Onset Of Type Research Articles

Change and onset-type differences in the prevalence of comorbidities in people with multiple sclerosis.

Little is known about the change in prevalence of comorbidities during the disease course of people with multiple sclerosis (MS) and whether the prevalences vary by MS onset type. To calculate the change in prevalence of comorbidities between symptom onset and the time of study, to compare the prevalences of comorbidities with those in the Australian population at the time of study and to examine onset-type differences. Comorbidity data from 1518 participants of the Australian MS Longitudinal Study and Australian population comparator data (2014-2015 National Health Survey) were used. The change in prevalence between time points and prevalence ratios (PR) at the time of study (crude, age and sex adjusted, and stratified by onset type) was calculated. Comorbidities were common, and those with the largest increases in prevalence between MS symptom onset and the time of study were depression (+ 26.9%), anxiety (+ 23.1%), hypertension (+ 21.9%), elevated cholesterol (+ 16.3%), osteoarthritis (+ 17.1%), eye diseases (+ 11.6%), osteoporosis (+ 10.9%) and cancer (+ 10.3%). Compared to the general population and after age and sex adjustment, participants had a significantly higher prevalence for 14/19 comorbidities at the time of study. The associations were strongest for anaemia, cancer (both PR > 4.00), anxiety, depression, migraine (all PR > 3.00), psoriasis and epilepsy (both PR > 2.00). No significant differences were seen by onset type. Comorbidities are common at MS symptom onset and increase with MS duration. Having MS may thus contribute to accrual of comorbidities. This emphasises the importance of optimal screening for and management of comorbidities in early MS and throughout the disease course.

A study of prevalence of microalbuminuria in recently detected type 2 diabetes and its relation to hypertension, dyslipidaemia and obesity

Background: Microalbuminuria is one of the earliest markers of diabetic nephropathy, and if not recognized and treated early it may lead to diabetic nephropathy resulting in chronic renal failure.
 Aims and Objective: The aim of the current study was to find out the prevalence of microalbuminuria among newly detected Type 2 diabetic patients and also compare prevalence of microalbuminuria in patients with or without hypertension, dyslipidaemia and obesity.
 Materials and Methods: In this retrospective study, we analysed 90 patients with new onset type 2 diabetes mellitus. We divided the patients into two groups, group 1 with comorbidities like hypertension, dyslipidaemia and obesity (50 patients) and group 2 without comorbidities (40 patients). We analysed urinary microalbumin level in all patients and compared the prevalence of microalbuminuria between group 1 and group 2.
 Results: In our cohort of 90 patients, urinary microalbuminuria was found in 30 patients (33.3%). When we divided these nephropathy patients to group1 and group 2, we observed that group 1 with comorbidities had higher percentage of nephropathy patients i.e 24 out of 50(48%). Group 2 with 40 patients had only 6 patients with microalbiminuria ie 6 out of 40(15%). Incidence of microalbiminuria was higher in patients with hypertension, dyslipidaemia and obesity.
 Conclusions: We conclude that incidence of microalbiminuria is much more common in newly diagnosed type 2 diabetes. We also conclude that hypertension, obesity and hypercholesterolemia are risk factors for nephropathy and urinary microalbuminuria appears to be much more sensitive than serum creatinine as screening tool to detect diabetic nephropathy.

A case of perinephric abscess in a child with diabetes mellitus: A rare manifestation of group B Streptococcal infection

