Computational Algorithm Based On Serum Immunoassays for the Identification of Haematological Disease May Identify Patients with Other Acute Disorders

Abstract Abstract 4001 Introduction Serum free light chain (FLC) measurements are used routinely to identify monoclonal immunoglobulin (M-Ig) production in patients. In addition, summated kappa + lambda concentrations have recently been shown to have prognostic value in chronic lymphocytic leukaemia (CLL), Hodgkins lymphoma and HIV patients; presumably reflecting immune stimulation. A recently developed companion assay to FLC testing measures intact immunoglobulin heavy chain/light chain (HLC) pairs in serum calculating Ig'κ/Ig'λ ratios as a reflection of clonality. Here we report on a computational approach combining FLC and HLC measurements to identify clonal disease, hyper- and hypo-gammaglobulinemia, and as markers of immune dysfunction. Furthermore, we comment on the potential of such an algorithm to risk stratify haematological and non-haematological malignancies. Patients, Materials and Methods 1468 patients referred to the Royal Wolverhampton Hospital for haematological evaluation were enrolled on to the study. Median patient age was 64 years, with a slight female preponderance (60%). Patient sera were analysed at presentation using routine electrophoresis tests (serum protein electrophoresis, SPEP and immunofixation, IFE). FLC and HLC (IgG, IgA and IgM) were measured by nephelometric immunoassay. Each immunoassay result was assessed with respect to individual normal ranges (FLCκ = 3.3–19.4mg/L, FLCλ = 5.71–26.30mg/L, IgGκ = 4.03–9.78g/L, IgGλ = 1.97–5.71g/L, IgAκ = 0.48–2.82g/L, IgAλ = 0.36–1.98, IgMκ = 0.29–1.82g/L, IgMλ = 0.17–0.94g/L) and ratios (FLCκ/FLCλ = 0.26–1.65, Gκ/Gλ = 0.98–2.75, Aκ/Aλ = 0.8–2.04, Mκ/Mλ = 0.96–2.3). The results were used to create an algorithm which assessed the degree of abnormality individually and with respect to the other results generated. Diagnosis was recorded ∼3 months after the analysis and patients were followed for up to 3 years. Results 293/1468 (19%) samples had an abnormal SPEP of which 95/293 were confirmed by IFE including: 10 intact immunoglobulin Multiple Myeloma (MM, 6 IgGκ, 1 IgGλ, 2 IgAκ, 1 IgAλ), 6 light chain MM (LCMM, 4 FLCκ, 2 FLCλ), 2 Waldenstrom macroglobulinemia (2 IgMκ), 1 IgMκ cryoglobulinemia, 3 CLL, 1 mantle cell lymphoma, 3 other lymphoma, 1 IgGκ plasmacytoma, and 68 MGUS patients, 26/68 were confirmed MGUS (1 FLCκ, 13 IgGκ, 4 IgGλ, 4 IgAκ, 2 IgMκ, 2 IgMλ), 42 were laboratory findings requiring follow up (1FLCκ, 3 FLCλ, 19 IgGκ, 5 IgGλ, 4 IgAκ, 1 IgAλ, 8 IgMκ, 1 IgMλ). FLC/HLC algorithm identified 85/95 IFE positive patients; of the 10 patients reported not identified by the algorithm, 3 had oligoclonal banding indicative of infection and 7 had monoclonal bands secondary to other diagnoses (including 2 colon cancer patients and 2 rheumatoid arthritis patients). In addition the algorithm identified 15 IFE negative patients with M-Ig production including: 2 AL amyloid patients, 1 asymptomatic LCMM, 1 patient with ∼1g/L FLCκ (lost to follow up), 1 follicular lymphoma patient and 1 CLL; diagnosis was not available for 9/15 patients. Furthermore, the algorithm identified 205/1468 patients as having elevated polyclonal FLC (cFLC) >50mg/L without evidence of clonal production. In a subset analysis comparing matched numbers of patients with elevated or normal cFLC concentrations, cFLC >50mg/L predicted all cause mortality (logistic regression odds ratio 9.96, 95% CI 4.72–21.0, p<0.001), and was associated with poorer overall survival (Kaplan Meier p<0.001, Cox regression hazard ratio 8.73, 95% CI 4.47–17.02). Discussion MM presents with disparate and vague symptoms pervasive in an elderly population. Current guidelines recommend SPEP and FLC analysis reflexing to IFE for confirmation in the event of abnormality. However, SPEP and IFE require interpretation making the assessment variable. Standardised immunoassays (FLC+HLC) may obviate the need for interpretation and in this study identified additional haematological malignancies. Furthermore, standard assessments can be used to identify M-Ig, but in the absence of this finding may offer little information pertaining to the symptoms that prompted referral. By contrast this algorithm identified patients with elevated cFLC which in agreement with other reports was associated with increased risk of mortality. Further work is required to assess the algorithm, and determine if cFLC measurements should be used as a prompt for additional diagnostic investigations. Disclosures: Faint: The Binding Site Group, Ltd.: Employment. Harding:The Binding Site Group Ltd.: Membership on an entity's Board of Directors or advisory committees. Mirbahai:The Binding Site Group, Ltd: Employment.

