Heart valve disease in primary antiphospholipid syndrome.

OBJECTIVES: Antiphospholipid syndrome (APS)-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS associated HVD. METHODS: In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group). RESULTS: pAPS-HVD patients had more cerebrovascular events 56.3% vs 25% (p= 0.005) and livedo reticularis 24.2% vs 7.8% (p= 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, p= 0.034), recurrent thrombosis (33.3% vs 4.7%, p< 0.001), and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-B2GPI-IgG. [84.8% vs 63.2% (p= 0.034)], anti-cardiolipin IgG [90.9% vs. 64.8% (p= 0.005)] and triple positive aPL [75.8% vs 56.5% (p= 0.047)] were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis. CONCLUSION: pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as with specific serology namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients.

Severe and fatal COVID-19 is characterised by increased circulating glucagon like peptide 1 and procalcitonin modulated by type 2 diabetes.

AIMS: Endotoxemia commonly occurs in severe and fatal COVID-19, suggesting that concomitant bacterial stimuli may amplify the innate immune response induced by SARS-CoV-2. We previously demonstrated that the endogenous glucagon like peptide 1 (GLP-1) system in conjunction with increased procalcitonin (PCT) is hyperactivated in patients with severe Gram-negative sepsis and modulated by type 2 diabetes (T2D). We aimed to determine the association of COVID-19 severity with endogenous GLP-1 activation upregulated by increased specific pro-inflammatory innate immune response in patients with and without T2D. MATERIALS AND METHODS: Plasma levels of total GLP-1, IL-6, and PCT were estimated on admission and during hospitalisation in 61 patients (17 with T2D) with non-severe and severe COVID-19. RESULTS: COVID-19 patients demonstrated ten-fold increase of IL-6 levels regardless of disease severity. Increased admission GLP-1 levels (p = 0.03) accompanied by two-fold increased PCT were found in severe as compared with non-severe patients. Moreover, GLP-1 and PCT levels were significantly increased in non-survived as compared with survived patients at admission (p = 0.01 and p = 0.001, respectively) and at 5 to 6 days of hospitalisation (p = 0.05). Both non-diabetic and T2D patients demonstrated a positive correlation between GLP-1 and PCT response (r = 0.33, p = 0.03, and r = 0.54, p = 0.03, respectively), but the intensity of this joint pro-inflammatory/GLP-1 response was modulated by T2D. In addition, hypoxaemia down-regulated GLP-1 response only in T2D patients with bilateral lung damage. CONCLUSIONS: The persistent joint increase of endogenous GLP-1 and PCT in severe and fatal COVID-19 suggests a role of concomitant bacterial infection in disease exacerbation. Early elevation of endogenous GLP-1 may serve as a new biomarker of COVID-19 severity and fatal outcome.

Long Term Follow up of Patients With Primary Obstetric Antiphospholipid Syndrome.

Introduction: Primary obstetric antiphospholipid syndrome (OAPS) is defined by specific morbidities and/or losses of pregnancy in the presence of persistent antiphospholipid antibodies (aPL). This variant of APS is usually treated during pregnancy and the post-partum period. Data on occurrence of thrombotic event during long term follow-up of OAPS patients is limited. Methods: A multi-centre retrospectively cohort of female patients with primary APS (pAPS) was assembled during 2004-2019. Patients were grouped according to disease presentation as pure OAPS or thrombotic APS (tAPS) for those presenting with thrombosis. Clinical and serological data were compared between groups. Results: Of 219 pAPS female patients 67 (30.6%) were diagnosed with OAPS and 152 (69.4%) with tAPS. During >10 years of follow-up 24/67 (35.8%) OAPS and 71/152 (50%) tAPS suffered a new thrombotic event (p = 0.06), while obstetric morbidity was more likely in the OAPS group (31.3 vs. 10.5%, p < 0.001) respectively. Among patients with OAPS at presentation heart valve disease and the presence of ANA were related to thrombosis following diagnosis (25 vs. 4.7%, p = 0.02; and 45.8 vs. 20.8%, p = 0.04 respectively). Conclusion: Thrombotic event following diagnosis were common among female patients with pAPS regardless of disease presentation. Heart valve disease and ANA positivity may be risk factors for thrombosis during follow-up of patients presenting with pure OAPS.

Patterns of Recurrent Thrombosis in Primary Antiphospholipid Syndrome-Multicenter, Real-Life Long-Term Follow-Up.