Perinephric abscess is an uncommon infection in children, but it is usually caused by Escherichia coli, Staphylococcus aureus, Proteus mirabilis and Pseudomonas aeruginosa . Group B Streptococcus (GBS) is an uncommon cause of perinephric abscess or serious bacterial infections beyond the neonatal period. Comorbid conditions such as diabetes mellitus and immunosuppression can increase the risk of GBS invasive disease. We describe a 10-year-old female who presented with 1-month of right-sided flank pain and swelling with ultrasound showing large (>3 cm) right perinephric and subcutaneous abscesses. She was additionally diagnosed with new onset type 2 diabetes mellitus (DM) during admission. Abscess cultures obtained after placement of two percutaneous drains and the initiation of broad-spectrum intravenous antibiotics grew beta-hemolytic GBS . Here, we present to our knowledge, the first known documented case of GBS perinephric abscess in a school-aged child with DM. Much of the knowledge of perinephric abscess management is extrapolated from adults, therefore making optimal treatment in the pediatric population challenging. We propose that GBS be considered in the etiology of perinephric abscess in children with DM and other immunosuppressing conditions. In addition, percutaneous drainage of larger abscesses (>3 cm) in conjunction with antibiotic therapy is a reasonable management strategy.

Characteristics of Post-Ictal Headaches in Patients with Epilepsy: a Longitudinal Study

ObjectivesThis study aimed to investigate the clinical predictors of post-ictal headache (PIH) in patients with epilepsy in a tertiary center in Brazil. Methods302 individuals with adult-onset epilepsy were followed for 9.8 years in our Hospital. Structured questionnaires about headaches were applied. The presence of PIH was the primary outcome. We used multilevel linear modeling in our data analysis. ResultsFrom the total, 46.3% had post-ictal headaches. Tension-type post-ictal headache was present in 55% (N = 77) of the subjects, migrainous in 32.1% (N = 45), and both types in 12.8% (N = 18). Family history of migraine (Odds ratio: 1.696; 95% CI: 1.372 to 2.096), diagnosis of drug-resistant epilepsy (Odds ratio: 1.169; 95% CI: 1.135 to 2.146), months since last visit (Odds ratio: 1.464; 95% CI: 1.243 to 2.888), and generalized seizure onset type of epilepsy (Odds ratio: 1.527; 95% CI: 1.114 to 1.668), were significant determinants of PIH on multilevel linear modeling. DiscussionPIH are associated with drug-resistant epilepsy, generalized seizures, and family history of migraine. The rates of pos-ictal headaches could be influenced by the use of antiepileptic drugs.

Rapid onset type 1 diabetes with anti-PD-1 directed therapy.

Type 1 diabetes is a rare immune-related adverse event (irAE) caused by checkpoint inhibitors with serious risk for diabetic ketoacidosis (DKA). Using our electronic medical record, we identified 1327 adult patients who received PD-(L)1 or CTLA-4 inhibitors from 2013 to 2018. Of the patients who received immunotherapy, 5 (0.38%) patients were found to have type 1 diabetes, all of whom presented with DKA requiring insulin at 20 to 972 days from their first anti-PD-(L)1 dose. All patients were treated with anti-PD-1 therapy (nivolumab or pembrolizumab). Four patients had new onset diabetes with mean HbA1c of 9.1% on DKA presentation and persistent elevations over time. Two patients who tested positive for glutamic acid decarboxylase (GAD) antibodies presented with DKA at 20 and 106 days from first anti-PD-1 administration whereas patients who were autoantibody negative had DKA more than a year later. Type 1 diabetes occurs within a wide time frame after anti-PD-1 initiation and commences with an abrupt course. Our case series suggests that monitoring glycemia in patients on PD-1 inhibitors is not predictive for diabetes occurrence. GAD autoantibodies could portend earlier onset for diabetes, although further prospective studies are needed to elucidate their diagnostic utility and contribution in therapeutic interception.

Measuring the health-related quality of life in Australians with multiple sclerosis using the assessment of quality of life-8-dimension (AQoL-8D) multi-attribute utility instrument