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Asbestos exposure and haematological malignancies: a Danish cohort study

European Journal of Epidemiology ◽

10.1007/s10654-020-00609-4 ◽

2020 ◽

Vol 35 (10) ◽

pp. 949-960

Author(s):

Else Toft Würtz ◽

Johnni Hansen ◽

Oluf Dimitri Røe ◽

Øyvind Omland

Keyword(s):

Cox Regression ◽

Haematological Malignancy ◽

Asbestos Exposure ◽

Production Plant ◽

Haematological Malignancies ◽

Asbestos Cement ◽

Increased Risk ◽

Reference Cohort

Abstract Environmental asbestos exposure and occupational asbestos exposure increase the risk of several types of cancer, but the role of such exposures for haematological malignancies remains controversial. We aimed to examine the risk of haematological malignancies: first, in subjects exposed early in life, independently of any occupational exposure occurring later; second, in subjects exposed occupationally. We established an environmentally exposed cohort from four schools located near the only former asbestos cement production plant in Denmark. We identified nearly all pupils in the seventh grade and created an age and sex-matched 1:9 reference cohort from the Danish Central Population Register. Participants were born 1940–1970 and followed up in national registers until the end of 2015. Occupational asbestos exposure was assessed for all participants using two different job exposure matrices. The school cohort included 12,111 participants (49.7% girls) and the reference cohort 108,987 participants. Eight subgroups of haematological malignancy were identified in the Danish Cancer Registry. These cases were analysed for combined overall haematological malignancy, a combined subgroup of lymphomas and a combined subgroup of leukaemias. The data were analysed using Cox regression (hazard ratios (HR)) including other cancers and death as competing risks. Haematological malignancy was identified in 1125 participants. The median follow-up was 49.3 years (0.1–63.4). Early environmental asbestos exposure was not associated with an increased risk of haematological malignancy. Long-term occupational asbestos exposure was associated with overall haematological malignancy (HR 1.69, 95% CI 1.04–2.73); in particular for the leukaemia subgroup (HR 2.14, 95% CI 1.19–3.84). This large follow-up study suggests that long-term occupational asbestos exposure is associated with increased leukaemia risk. However, further studies are needed to confirm these observations.

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The Ratio of Monoclonal to Polyclonal Immunoglobulins Assessed with the Hevylite Test Predicts Prognosis, Is Superior for Monitoring the Course of the Disease and Allows Detection of Monoclonal Immunoglobulin In Patients with Normal or Subnormal Involved Immunoglobulin Isotype

Blood ◽

10.1182/blood.v116.21.4038.4038 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4038-4038

Author(s):