Background: Antiphospholipid syndrome (APS) is an acquired hypercoagulable condition associated with antiphospholipid antibody (aPL) presence. Data on re-thrombosis following APS-diagnosis are limited. Methods: This is a retrospective analysis of new thrombotic events among primary APS (pAPS) patients followed for up to 15 years in three medical centers in Israel. Results: Among 312 primary-APS patients, 143 (46%) had new thrombotic event classified to three patterns: (1) Arterial-associated with heart valve disease (OR 7.24, 95% C.I. 2.26-24.6), hypertension (OR 3, 95% C.I. 1.44-6.25), elevated anti-B2-GPI IgM (OR 1.04, 95% C.I. 0.996-1.08), arterial thrombosis at presentation (OR 1.74 95% C.I. 0.992-3.26), and older age (41 vs. 34 years, p < 0.001). (2) Venous-linked with venous thrombosis at presentation (OR 12.9, 95% C.I. 5.27-31.6, p < 0.001), heart valve disease (OR 9.81 95% C.I. 1.82-52.9, p = 0.018), aGAPSS (OR 1.15 95% C.I. 1.02-1.29), and younger age (31 vs. 36.5 years, p = 0.001); and (3) Combined pattern-associated with heart valve disease (OR 40.5 95% C.I. 7.7-212) and pulmonary embolism (OR 7.47 95% C.I. 1.96-28.5). A 4th variant "the Breakthrough pattern" defined by re-thrombosis despite prophylactic therapy was observed in 100/143 (70%) patients and linked with heart valve disease (OR 8. 95% C.I. 2.43-26.3), venous thrombosis at presentation (OR 2.61 95% C.I. 1.47-4.66), leg ulcers (OR 12.2, 95% C.I. 1.4-107), hypertension (OR 1.99, 95% C.I. 0.92-4.34), and higher aGAPSS (OR 1.08, 95% C.I. 0.99-1.18). Conclusion: In this real-life observation, re-thrombosis was common among pAPS patients including in those recommended to receive prophylactic therapy. Different patterns of recurrence were identified and linked with presenting symptoms, specific serological markers, APS manifestations, and comorbidities. Studies that will address interventions to prevent recurrences of APS-related events are needed.

Ethnicity and Antiphospholipid Syndrome in Israel.

OBJECTIVE: Antiphospholipid syndrome (APS) is an acquired coagulopathy associated with the presence of antiphospholipid antibodies. Whether ethnicity modulates APS clinical course is not known. The aim of our study was to assess the interplay of ethnicity and APS in Israel. METHODS: We retrospectively evaluated the ethnic distribution of APS patients from 3 medical centers in Israel compared to the general population. Ethnic groups were defined according to the Israeli Bureau of Statistics as Ashkenazi (European), former Union of Soviet Socialist Republics (USSR), North African, Asian (West Asia, Greece, and Turkey), Israeli Arab individuals, and others. RESULTS: Our cohort included 382 patients. The prevalence of Ashkenazi and Asian ethnicities was more pronounced (33% versus 12.8% and 15.4% versus 7.7%, respectively; P < 0.001), while Israeli Arabs were less represented (5.2% versus 31.1%; P < 0.001) relative to their part in the general population. Arab patients were younger at presentation (mean ± SD 28 ± 10 years versus 34 ± 13 years; P < 0.001) and were more likely to present with venous thrombosis (50% versus 35%; P = 0.037) and to suffer from venous thrombotic recurrence (45% versus 16%; P < 0.001) compared to other ethnicities. Mortality was higher among patients of Asian ethnic origin (8.8% versus 1.1%; P = 0.005); intriguingly, this group experienced cardiovascular risk factors more often (i.e., dyslipidemia and hypertension). CONCLUSION: Ethnicity may affect the prevalence and/or natural course of APS, which is less prevalent and differs clinically in Israeli Arab patients, while mortality was linked with Asian ethnicity.

Indwelling Urinary Catheter and Dementia Are Associated with Enterococcal Urinary Tract Infections in Hospitalized Patients.

BACKGROUND: The recent increase in enterococcal urinary tract infections (EUTI) and the potential morbidity and mortality associated with inappropriate antimicrobial treatment underscores the need for early risk assessment and institution of appropriate empirical antimicrobial therapy. OBJECTIVES: To identify high-risk features associated with hospitalized patients with EUTI. METHODS: Demographic, clinical, laboratory, and bacteriological data of 285 patients hospitalized with UTI during 2016 were retrieved from the computerized database of Shamir Medical Center. Patients were divided into two groups: EUTI and non-EUTI (NEUTI), according to the presence or absence of enterococcus in the urine culture. The features of the two groups were compared. RESULTS: We obtained 300 urine cultures from 285 patients. Of the total, 80 patients (26.6%) had EUTI and 220 patients (73.3%) had NEUTI. A higher prevalence of urinary multi-bacterial cultures was found in EUTI compared to NEUTI patients (P < 0.01). Higher prevalence of permanent indwelling urinary catheter and dementia were found in hospitalized patients with community-acquired EUTI and nosocomial EUTI respectively (P = 0.02, P = 0.016) compared to patients with NEUTI. CONCLUSIONS: Indwelling urinary catheter and dementia are risk factors for EUTI in patients with community and hospital acquired infection, respectively.

