionine substitution at codon 66 (Val66Met) single-nucleotide polymorphism (SNP) as potential biomarkers for the early recognition of chemotherapy-induced peripheral neuropathy (CIPN) in non-Hodgkin lymphoma and multiple myeloma patients.
    Methods: CIPN was assessed in 45 patients at the diagnosis and during vincristine or bortezomib-based therapy using objective [reduced version of the Total Neuropathy Score (TNSr)] and subjective (FACT-GOG-NTx) tools. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) questionnaire. BDNF protein levels and the Val66Met SNP were determined using ELISA and Sanger sequencing.
    Results: The pretreatment BDNF protein level was inversely correlated with the maximum TNSr, FACT-GOG-NTx, and PHQ-9 scores in both genotypes. BDNF patients with the Val/Val genotype demonstrated significantly higher maximum FACT-GOG-NTx and PHQ-9 scores than those with the Val/Met and Met/Met genotypes (Met-BNDF carriers). Correlations between PHQ-9 and TNSr score were found only in Met-BDNF carriers, suggesting that peripheral neuropathy and depression coincide in Met-BDNF carriers.
    Conclusions: Determining the BDNF protein levels before initiating chemotherapy might be a useful tool for CIPN risk assessment and preemptive dose modification. The present data should be validated in larger studies that include other neurotoxic agents.
    Language English
    Publishing date 2019-10-07
    Publishing country Korea (South)
    Document type Journal Article
    ZDB-ID 2500489-X
    ISSN 2005-5013 ; 1738-6586
    ISSN (online) 2005-5013
    ISSN 1738-6586
    DOI 10.3988/jcn.2019.15.4.511
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  6. Article ; Online: A role for neutrophils in early enthesitis in spondyloarthritis.

    Stavre, Zheni / Bridgewood, Charles / Zhou, Qiao / Maeda, Yukiko / Huang, Ting-Ting / Karman, Jozsef / Khan, Almas / Giryes, Sami / Sharif, Kassem / McGonagle, Dennis / Gravallese, Ellen M

    Arthritis research & therapy

    2022  Volume 24, Issue 1, Page(s) 24

    Abstract: Background: Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of ... ...

    Abstract Background: Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses.
    Methods: Early inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue. Whole transcriptome analysis was carried out using Affymetrix gene array MTA 1.0, and data was analyzed via IPA. We further isolated neutrophils from human peri-entheseal bone and fibroblasts from entheseal soft tissue obtained from the axial skeleton of healthy patients and determined the response of these cells to fungal adjuvant.
    Results: Following fungal adjuvant administration, early axial and peripheral inflammation in SKG mice was characterized by prominent neutrophilic entheseal inflammation. Expression of transcripts arising from neutrophils include abundant mRNA for the alarmins S100A8 and S100A9. In normal human axial entheses, neutrophils were present in the peri-entheseal bone. Upon fungal stimulation in vitro, human neutrophils produced IL-23 protein, while isolated human entheseal fibroblasts produced chemokines, including IL-8, important in the recruitment of neutrophils.
    Conclusion: Neutrophils with inducible IL-23 production are present in uninflamed human entheseal sites, and neutrophils are prominent in early murine spondyloarthritis-related enthesitis. We propose a role for neutrophils in the early development of enthesitis.
    MeSH term(s) Animals ; Bone and Bones/pathology ; Enthesopathy ; Humans ; Mice ; Neutrophils/pathology ; Spondylarthritis/pathology
    Language English
    Publishing date 2022-01-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2107602-9
    ISSN 1478-6362 ; 1478-6354
    ISSN (online) 1478-6362
    ISSN 1478-6354
    DOI 10.1186/s13075-021-02693-7
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  7. Article ; Online: T Helper 2 IL-4/IL-13 Dual Blockade with Dupilumab Is Linked to Some Emergent T Helper 17‒Type Diseases, Including Seronegative Arthritis and Enthesitis/Enthesopathy, but Not to Humoral Autoimmune Diseases.