Heinz Ludwig ◽

Ladan Mirbahai ◽

Niklas Zojer ◽

Arthur Bradwell ◽

Stephen Harding

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Risk Stratification ◽

Binding Site ◽

Light Chain ◽

Monoclonal Immunoglobulin ◽

Immunoglobulin Isotype ◽

Site Group ◽

Risk Stratification Model

Abstract Abstract 4038 Parameters that appraise the prognosis of an individual multiple myeloma (MM) patient are essential for clinical guidance and treatment planning. Similarly important for clinical care are factors that assess variations in the course of the disease and that allow accurate measurement of residual monoclonal proteins. Presently, the International Staging System (ISS) stage, and cytogenetics are used for prognostication, EBMT or IMWG response criteria are applied for evaluation of response and of progressive disease, and conventional protein analytics including serum free light chain (FLC) measurement, serum protein electrophoresis (SPE) and immunofixation (IF) for detection of residual paraprotein. Here, we evaluate the prognostic relevance of the ratio of monoclonal to isotype matched polyclonal immunoglobulins for prognostication at start of therapy, for evaluation of response for long term follow up and for measurement of monoclonal immunoglobulin in patients with normal or below normal levels of the involved immunoglobulin isotype. 103 previously untreated patients with multiple myeloma were enrolled (35 IgGκ, 17 IgGλ, 29 IgAκ, 22 IgAλ). 39 (38%) presented with ISS stage I, 42 (41%) with stage II, and 22 (21%) with stage III disease; there was insufficient data to assign ISS in 2 cases. Median age was 67 (range: 32,86) years. Patients were enrolled from 1994 to 2007, either into a trial comparing thalidomide-dexamethasone with Melphalan-Prednisone or into a study comparing double with triple autologous transplantation after 4 cycles of VAD induction therapy. Patients were followed for a median of 13 months (range: 85 days -158 months). Immunoglobulin heavy/light chain (HLC) pairs were assessed by using polyclonal antibodies targeted at unique junctional epitopes between heavy chain and light chain constant regions of intact immunoglobulins using the Hevylite IgA kappa, IgA lambda, IgG kappa and IgG lambda kits (HevylitêO Binding Site, Birmingham, UK) on a Siemens BN̂OII Analyzer. Concentrations of conventional parameters such as IgA, IgG, ß2-microglobulin (β2-M), FLC, immunofixation, LDH, creatinine, were assessed by standard techniques. Survival analysis and Cox proportional hazards were performed using SPSS v18 program Median OS of the entire group was 37.9 months with 39 (37 %) of the103 (6 patients were lost to follow up) patients being alive at 4 years follow up. Univariate analysis revealed a correlation between OS and β2-M, (HR: 1.411, 95% CI: 1.369–4.248, p=0.002), the HLC ratio (HR: 1.9, 95% CI: 1.092–3.36, p=0.02), and LDH (HR:1.006, 95%CI 1.00–1.014, p=0.0396) but not with Albumin, age, and creatinine. In multivariate analysis, β2-M (HR: 1.9, 95% CI: 1.105–3.93, p=0.028), and the HLC ratio (HR: 1.89, 95% 1.092–3.362: x-y, p=0.039), were found as the only parameters correlating with survival. A three tiered risk stratification model utilizing ß2-M >3.5mg/L and HLC >median value had a greater prognostic value than ISS (p=0.001 v p=0.09). Patients with 0 risk factors (ß2-M <3.5mg/L, HLC ratio <median) had a 50% survival time of 118 months, patients with 1 risk factor (either ß2-M >3.5mg/L or HLC ratio >median) had a 50% survival of 53 months and those with both risk factors (ß2-M >3.5mg/L and HLC ratio >median) had a 50% survival of 29 months (p=0.001). During follow up 46 (45%) of the patients achieved normal or subnormal levels of their involved immunoglobulin isotype. Abnormal HLC ratios were identified in 35/46, interestingly 7/35 patients (IgA kappa: 2 pts, IgA lambda: 2pts. IgG kappa: 3pts) were negative by IFE, indicating that the hevylite test is more sensitive than IF in identifying residual disease. In addition in 7/35 patients HLC ratio indicated relapse when immunoglobulin levels where within normal ranges. In conclusion, the HLC ratio is highly prognostic. Furthermore, HLC analysis improved the detection of variations in the course of the disease and increased the diagnostic accuracy in patients with normal or subnormal levels of the involved isotype and even in patients shown to ne negative in IF. Determination of the HLC ratio seems to overcome a hitherto unmet need for improvement in assessment of response and of variations in the production of the monoclonal protein.Figure 1:Risk stratification model based upon ß2-M >3.5mg/L and HLC >medianFigure 1:. Risk stratification model based upon ß2-M >3.5mg/L and HLC >median Disclosures: Mirbahai: Binding Site Group Ltd: Employment. Bradwell:Binding Site: Equity Ownership, Patents & Royalties. Harding:Binding Site Group Ltd: Employment.

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Risk of infective endocarditis among patients with tetralogy of fallot

European Heart Journal ◽

10.1093/ehjci/ehaa946.2171 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Havers-Borgersen ◽

J.H Butt ◽

M Groening ◽

M Smerup ◽

G.H Gislason ◽

...