The First Fatal Post-COVID-19 Adult Patient with Multi-System Inflammatory Syndrome in Israel.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is recognized as a respiratory illness, which includes pulmonary consolidations, hypoxemic states, and hypercoagulopathic tendencies with a broad clinical severity. Recently, more reports have described post-infection manifestations. These include multi-system inflammatory syndrome in children (MIS-C) with more than 400 cases published since the start of the coronavirus disease pandemic. In October 2020, the U.S. Centers for Disease Control and Prevention (CDC) published 27 cases [1] describing the new multi-system inflammatory syndrome in adults (MIS-A). Nine of the cases were reported directly to the CDC, 7 from published case reports and another 11 patients found in three distinct case series.

Coronary atherosclerosis severity is closely associated with decreased GLP-1R positivity among CD16+ pro-inflammatory and patrolling monocyte subsets.

Background and aims: Glucagon Like Peptide-1 Receptor (GLP-1R) activation reduces pro-inflammatory responses of human monocytes, their accumulation in the vascular wall and foam cell formation inhibiting atherosclerogenesis. This suggests that reduction of circulating GLP-1-1R positive monocytes may have pro-atherogenic effects. It is unknown whether different CD14/CD16 monocytes subsets display GLP-1R and whether their relative proportions correlate with atherosclerosis severity. We evaluated the association between GLP-1R positivity in different CD14/CD16 monocyte subsets and coronary atherosclerosis severity. Methods: Relative amounts of classical (CD14+/CD16-), intermediate pro-inflammatory (CD14+/CD16+) and non-classical patrolling (CD14-/CD16+) subsets of total circulating monocytes and the proportions of GLP-1R positive monocytes in these subsets were determined in 13 control subjects and 10 dyslipidemic ischemic heart disease (IHD) patients with severe angiographic proven coronary atherosclerosis using flow cytometry analysis. Atherosclerosis severity was calculated by SYNTAX score. Results: In univariable analysis, severe atherosclerosis was associated with decreased proportion of classical monocytes and two fold increased CD16+ pro-inflammatory and patrolling subsets as compared with controls (p = 0.01, p = 0.02 and p = 0.01, respectively). Frequency of GLP-1R positive monocytes was decreased in both CD16+ subsets (p = 0.02 and p = 0.05, respectively) and negatively correlated with atherosclerosis severity (r = -0.65, p = 0.005 and r = -0.44, p = 0.05, respectively). Conclusions: Increased skewing of the classical monocyte population toward CD16+ pro-inflammatory and patrolling subsets accompanied by decreased in GLP-1R positivity are associated with coronary atherosclerosis severity in IHD patients with dyslipidemia. Although the effect of potential confounders cannot be ruled out, our data suggest that failure of GLP-1R-dependent anti-inflammatory/anti-atherogenic control results in innate immune system dysfunction and can promote atherosclerogenesis.

Hyper-Activation of Endogenous GLP-1 System to Gram-negative Sepsis Is Associated With Early Innate Immune Response and Modulated by Diabetes.

BACKGROUND: Culture-positive gram-negative sepsis induces greater magnitude of early innate immunity /inflammatory response compared with culture-negative sepsis. We previously demonstrated increased activation of anti-inflammatory Glucagon Like Peptide-1 (GLP-1) hormone in initial phase of sepsis more pronounced in diabetes patients. However, whether GLP-1 system is hyperactivated during the early innate immune response to gram-negative sepsis and modulated by diabetes remains unknown. OBJECTIVES: Total and active GLP-1, soluble Dipeptidyl peptidase 4 (sDPP-4) enzyme, and innate immunity markers presepsin (sCD14) and procalcitonin (PCT) in plasma were determined by ELISA on admission and after 2 to 4 days in 37 adult patients with and without type 2 diabetes and gram-negative or culture-negative sepsis of different severity. RESULTS: Severe but not non-severe sepsis was associated with markedly increased GLP-1 system response, which correlated with PCT and the organ dysfunction marker lactate. Culture-positive gram-negative bacteria but not culture-negative sepsis induced hyper-activation of GLP-1 system, which correlated with increased innate immune markers sCD14, PCT, and lactate. GLP-1 inhibitory enzyme sDPP-4 was down regulated by sepsis and correlated negatively with sCD14 in gram-negative sepsis. Diabetic patients demonstrated increased GLP-1 response but significantly weaker innate immune response to severe and gram-negative sepsis. CONCLUSIONS: Early stage of gram-negative sepsis is characterized by endogenous GLP-1 system hyperactivity associated with over activation of innate immune response and organ dysfunction, which are modulated by diabetes. Total GLP-1 may be novel marker for rapid diagnosis of gram-negative sepsis and its severity.