    Bridgewood, Charlie / Wittmann, Miriam / Macleod, Tom / Watad, Abdulla / Newton, Darren / Bhan, Kanchan / Amital, Howard / Damiani, Giovanni / Giryes, Sami / Bragazzi, Nicola Luigi / McGonagle, Dennis

    The Journal of investigative dermatology

    2022  Volume 142, Issue 10, Page(s) 2660–2667

    Abstract: Dupilumab, an IL-4/IL-13 receptor blocker, has been linked to emergent seronegative inflammatory arthritis and psoriasis that form part of the spondyloarthropathy spectrum. We systematically investigated patterns of immune disorders, including ... ...

    Abstract Dupilumab, an IL-4/IL-13 receptor blocker, has been linked to emergent seronegative inflammatory arthritis and psoriasis that form part of the spondyloarthropathy spectrum. We systematically investigated patterns of immune disorders, including predominantly T helper 17‒(spondyloarthropathy pattern) and T helper 2‒mediated disorders and humoral autoimmune pattern diseases, using VigiBase, the World Health Organization's global pharmacovigilance of adverse drug reactions. Several bioinformatics databases and repositories were mined to couple dupilumab-related immunopharmacovigilance with molecular cascades relevant to reported findings. A total of 37,848 dupilumab adverse drug reaction cases were reported, with skin, eye, and musculoskeletal systems most affected. Seronegative arthritis (OR = 9.61), psoriasis (OR = 1.48), enthesitis/enthesopathy (OR = 12.65), and iridocyclitis (OR = 3.77) were highly associated. However, ankylosing spondylitis and inflammatory bowel disease were not conclusively associated. Overall, classic polygenic humoral‒mediated autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus were not associated with dupilumab use. Pathway analysis identified several biological pathways potentially involved in dupilumab‒associated adverse drug reactions, including the fibroblast GF receptor (in particular, FGFR2) pathway. MicroRNAs analysis revealed the potential involvement of hsa-miR-21-5p and hsa-miR-335-5p. In conclusion, IL-4/IL-13 blockers are not unexpectedly protective against humoral autoimmune diseases but dynamically skew immune responses toward some IL-23/IL-17 cytokine pathway‒related diseases. IL-4/13 axis also plays a role in homeostatic tissue repair and we noted evidence for a link with ocular and arterial pathology.
    MeSH term(s) Antibodies, Monoclonal, Humanized ; Arthritis, Rheumatoid ; Autoimmune Diseases/drug therapy ; Drug-Related Side Effects and Adverse Reactions ; Enthesopathy ; Humans ; Interleukin-13/genetics ; Interleukin-17/metabolism ; Interleukin-23/metabolism ; Interleukin-4/genetics ; MicroRNAs ; Psoriasis/drug therapy ; Receptors, Interleukin-13 ; Spondylarthropathies
    Chemical Substances Antibodies, Monoclonal, Humanized ; Interleukin-13 ; Interleukin-17 ; Interleukin-23 ; MicroRNAs ; Receptors, Interleukin-13 ; Interleukin-4 (207137-56-2) ; dupilumab (420K487FSG)
    Language English
    Publishing date 2022-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2022.03.013
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  8. Article ; Online: Sex difference in the association between malnutrition and hypoglycemia in hospitalized patients.

    Gur Arieh, Noa / Adler, Henriett / Khanimov, Israel / Giryes, Sami / Ditch, Meital / Felner Burg, Noa / Boaz, Mona / Shimonov, Mordechai / Leibovitz, Eyal

    Minerva endocrinology

    2020  Volume 46, Issue 3, Page(s) 303–308

    Abstract: Background: The aim of this paper was to examine the difference between males and females regarding association between malnutrition risk and hypoglycemia through a sub-analysis of a cross-sectional study of newly admitted patients to internal medicine ... ...