Keyword(s):

Infective Endocarditis ◽

Tetralogy Of Fallot ◽

Valve Replacement ◽

Pulmonary Valve ◽

Cox Regression ◽

Pulmonary Valve Replacement ◽

Varying Coefficients ◽

Background Population ◽

Increased Risk

Abstract Introduction Patients with tetralogy of Fallot (ToF) are considered at high risk of infective endocarditis (IE) as a result of altered hemodynamics and multiple surgical and interventional procedures including pulmonary valve replacement (PVR). The overall survival of patients with ToF has increased in recent years. However, data on the risk of adverse outcomes including IE are sparse. Purpose To investigate the risk of IE in patients with ToF compared with controls from the background population. Methods In this nationwide observational cohort study, all patients with ToF born in 1977–2017 were identified using Danish nationwide registries and followed from date of birth until occurrence of an outcome of interest (i.e. first-time IE), death, or end of study (July 31, 2017). The comparative risk of IE among ToF patients versus age- and sex-matched controls from the background population was assessed. Results A total of 1,156 patients with ToF were identified and matched with 4,624 controls from the background population. Among patients with ToF, 266 (23.0%) underwent PVR during follow-up. During a median follow-up time of 20.4 years, 38 (3.3%) patients and 1 (0.03%) control were admitted with IE. The median time from date of birth to IE was 10.8 years (25th-75th percentile 2.8–20.9 years). The incidence rates of IE per 1,000 person-years were 2.2 (95% confidence interval (CI) 1.6–3.0) and 0.01 (95% CI 0.0001–0.1) among patients and controls, respectively. In multivariable Cox regression models, in which age, sex, pulmonary valve replacement, and relevant comorbidities (i.e. chronic renal failure, diabetes mellitus, presence of cardiac implantable electronic devices, other valve surgeries), were included as time-varying coefficients, the risk of IE was significantly higher among patients compared with controls (HR 171.5, 95% CI 23.2–1266.7). Moreover, PVR was associated with an increased risk of IE (HR 3.4, 95% CI 1.4–8.2). Conclusions Patients with ToF have a substantial risk of IE and the risk is significantly higher compared with the background population. In particular, PVR was associated with an increased risk of IE. With an increasing life-expectancy of these patients, intensified awareness, preventive measures, and surveillance of this patient group are advisable. Figure 1. Cumulative incidence of IE Funding Acknowledgement Type of funding source: None

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Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study

Antioxidants ◽

10.3390/antiox10071102 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1102

Author(s):

Angelica Rodriguez-Niño ◽

Diego O. Pastene ◽

Adrian Post ◽

M. Yusof Said ◽

Antonio W. Gomes-Neto ◽

...

Keyword(s):

Kidney Transplant ◽

Graft Failure ◽

Cox Regression ◽

Carbonyl Stress ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Increased Risk ◽

High Concentrations ◽

Kidney Function Decline

Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4–33.3] µmol/24 h versus 34.8 [IQR 25.6–46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06–1.45]; p = 0.007). During median follow-up for 5.3 [4.5–6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44–2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted.

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Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study

Diabetologia ◽

10.1007/s00125-021-05508-1 ◽

2021 ◽

Author(s):

Peter Ueda ◽

Viktor Wintzell ◽

Mads Melbye ◽

Björn Eliasson ◽

Ann-Marie Svensson ◽

...

Keyword(s):

Incidence Rate ◽

Cox Regression ◽

Absolute Rate ◽

Dipeptidyl Peptidase 4 ◽

Rate Difference ◽

Receptor Agonists ◽

Dpp4 Inhibitors ◽

Increased Risk ◽

Increase In Risk

Abstract Aims/hypothesis Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. Methods We used data from nationwide registers in Sweden, Denmark and Norway, 2007–2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. Results The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6–7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9–7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4–6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2–8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). Conclusions/interpretation In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma. Graphical abstract

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Global longitudinal strain predicts outcome in chronic heart failure across American Heart Association stages: results from the MyoVasc study

European Heart Journal ◽

10.1093/ehjci/ehaa946.0964 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S.O Troebs ◽

A Zitz ◽

S Schwuchow-Thonke ◽

A Schulz ◽

M.W Heidorn ◽

...