BackgroundHealth-related quality of life (HRQoL) has not been assessed in Australians with multiple sclerosis (MS) using a preferentially sensitive multi-attribute utility instrument. ObjectivesTo assess HRQoL and to quantify the impact of disability on health state utility values (HSUVs), and the physical and psychosocial health of people with MS using the Assessment of Quality of Life-8-Dimension (AQoL-8D) instrument. MethodsWe estimated HSUVs and the unique composite individual and super dimensional (physical and psychosocial) scores of the AQoL-8D for a large, representative sample (n=1,577) of Australians with MS. The estimates were compared to Australian general population norms and broken down by disability severity, classified as no disability (Expanded Disability Status Scale [EDSS] level: 0), mild (EDSS: 1-3.5), moderate (EDSS: 4-6) and severe (EDSS: 6.5-9.5). A multivariable regression model adjusted the association between MS disability severity and HSUVs for age, sex, MS onset type, DMTs usage status, and MS duration. Results: Mean overall HSUV at 0.61 (95% confidence interval [CI]: 0.60-0.62) was 0.18 units lower than the Australian population norm. HSUV decreased with increasing disability severity: 0.81 (95% CI: 0.80-0.83), 0.65 (95% CI: 0.63-0.67), 0.54 (95% CI: 0.52-0.56) and 0.48 (95% CI: 0.46-0.50) for no, mild, moderate and severe disability, respectively. The mean Physical super-dimension score of 0.57 (95% CI: 56-0.58) was 0.21 units lower than the Australian norm and the Psychosocial super-dimension of 0.33(95% CI: 32-0.34) was 0.16 units lower. Lower HRQoL was primarily driven by reduced scores on Independent living (-0.23), Pain (-0.15), Relationships (-0.13), Coping (-0.12), and Self-worth (-0.12). ConclusionsMS impacts all aspects of HRQoL. Effective pain management and support to maintain independent living, relationships, and self-worth can significantly improve the HRQoL of people with MS. Early diagnosis and affordable access to effective treatments to slow or prevent disability accumulation may also be helpful.

Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF

Objectives: The World Health Organization Quality of Life-BREF Scale (WHOQOL-BREF) is a generic QOL measure with four domains covering Physical, Psychological, Social and Environment. Providing the opportunity to contrast QoL with other conditions, or with population norms, the current study had three aims: 1) can the established domains of the WHOQOL-BREF be validated within a large ALS/MND population; 2) can a total score be validated and 3) can they provide interval level measurement? Methods: Data were obtained from the Trajectories of Outcomes in Neurological Conditions study. Internal construct validity was determined by fit of the data to the Rasch measurement model. Results: 636 participants with ALS/MND were included. All domains, except the Social domain, showed satisfactory fit to the Rasch model. All were unidimensional, and showed no Differential Item Functioning by age, gender, or onset type. Finally, a total score was validated from a bi-factor perspective. Conclusions: The WHOQOL-BREF is valid for use in populations with ALS/MND and can be analyzed to yield interval level measurement: It offers a range of domains that reflect QOL, which can be used for parametric analysis and for comparison with other conditions or general populations, two advantages for its inclusion as a trial outcome measure and for observational studies.

Ten-year disease progression in multiple sclerosis: walking declines more rapidly than arm and hand function

Background and aimsFrom a clinical perspective there is a difference in the decline of arm and hand function and leg function in patients with multiple sclerosis (PwMS). Therefore, this study investigated the course of walking and arm and hand functions in PwMS over the first 10 years after diagnosis, including whether any function declined earlier or faster. MethodsA long-term prospective follow-up study of an incidence cohort of 156 patients with a definite diagnosis of MS, either non-relapse onset (n=28) or relapse onset (n=128) type. Participants were systematically examined immediately after definite diagnosis, at 6 months, and at 1, 2, 3, 6 and 10 years. Walking was determined with the fast 10-meter timed walk test (10mTWT), arm and hand function with the Action Research Arm test (ARAT) and the nine-hole peg test (9HPT). The 10-year trajectories of walking and arm and hand functions were compared using standardized z-scores. ResultsFrom 3 years onwards the z-scores of the arm and leg function were visually diverging, with a trend towards significance at 6 years, and at 10 years the 10mTWT z-score is significantly higher than the 9HPT. This difference is more pronounced in non-relapse onset patients than in patients with relapse onset type MS, but present in both groups over the first 10 years. In the non-relapse onset group a difference in z-scores at 10 years post-diagnosis between the 10m TWT and 9HPT was found of -12.94 (95% confidence interval (CI) -20.2 to -5.73) for the right and -10.14 (95% CI -17.3 to -2.93) for the left hand. In the relapse onset group there was a difference at 10 years post-diagnosis of -2.17 (95% CI -3.75 to -0.59) for the right and a difference of -2.29 (95% CI -3.87 to -0.71) for the left hand. ConclusionThis is the first longitudinal study that shows that walking declines earlier and more rapidly than arm and hand function in patients with MS. These results give important insights that can be linked to the pathophysiological disease process regarding the ascending order of deterioration in patients with MS.