    Abstract Background: The aim of this paper was to examine the difference between males and females regarding association between malnutrition risk and hypoglycemia through a sub-analysis of a cross-sectional study of newly admitted patients to internal medicine departments.
    Methods: Malnutrition risk, assessed with Nutritional Risk Screening 2002 (NRS2002), and serum albumin were measured upon admission. Logistic regression was applied to men and women separately, to test the effect of malnutrition and hypoalbuminemia on incidence of hypoglycemia.
    Results: Included were 1186 patients (50.4% males, 39.2% with positive NRS2002). Rate of positive NRS2002 was similar across sexes (36.5% vs. 41.2% in males and females respectively, P=0.204). Among females, NRS2002 was associated with higher incidence of hypoglycemia (9.5% vs. 2.4% in NRS2002 negative females, P<0.001). Among males, no such difference was noted (9.2% compared to 7.1% in NRS2002 positive and negative males respectively, P=0.520). The weight loss/decreased food intake criterion of the NRS2002 was significantly higher in the hypoglycemic group within females (P=0.03). Logistic regression showed that serum albumin was inversely associated with hypoglycemia in both females (OR 0.477, 95% CI 0.282-0.806, P=0.006) and males (OR 0.532, 95% CI 0.355-0.795, P=0.002). However, increased malnutrition risk was associated with hypoglycemia only among females (OR 2.007, 95% CI 1.058-3.809, P=0.033). Diabetes status was associated with hypoglycemia (OR 1.907, 95% CI 1.056-3.445, P=0.032) only in males; this association did not occur in females.
    Conclusions: Malnutrition risk, as measured by the NRS2002, is associated with significantly increased incidence of hypoglycemia in women alone. Females who lose weight prior to hospitalization have an increased risk to develop hypoglycemia.
    MeSH term(s) Cross-Sectional Studies ; Female ; Humans ; Hypoglycemia/epidemiology ; Male ; Malnutrition/epidemiology ; Nutrition Assessment ; Nutritional Status ; Sex Characteristics
    Language English
    Publishing date 2020-10-02
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 3062786-2
    ISSN 2724-6116
    ISSN (online) 2724-6116
    DOI 10.23736/S2724-6507.20.03143-0
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  9. Article ; Online: Prediction of Hypoglycemia During Admission of Non-Critically Ill Patients: Results from the MENU Study.

    Khanimov, Israel / Ditch, Meital / Adler, Henriett / Giryes, Sami / Felner Burg, Noa / Boaz, Mona / Leibovitz, Eyal

    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme

    2020  Volume 52, Issue 9, Page(s) 660–668

    Abstract: The objective of the work was to study admission parameters associated with an increased incidence of hypoglycemia during hospitalization of non-critically ill patients. Included in this cross-sectional study were patients admitted to internal medicine ... ...

    Abstract The objective of the work was to study admission parameters associated with an increased incidence of hypoglycemia during hospitalization of non-critically ill patients. Included in this cross-sectional study were patients admitted to internal medicine units. The Nutritional Risk Screening 2002 (NRS2002) was used for nutritional screening. Data recorded included admission serum albumin (ASA) and all glucose measurements obtained by the institutional blood glucose monitoring system. Neither of these are included in the NRS2002 metrics. Hypoalbuminemia was defined as ASA<3.5 g/dl. Patients were categorized as hypoglycemic if they had at least one documented glucose≤70 mg/dl during the hospitalization period. Included were 1342 patients [median age 75 years (IQR 61-84), 51.3% male, 52.5% with diabetes mellitus, (DM)], who were screened during three distinct periods of time from 2011-2018. The incidence of hypoglycemia was 10.8% with higher rates among DM patients (14.6 vs. 6.6%, p<0.001). Hypoglycemia incidence was negatively associated with ASA regardless of DM status. Multivariable regression showed that ASA (OR 0.550 per g/dl, 95% CI 0.387-0.781, p=0.001) and positive NRS2002 (OR 1.625, 95% CI 1.072-2.465, p=0.022) were significantly associated with hypoglycemia. The addition of hypoalbuminemia status to the NRS2002 tool improved the overall sensitivity from 0.55 to 0.71, but reduced specificity from 0.63 to 0.46. The negative predictive value was 0.93. Our data suggest that the combination of positive malnutrition screen and hypoalbuminemia upon admission are independently associated with the incidence of hypoglycemia among non-critically ill patients, regardless of diabetes mellitus status.
    MeSH term(s) Aged ; Aged, 80 and over ; Blood Glucose/analysis ; Cross-Sectional Studies ; Diabetes Mellitus/physiopathology ; Female ; Hospitalization/statistics & numerical data ; Humans ; Hypoglycemia/blood ; Hypoglycemia/diagnosis ; Hypoglycemia/epidemiology ; Hypoglycemia/etiology ; Incidence ; Israel/epidemiology ; Male ; Malnutrition/complications ; Middle Aged ; Nutrition Assessment ; Risk Factors
    Chemical Substances Blood Glucose
    Language English
    Publishing date 2020-07-06
    Publishing country Germany
    Document type Clinical Trial ; Journal Article ; Observational Study
    ZDB-ID 80125-2
    ISSN 1439-4286 ; 0018-5043
    ISSN (online) 1439-4286
    ISSN 0018-5043
    DOI 10.1055/a-1181-8781
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  10. Article ; Online: Malnutrition risk is associated with hypoglycemia among general population admitted to internal medicine units. Results from the MENU study.