Keyword(s):

American Heart Association ◽

Prognostic Value ◽

Longitudinal Strain ◽

American Heart ◽

Cox Regression ◽

Global Longitudinal Strain ◽

Heart Association ◽

Increased Risk ◽

Systolic And Diastolic Function

Abstract Background Global longitudinal strain (GLS) demonstrated a superior prognostic value over left ventricular ejection fraction (LVEF) in acute heart failure (HF). Its prognostic value across American Heart Association (AHA) stages of HF – especially under considering of conventional echocardiographic measures of systolic and diastolic function – has not yet been comprehensively evaluated. Purpose To evaluate the prognostic value of GLS for HF-specific outcome across AHA HF stages A to D. Methods Data from the MyoVasc-Study (n=3,289) were analysed. Comprehensive clinical phenotyping was performed during a five-hour investigation in a dedicated study centre. GLS was measured offline utilizing QLab 9.0.1 (PHILIPS, Germany) in participants presenting with sinus rhythm during echocardiography. Worsening of HF (comprising transition from asymptomatic to symptomatic HF, HF hospitalization, and cardiac death) was assessed during a structured follow-up with subsequent validation and adjudication of endpoints. AHA stages were defined according to current guidelines. Results Complete information on GLS was available in 2,400 participants of whom 2,186 categorized to AHA stage A to D were available for analysis. Overall, 434 individuals were classified as AHA stage A, 629 as stage B and 1,123 as stage C/D. Mean GLS increased across AHA stages of HF: it was lowest in stage A (−19.44±3.15%), −18.01±3.46% in stage B and highest in AHA stage C/D (−15.52±4.64%, P for trend <0.0001). During a follow-up period of 3.0 [1.3/4.0] years, GLS denoted an increased risk for worsening of HF after adjustment for age and sex (hazard ratio, HRGLS [per standard deviation (SD)] 1.97 [95% confidence interval 1.73/2.23], P<0.0001) in multivariable Cox regression analysis. After additional adjustment for cardiovascular risk factors, clinical profile, LVEF and E/E' ratio, GLS was the strongest echocardiographic predictor of worsening of HF (HRGLS [per SD] 1.47 [1.20/1.80], P=0.0002) in comparison to LVEF (HRLVEF [per SD] 1.23 [1.02/1.48], P=0.031) and E/E' ratio (HRE/E' [per SD] 1.12 [0.99/1.26], P=0.083). Interestingly, when stratifying for AHA stages, GLS denoted a similar increased risk for worsening of HF in individuals classified as AHA stage A/B (HRGLS [per SD] 1.63 [1.02/2.61], P=0.039) and in those classified as AHA stage C/D (HRGLS [per SD] 1.95 [1.65/2.29], P<0.0001) after adjustment for age and sex. For further evaluation, Cox regression models with interaction analysis indicated no significant interaction for (i) AHA stage A/B vs C/D (P=0.83) and (ii) NYHA functional class <II vs ≥II in individuals classified as AHA stage C/D (P=0.12). Conclusions GLS demonstrated a higher predictive value for worsening of HF than conventional echocardiographic measures of systolic and diastolic function. Interestingly, GLS indicated an increased risk for worsening of HF across AHA stages highlighting its potential value to advance risk prediction in chronic HF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Center for Cardiovascular Research (DZHK), Center for Translational Vascular Biology (CTVB) of the University Medical Center of the Johannes Gutenberg-University Mainz

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Abstract P060: Plasma Osteocalcin And Incident Diabetes Mellitus: The Atherosclerosis Risk In Communities (ARIC) Study

Circulation ◽

10.1161/circ.143.suppl_1.p060 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Jeffrey R Misialek ◽

Elizabeth R Stremke ◽

Elizabeth Selvin ◽

Sanaz Sedaghat ◽

James S Pankow ◽

...