Combined Vitamin D, Ibuprofen and Glutamic Acid decarboxylase-alum Treatment in Recent Onset Type I Diabetes: Lessons from the DIABGAD Randomized Pilot Trial

Aim:Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D).Methods64 patients (T1D since <4 months, age 10–17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1–90 400 mg/day Ibuprofen, D1–450 vitamin D 2000 IU/day, D15, 45 sc. 20 μg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 μg GAD-alum D15, 45; placebo.Results:Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001).Conclusion:Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (ClinicalTrials.gov).

Narratives of Gestational Diabetes Provide a Lens to Tailor Postpartum Prevention and Monitoring Counseling.

Women with gestational diabetes mellitus (GDM) have a marked increased risk of early onset type 2 diabetes, but less than half initiate postpartum glucose testing or connect with a primary care provider for continued follow-up after giving birth. This study analyzed women's narratives about their GDM-affected pregnancies to (1) identify different patterns (narrative archetypes) that capture the GDM experience; (2) explore how these patterns relate to awareness of ongoing risk after pregnancy and affect participation in self-care, monitoring, and preventive health care going forward; and (3) explore the use of identified patterns to tailor conversations with patients during prenatal and postpartum care to their actual perceptions and concerns about future risk. Open-ended interviews elicited women's experiences and perspectives about GDM and its management. A narrative analysis first identified segments of text related to risk and behaviors and then applied Frank's narrative archetypes (restitution, chaos, quest) as an interpretive lens. Interviews were completed in English (n = 15), Spanish (n = 7), and Haitian Creole (n = 7). We found distinct patterns: stories of restitution (n = 13), quest (n = 4), chaos (n = 4), and mixed narratives (n = 7). Using these archetypes, we found differences in how women respond to challenges related to disease complexity, treatment, and future risks. These patterns led to marked differences in the steps women took to prevent early onset type 2 diabetes. Frank's narrative types provided insight into women's responses to clinical protocols, health care advice, and subsequent prevention actions. A restitution pattern may result in premature closure and lack of awareness of risk. Similarly, a chaos pattern may contribute to a sense of helplessness to implement follow-up recommendations, despite risk awareness. Understanding these patterns can help clinicians tailor individualized support as women transition from GDM with its focus on a healthy fetus and newborn to preventive self-care to protect their health.

Dyslipidemia in adolescents and young adults with type 1 and type 2 diabetes: a retrospective analysis

BackgroundYouth onset type 1 diabetes (T1D) and type 2 diabetes (T2D) is increasing and associated with earlier vascular complications and mortality. Dyslipidemia is an important modifiable cardiovascular (CVD) risk factor that is under-recognized and undertreated in youth with T1D and T2D. Given this, we evaluated the prevalence and associations between lipid concentrations and clinical CVD risk factors in youth with T1D compared to T2D at our large ethnically diverse diabetes center.MethodsA retrospective chart review was performed, evaluating patients with T1D or T2D seen at least once in clinic from 2015 to 2017, age 10–22 years of age, duration of diabetes at least 6 months on the date of most recent LDL-cholesterol (LDL-C) concentration, and not on statin therapy. We performed independent and multivariable linear regressions of LDL-C and HDL-cholesterol (HDL-C) concentrations.ResultsThere were 32.7% with T1D (n = 1701) and 47.7% with T2D (n = 298) with LDL-C above recommend goal (> 100 mg/dL/2.6 mmol/L). Furthermore, there were 9% with T1D and 16.4% with T2D with LDL > 130 mg/dL (> 3.4 mmol/L), who likely met criteria for starting statin therapy. Higher LDL-C and/or lower HDL-C were associated with increased age, diabetes duration, higher HbA1C, female sex, Hispanic ethnicity, obesity, and T2D. After adjusting for these risk factors in a multivariable linear regression model, the association of higher LDL-C and lower HDL-C was higher with T2D than T1D.ConclusionsThis highlights the need for more aggressive dyslipidemia screening and treatment in youth with diabetes, especially T2D. At our institution we have created and instituted quality improvement algorithms to try to address this need.