Single Admission C-reactive protein Levels as a Sole Predictor of Patient Flow and Clinical Course in a General Internal Medicine Department.

BACKGROUND: C-reactive protein (CRP) blood level is associated with clinical outcomes of several diseases. However, the independent predictive role of CRP in the heterogeneous population of patients admitted to internal medicine wards is not known. OBJECTIVES: To determine whether single CRP levels at admission independently predicts clinical outcome and flow of patients in general medicine wards. METHODS: This study comprised 275 patients (50.5% female) with a mean age of 68.25 ± 17.0 years, hospitalized with acute disease in a general internal medicine ward. The association between admission CRP levels and clinical outcomes including mortality, the need for mechanical ventilation, duration of hospitalization, and re-admission within 6 months was determined. RESULTS: A significant association was found between CRP increments of 80 mg/L and risk for the major clinical outcomes measured. The mortality odds ratio (OR) was 1.89 (95% confidence interval (95%CI, 1.37-2.61, P < 0.001), mechanical ventilation OR 1.67 (95%CI, 1.10-2.34, P = 0.006), re-admission within 6 months OR 2.29 (95%CI, 1.66-3.15 P < 0.001), and prolonged hospitalization >7 days OR 2.09 (95%CI, 1.59-2.74, P < 0.001). Lower increments of10 mg/L in CRP levels were associated with these outcomes although with lower ORs. Using a stepwise regression model for admission CRP levels resulted in area under the receiver operating characteristics curves between 0.70 and 0.76 for these outcomes. CONCLUSIONS: A single admission CRP blood level is independently associated with major parameters of clinical outcomes in acute care patients hospitalized in internal medicine wards.

Endogenous glucagon-like peptide-1 system response is impaired during ST-elevation myocardial infarction in type 2 diabetes patients.

We previously demonstrated increased glucagon-like peptide-1 (GLP-1) secretion during acute ST elevation myocardial infarction (STEMI) in non-diabetic (ND) patients. Whether the endogenous GLP-1 system response is different in patients with type 2 diabetes (T2D) during STEMI is unknown. Patients with STEMI (20 ND, 13 T2D) and 3 control groups (non-STEMI [14 ND, 13 T2D], stable angina pectoris [SAP] [8 ND, 10 T2D] patients and healthy subjects) (n = 25) were studied. Plasma levels of total and active GLP-1 and soluble dipeptidyl peptidase-4 (sDPP4) were estimated by enzyme-linked immunosorbent assay on admission and at 24 and 48 hours after percutaneous coronary intervention in all patients. Sharply elevated levels of total and active GLP-1 were found in ND STEMI patients at 24 h (P < 0.05 and P < 0.005, respectively), but not in T2D STEMI patients. All patients demonstrated decreased sDPP4 levels compared with healthy controls (P < 0.0005) accompanied by increased active/total GLP-1 ratio regardless of their ischemic state. These data demonstrate that T2D patients fail to further upregulate their endogenous GLP-1 system during STEMI. This may underlie their worse cardiovascular outcome.

Short-term Adherence with Discharge Recommendation for Insulin Treatment among Patients with Type 2 Diabetes.