Keyword(s):

Diabetes Mellitus ◽

Cox Regression ◽

Self Report ◽

Incident Diabetes ◽

Blood Levels ◽

Total Plasma ◽

Phone Calls ◽

Increased Risk ◽

Primary Model

Introduction: Diabetes is a major risk factor for cardiovascular disease. Osteocalcin is a vitamin K-dependent, bone-derived hormone that functions as an endocrine regulator of energy metabolism, male fertility, and cognition. Early studies of endocrine effects of osteocalcin have shown that genomic deletion of osteocalcin in mice resulted in a diabetic phenotype (i.e. glucose intolerance, and insulin resistance). However, results from clinical studies have shown mixed associations between blood levels of osteocalcin and risk of incident type 2 diabetes mellitus. Hypothesis: Lower values of plasma osteocalcin would be associated with an increased risk of diabetes. Methods: A total of 11,557 ARIC participants without diabetes at baseline were followed from ARIC visit 3 (1993-1995) through 2018. Diabetes cases were identified through self-report on annual and semi-annual follow-up phone calls. Plasma osteocalcin data was measured using an aptamer-based proteomic profiling platform (SomaLogic). We used Cox regression to evaluate the association of quintiles of plasma osteocalcin and incident diabetes. The primary model adjusted for age, sex, and race-center. Results: Participants were age 60 ± 5.6 years at visit 3, 56% identified as female, 21% identified as Black. There were 3,031 incident diabetes cases over a median follow-up of 17.9 years. Mean ± SD was 10.053 ± 0.775. When comparing the highest quintile of plasma osteocalcin (values 10.42 to 14.66) to the lowest quintile (values 9.03 to 9.52), there was no association with incident diabetes (HRs [95% CIs]: 0.92 [0.81, 1.02]). There was also no significant trend across the quintiles (p = 0.19). Results were similar when adjusting for additional potential confounders, and when limiting the follow-up time to 10 years. Conclusions: These data do not support the hypothesis that total plasma osteocalcin, as measured by Somalogic proteomic panel, is a biomarker associated with diabetes risk. It is possible that total plasma or serum osteocalcin and/or other isoforms of osteocalcin protein (i.e. gamma carboxylated or uncarboxylated osteocalcin) measured via other validated methodologies may be linked to diabetes.

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Risk and Prognosis of Subsequent Primary Gastric Cancer

Oncology Research and Treatment ◽

10.1159/000521846 ◽

2022 ◽

Author(s):

Rongrong Wei ◽

Xinyu Du ◽

Jing Wang ◽

Qi Wang ◽

Xiaojie Zhu ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Survivors ◽

Cox Regression ◽

Prognostic Impact ◽

Cancer Specific Survival ◽

Cancer History ◽

Primary Gastric Cancer ◽

Actual Observation ◽

Increased Risk

Introduction: The incidence and prognostic impact of subsequent primary gastric cancer (GC) in a population of other cancer survivors is unclear. We aimed to evaluate susceptibility to subsequent primary GC in cancer survivors and prognosis of GC with prior cancer history. Methods: 2,211 and 23,416 GC cases with and without prior cancer history were retrospectively selected from the Surveillance, Epidemiology and End Results (SEER) database. Potential risk of developing subsequent primary GC was assessed through standardized incidence ratios (SIRs). Cox regression were adopted to analyze the influence of prior cancer history and clinical characteristic factors on the prognosis of subsequent primary GC. A nomogram was established to predict overall survival (OS). Propensity score matching (PSM) was conducted to eliminate possible bias. Results: Compared with general population, cancer survivors had an increased risk of subsequent primary GC (SIR 1.17, 95% CI 1.15-1.20, P<0.05). Prior cancer history was related to poor OS of GC [adjusted hazard ratio (aHR) 1.12, 95% CI 1.06-1.19, P<0.001], but not cancer-specific survival (aHR 0.97, 95% CI 0.89-1.05, P=0.441). In addition, age, grade, stage, year of diagnosis, surgery, TNM stage and tumor size were independent prognostic factors for OS in GC cases with prior cancers. The concordance index of the nomogram was 0.72 (95% CI 0.71-0.74), and calibrate curves showed good agreement between prediction by the nomogram and actual observation. Conclusions: Cancer survivors with increased risk of developing subsequent primary GC should strengthen their monitoring and follow-up to prevent occurrence of subsequent primary gastric cancer.