Continuous Glucose Monitoring Decreases Hypoglycemia Avoidance Behaviors, but Not Worry in Parents of Youth With New Onset Type 1 Diabetes.

Existing research shows that hypoglycemia fear (HF) is common in parents of children with established type 1 diabetes (T1D). We examined parental HF in the T1D recent-onset period and evaluated whether continuous glucose monitoring (CGM) adoption relates to improved outcomes of parental HF. In TACKLE-T1D, a prospective study of five- to nine-year olds with recent-onset T1D, parents completed the Hypoglycemia Fear Survey-Parents (HFS-P) at baseline (T1) and 6 (T2) and 12 (T3) months post-baseline. The HFS-P measures worry about hypoglycemia (HFS-Worry score) as well as hypoglycemia avoidance behaviors (HFS-Behavior score). We recorded CGM start dates for youth during the same time period through medical record review. Between T1 and T2, 31 youth (32.3%) initiated CGM therapy, and between T2 and T3, an additional 17 youth (17.7%) began using CGM, leaving 48 youth who never initiated CGM therapy (50%) in the recent-onset period. Parents reported moderate HFS-Worry scores at T1 (32.9 ± 11.9), which increased between T1 and T2 (37.6 ± 11.4, P < .001) and plateaued between T2 and T3 (37.7 ± 12.4, P = .89). In contrast, parental HFS-Behavior scores decreased between T1 (33.1 ± 5.8) and T2 (32.2 ± 6.0, P = .005) and plateaued between T2 and T3 (32.2 ± 6.0, P = .95). Baseline HFS-Behavior and Worry scores were associated with increased adoption of CGM between T1-T2 and T2-T3, respectively. Parents of children initiating CGM therapy between T1 and T2 showed the largest decrease in HFS-Behavior (P = .03). Initiating CGM therapy within the first 12 months of T1D may help reduce parents' use of hypoglycemia avoidance behaviors, but has little effect on parents' hypoglycemia worry.

Predictors of subclinical cardiovascular affection in Egyptian patients with juvenile idiopathic arthritis subtypes

BackgroundTo assess the subclinical cardiovascular affection in juvenile idiopathic arthritis (JIA) Egyptian patient subtypes using Doppler ultrasonography (US) for carotid and femoral arteries and detecting their predictorsResultsForty percent of the patients were polyarticular type, while 40% were systemic onset and 20% were oligoarticular. There was a statistically significant difference between JIA and controls in all parameters of subclinical atherosclerosis by ultrasonography except right external carotid velocity and (right and left) femoral velocity. There was also a highly significant increase in intima-media thickness (IMT) in systemic onset type of JIA. There was a statistically positive correlation between increased internal carotid velocity (right and left) and high erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP), lipid profile, and disease activity. High disease activity and lipid profile were valid predictors of subclinical atherosclerotic cardiovascular affection in JIA.ConclusionIncreased cardiovascular risks and subclinical atherosclerosis in patients with JIA especially systemic onset type may be due to higher prevalence of multiple risk factors in these patients. Doppler ultrasonography is a simple, non-invasive technique which can be used to detect subclinical atherosclerosis in JIA. Control of disease activity by treat to target strategy and proper diet control should be applied for every patient with JIA especially those with systemic onset type for future prevention of cardiovascular disease.