    Leibovitz, Eyal / Adler, Henriett / Giryes, Sami / Ditch, Meital / Burg, Noa Felner / Boaz, Mona

    European journal of clinical nutrition

    2018  Volume 72, Issue 6, Page(s) 888–893

    Abstract: Background/objectives: To examine the association between increased malnutrition risk upon admission, and the incidence of hypoglycemia among adult patients admitted to internal medicine units in Israel.: Subjects/methods: This was a cross-sectional ... ...

    Abstract Background/objectives: To examine the association between increased malnutrition risk upon admission, and the incidence of hypoglycemia among adult patients admitted to internal medicine units in Israel.
    Subjects/methods: This was a cross-sectional study, and included were all adult patients admitted to internal medicine units, regardless of reason for admission. The NRS2002 was used to for nutritional screening. All glucose measurements were obtained using an institutional blood glucose-monitoring system, which consisted of a point of care, automated glucometer, and an interactive database. Patients were categorized as hypoglycemic if they had at least one documented hypoglycemia (= <70 mg/dL) event during the hospitalization period. Blood chemistry measured at admission was also recorded.
    Results: Included were 876 patients (mean age 70.0 ± 17.3, 50.6% were males). Rate of positive malnutrition screen was 39.7% of the population. A total of 5.4% of the study population had at least one hypoglycemic event during hospitalization. Rate of diabetes mellitus did not differ between patients with or without hypoglycemia. A greater proportion of patients with hypoglycemia were at increased malnutrition risk compared to patients without documented hypoglycemic events (56.8% vs. 38.9%, p = 0.018). Patients who had hypoglycemia had higher NRS2002 scores for pre-hospitalization unintentional weight loss and reduced food consumed. In logistic regression analysis, increased malnutrition risk was associated with hypoglycemia occurrence (OR 1.982, 95% confidence interval 1.056-3.718, p = 0.033). Age, sex, and diabetes mellitus status did not affect the rate of hypoglycemia.
    Conclusions: Our data suggest increased malnutrition risk as measured by the NRS2002 almost doubled the risk for hypoglycemia during the hospitalization.
    MeSH term(s) Aged ; Aged, 80 and over ; Biomarkers/blood ; Blood Glucose/metabolism ; Cross-Sectional Studies ; Female ; Hospitalization ; Humans ; Hypoglycemia/complications ; Hypoglycemia/epidemiology ; Incidence ; Israel/epidemiology ; Male ; Malnutrition/complications ; Malnutrition/epidemiology ; Middle Aged ; Risk Factors
    Chemical Substances Biomarkers ; Blood Glucose
    Language English
    Publishing date 2018-03-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 639358-5
    ISSN 1476-5640 ; 0954-3007
    ISSN (online) 1476-5640
    ISSN 0954-3007
    DOI 10.1038/s41430-018-0143-9
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