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Correlation between markers of renal function and sight-threatening diabetic retinopathy in type 2 diabetes: a longitudinal study in an Indian clinic population

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001325 ◽

Cited By ~ 1

Author(s):

Ramachandran Rajalakshmi ◽

Coimbatore Subramanian Shanthi Rani ◽

Ulagamathesan Venkatesan ◽

Ranjit Unnikrishnan ◽

Ranjit Mohan Anjana ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Serum Creatinine ◽

Cox Regression ◽

Tertiary Care ◽

Cox Regression Analysis ◽

Increased Risk ◽

New Onset

IntroductionPrevious epidemiological studies have reported on the prevalence of diabetic kidney disease (DKD) and diabetic retinopathy (DR) from India. The aim of this study is to evaluate the effect of DKD on the development of new-onset DR and sight-threatening diabetic retinopathy (STDR) in Asian Indians with type 2 diabetes (T2D).Research design and methodsThe study was done on anonymized electronic medical record data of people with T2D who had undergone screening for DR and renal work-up as part of routine follow-up at a tertiary care diabetes center in Chennai, South India. The baseline data retrieved included clinical and biochemical parameters including renal profiles (serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria). Grading of DR was performed using the modified Early Treatment Diabetic Retinopathy Study grading system. STDR was defined as the presence of proliferative diabetic retinopathy (PDR) and/or diabetic macular edema. DKD was defined by the presence of albuminuria (≥30 µg/mg) and/or reduction in eGFR (<60 mL/min/1.73 m2). Cox regression analysis was used to evaluate the hazard ratio (HR) for DR and STDR.ResultsData of 19 909 individuals with T2D (mean age 59.6±10.2 years, mean duration of diabetes 11.1±12.1 years, 66.1% male) were analyzed. At baseline, DR was present in 7818 individuals (39.3%), of whom 2249 (11.3%) had STDR. During the mean follow-up period of 3.9±1.9 years, 2140 (17.7%) developed new-onset DR and 980 individuals with non-proliferative DR (NPDR) at baseline progressed to STDR. Higher serum creatinine (HR 1.5, 95% CI 1.3 to 1.7; p<0.0001), eGFR <30 mL/min/1.73 m2 (HR 4.9, 95% CI 2.9 to 8.2; p<0.0001) and presence of macroalbuminuria >300 µg/mg (HR 3.0, 95% CI 2.4 to 3.8; p<0.0001) at baseline were associated with increased risk of progression to STDR.ConclusionsDKD at baseline is a risk factor for progression to STDR. Physicians should promptly refer their patients with DKD to ophthalmologists for timely detection and management of STDR.

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Pregnancy, pregnancy loss and the risk of diabetes in Chinese women: findings from the China Kadoorie Biobank

European Journal of Epidemiology ◽

10.1007/s10654-019-00582-7 ◽

2019 ◽

Vol 35 (3) ◽

pp. 295-303

Author(s):

Sanne A. E. Peters ◽

◽

Ling Yang ◽

Yu Guo ◽

Yiping Chen ◽

...

Keyword(s):

Pregnancy Loss ◽

Cox Regression ◽

Chinese Women ◽

Later Life ◽

Induced Abortion ◽

Hazard Ratios ◽

Increased Risk ◽

History Of ◽

Incident Cases

AbstractPregnancy and pregnancy loss may be associated with increased risk of diabetes in later life. However, the evidence is inconsistent and sparse, especially among East Asians where reproductive patterns differ importantly from those in the West. We examined the associations of pregnancy and pregnancy loss (miscarriage, induced abortion, and still birth) with the risk of incident diabetes in later life among Chinese women. In 2004–2008, the nationwide China Kadoorie Biobank recruited 302 669 women aged 30–79 years from 10 (5 urban, 5 rural) diverse localities. During 9.2 years of follow-up, 7780 incident cases of diabetes were recorded among 273,383 women without prior diabetes and cardiovascular disease at baseline. Cox regression yielded multiple-adjusted hazard ratios (HRs) for the risk of diabetes associated with pregnancy and pregnancy loss. Overall, 99% of women had been pregnant, of whom 10%, 53%, and 6% reported having a history of miscarriage, induced abortion, and stillbirth, respectively. Among ever pregnant women, each additional pregnancy was associated with an adjusted HR of 1.04 (95% CI 1.03; 1.06) for diabetes. Compared with those without pregnancy loss, women with a history of pregnancy loss had an adjusted HR of 1.07 (1.02; 1.13) and the HRs increased with increasing number of pregnancy losses, irrespective of the number of livebirths; the adjusted HR was 1.03 (1.00; 1.05) for each additional pregnancy loss. The strength of the relationships differed marginally by type of pregnancy loss. Among Chinese women, a higher number of pregnancies and pregnancy losses were associated with a greater risk of diabetes.

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