249-OR: A Randomized, Double-Blind Phase 2 Trial of the CXCR1/2 Inhibitor Ladarixin in Adult Patients with New-Onset Type 1 Diabetes

In preclinical studies, the investigational CXCR1/2 inhibitor ladarixin was shown to prevent and reverse diabetes in NOD mice. On this basis, a multicenter clinical trial in adult patients with new onset type 1 diabetes (T1D) was conducted (NCT02814838). Patients (Table 1) were randomized 2:1 to ladarixin (LDX) 400 mg BID or placebo (PLA) and randomized within 100 days from first insulin administration. Patients received 3 treatment cycles, each consisting of 14 days on and 14 days off drug, and were then followed up for 12 months. The difference between LDX and PLA in mixed meal tolerance test (MMTT) AUC of C peptide was statistically significant neither at week 13 (primary endpoint, p=0.330) nor at week 26 (p=0.404). Conversely, at week 26 patients having HbA1c&amp;lt;7% and daily insulin requirements &amp;lt;0.50 IU/kg were 76.6% and 45.8% in LDX and PLA, respectively (p=0.0095). In patients with baseline fasting C-peptide below the median value of trial population (prespecified subgroup analysis), the difference between LDX and PLA in MMTT AUC of C peptide trended at week 13 (p=0.111) and reached statistical significance at week 26 (p=0.041). Adverse Reactions occurring in ≥10% of patients included dyspepsia (16% LDX vs. 0% PLA) and headache (16% LDX vs. 15.4% PLA). Although primary endpoint was not met, secondary and subgroup analyses suggest further investigation of LDX in new onset T1D may be warranted. Disclosure E. Bosi: Consultant; Self; Abbott, Eli Lilly and Company, Medtronic, Novartis AG, Roche Diabetes Care, Sanofi. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd. E. Cossu: None. T. Linn: Advisory Panel; Self; Dompe Pharmaceuticals. L. Rose: None. B. Keymeulen: None. P. Gillard: None. L. Daffonchio: Employee; Self; Domp farmaceutici S.p.A. P.A. Ruffini: Employee; Self; Domp farmaceutici S.p.A., Domp farmaceutici S.p.A. M. Allegretti: Employee; Self; Domp Farmaceutici spa. L. Piemonti: Advisory Panel; Self; AstraZeneca, Roche Diabetes Care, Semma Therapeutics, Inc.

1297-P: Early CGM Initiation Improves HbA1c in T1D Youth over the First 15 Months

CGM use is associated with lower HbA1c in people with T1D. We hypothesize early CGM initiation will improve longer term HbA1c. Youth with newly diagnosed T1D from July 2018 to May 2019 (pilot cohort, n=65), were offered CGM initiation in the 1st month of T1D diagnosis with 62 initiating CGM. We compared HbA1c outcomes in this pilot cohort with those diagnosed in 2014-2016 (control cohort, n=272) with follow-up duration restricted to 15 months. HbA1c trajectories were visualized using locally estimated scatter plot smoothing (Figure 1) and compared using a generalized mixed effects regression model adjusted for baseline characteristics (HbA1c at onset, age, sex, race and insurance type). Mean HbA1c at diagnosis was higher in the pilot cohort (12.0% vs. 10.7%). Over the first 15 months of T1D, CGM was initiated in 95% of the pilot cohort (78.5% within 30 days), whereas 56% initiated in the control cohort (1.8% within 30 days). Adjusting for baseline characteristics, mean HbA1c levels were 0.5% lower (95%CI: -1.0, -0.1) in the pilot cohort at 3 months and 1.7% lower (95% CI: -2.6, -0.8) at 6 months compared to the control cohort. Differences beyond 6 months were also in the expected direction and statistically significant at the 0.05 level. Early initiation of CGM in the new onset period was associated with lower HbA1c compared to historic controls. These data suggest that early CGM initiation should be considered a part of standard new onset T1D care. Disclosure P. Prahalad: None. V. Ding: None. A. Addala: None. C. New: None. B.P. Conrad: None. A. Chmielewski: None. E. Geels: None. J. Leverenz: None. A. Martinez-Singh: None. P. Sagan: None. J. Senaldi: None. A. Freeman: None. D. Scheinker: None. K.K. Hood: Research Support; Self; Dexcom, Inc. Speaker’s Bureau; Self; LifeScan, Inc., MedIQ. M. Desai: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care.