BACKGROUND: Basal-bolus (BB) insulin treatment is increasingly used in poorly controlled diabetes patients during hospitalization and is commonly recommended at discharge; however, the extent of adherence with this recommendation is unknown. OBJECTIVES: To determine short-term adherence of type 2 diabetes mellitus (T2DM) patients discharged from internal medicine wards with recommendation for BB insulin treatment. METHODS: Prescription (primary physician adherence) and purchase (patient adherence) of long-acting and short-acting insulins during the first month following discharge from internal medicine wards was determined in 153 T2DM patients. Adherence was defined as full if prescription/purchase of both basal (long-acting) and bolus (short-acting) insulin was completed, and as partial if only one kind of insulin (basal or bolus) was prescribed/purchased. Association between demographic and clinical parameters and adherence was determined. RESULTS: Full adherence with discharge instructions was higher for primary physicians than for patients )79.1% vs. 69.3%, respectively, P = 0.0182). Pre-hospitalization hemoglobin A1C was significantly associated with adherence by both patients and primary physicians (full-adherence group 9.04% ± 2.04%; no-adherence group 7.51% ± 1.35%, P = 0.002). Age was negatively associated with adherence of both primary physicians and patients; however, this association did not reach statistical significance. Patients with certain background diseases such as atrial fibrillation, coronary heart disease, and chronic heart failure had significantly worse adherence (P < 0.05). When the sole cause of admission was diabetes, full adherence (100%) of both primary physicians and patients was found. CONCLUSIONS: Short-term adherence with discharge recommendation for BB insulin treatment is associated with pre-hospitalization patient characteristics.

[NEW TREATMENTS IN DIABETES MELLITUS - AN UPDATE].

INTRODUCTION: Diabetes is one of the most common chronic diseases. Most patients with type 2 diabetes are obese, and the global epidemic of obesity largely explains the dramatic increase in the incidence and prevalence of type 2 diabetes over the past 20 years. In the last decade intensive research has brought about an enormous change in the clinical approach to diabetes treatment. In this review we briefly discuss the main changes in diabetes treatment, such as new medications, bariatric surgeries and technology innovations. We hope that this short review would urge the reader to expand his knowledge on the subject.

Sepsis-induced activation of endogenous GLP-1 system is enhanced in type 2 diabetes.

BACKGROUND: High levels of circulating GLP-1 are associated with severity of sepsis in critically ill nondiabetic patients. Whether patients with type 2 diabetes (T2D) display different activation of the endogenous GLP-1 system during sepsis and whether it is affected by diabetes-related metabolic parameters are not known. METHODS: Serum levels of GLP-1 (total and active forms) and its inhibitor enzyme sDPP-4 were determined by ELISA on admission and after 2 to 4 days in 37 sepsis patients with (n = 13) and without T2D (n = 24) and compared to normal healthy controls (n = 25). Correlations between GLP-1 system activation and clinical, inflammatory, and diabetes-related metabolic parameters were performed. RESULTS: A 5-fold (P < .001) and 2-fold (P < .05) increase in active and total GLP-1 levels, respectively, were found on admission as compared to controls. At 2 to 4 days from admission, the level of active GLP-1 forms in surviving patients were decreased significantly (P < .005), and positively correlated with inflammatory marker CRP (r = 0.33, P = .05). T2D survivors displayed a similar but more enhanced pattern of GLP-1 response than nondiabetic survivors. Nonsurvivors demonstrate an early extreme increase of both total and active GLP-1 forms, 9.5-fold and 5-fold, respectively (P < .05). The initial and late levels of circulating GLP-1 inhibitory enzyme sDPP-4 were twice lower in all studied groups (P < .001), compared with healthy controls. CONCLUSIONS: Taken together, these data indicate that endogenous GLP-1 system is activated during sepsis. Patients with T2D display an enhanced and prolonged activation as compared to nondiabetic patients. Extreme early increased GLP-1 levels during sepsis indicate poor prognosis.

Hyperglycemia in Diabetic Patients in General Medicine Wards: No independent correlation with In- and Out-Of-Hospital Mortality.

BACKGROUND: Admission glucose levels correlate with clinical outcome in patients with type 2 diabetes mellitus (T2DM) hospitalized in general medicine wards. OBJECTIVE: To investigate whether in-hospital hyperglycemia alone, and after adjustment for age, gender and lipidemia, correlates with in- and out-of-hospital mortality. METHODS: Capillary glucose, serum lipids and diagnoses at discharge among patients with T2DM hospitalized in the general medical wards of our hospital were documented. Correlation with in- and out-of-hospital mortality was determined through uni- and multivariate analyses. RESULTS: Of the 4607 patients included in the study 22% died while hospitalized. From a median of five capillary glucose tests obtained per patient, average capillary glucose level was significantly lower in those who survived than in those who died (174 ± 64 vs. 180 ± 65 mg/dl, P = 0.005). Overall, blood cholesterol was higher in those who survived than in those who died (P < 0.001). Multivariate analysis, however, including age, gender, lipidemia and glycemia, showed that only age and male gender correlated with mortality. CONCLUSIONS: Hyperglycemia was associated with increased in- and out-of-hospital mortality on univariate analysis. However, it was not an independent risk factor when corrected for age, gender and hyperlipidemia.