1677-P: Higher Frequency of HLA DRB1*08:03 and DRB1*04:01 Observed in A-beta+ Ketosis-Prone Type 2 Diabetes in Japanese Subjects

Ketosis-prone type 2 diabetes, especially islet-associated autoantibody negative and beta-cell function reserved (A-beta+; KPD) group, is recognized as atypical diabetes. Because we detected insulin peptide reactive T cells in these KPD subjects, we realized that KPD possesses characteristics of type 1 diabetes (ADA meeting, 2017). Therefore, in this study, we examined HLA types. After institutional review board permission was obtained, written informed consent and blood samples were obtained from the enrolled Japanese subjects (KPD: 22 males and 0 female, mean onset age 36.4 years of age; acute onset type 1 diabetes (AT1D): 21 males and 22 females, mean onset age 36.3 years of age; slowly progressive type 1 diabetes (SP): 10 males and 10 females, mean onset age 49.0 years of age). Then the HLA allele frequency was compared to normal controls (http://hla.or.jp/med/frequency_search/ja/allele/search/R/). The frequencies of HLA DRB1*04:05 and DRB1*09:01, which are known susceptible alleles in Japanese type 1 diabetes, were not higher in KPD (13.6%, 27.3%, respectively) subjects as compared to controls (13.5%, 14.3%, respectively), whereas were significantly higher in AT1D (41.9%, 53.5%, respectively; both p&amp;lt;0.001) and SP subjects (45.0%, 40.0%, respectively; both p&amp;lt;0.002). However, interestingly, the frequency of HLA DRB1*08:03 was significantly higher in KPD (34.8%, p&amp;lt;0.001) subjects as compared to controls (8.3%), whereas it was not the case both in AT1D (4.7%) and SP (10.0%) subjects. Moreover, the frequency of HLA DRB1*04:01 which is known susceptible alleles in Caucasian type 1 diabetes was significantly higher in KPD (18.2%, p&amp;lt;0.001) subjects as compared to controls (0.9%), whereas it was not the case both in AT1D (2.3%) and SP (5.0%) subjects. In conclusion, although KPD subjects possess similar insulin peptide T cell responses to type 1 diabetes, different genetic background seems to exist probably leading to different clinical phenotype. Disclosure A. Shimada: Advisory Panel; Self; Astellas Pharma Inc. Speaker’s Bureau; Self; Eli Lilly Japan K.K., Novo Nordisk Inc., Sanofi-Aventis. A. Satomura: None. S. Suzuki: None. A. Haisa: None. Y. Oikawa: None. Funding Saitama Medical University

195-LB: Metabolomic Characterization of Laron and Guevara-Rosenbloom Syndromes Using UHPLC-HRMS

Laron syndrome (LS) is a rare autosomal recessive growth hormone (GH) insensitivity condition due to GH receptor mutation, and with phenotypic features likened to GH deficiency. The incidence of LS in Ecuador is very high and has gained worldwide attention due to its low incidence of cancer and diabetes mellitus. A more recently described population is affected with “Guevara-Rosenbloom syndrome” (GRS). While both groups exhibit severe short stature (-4 to -12 SDS), GRS subjects have normal GH signaling and responses and, unlike LS, have intrauterine growth retardation and early onset type 2 diabetes (T2DM). Since both groups have diminished insulin secretion, there is a unique opportunity to investigate their metabolome under each specific disease. Levels of certain amino acids in insulin-resistant (IR) states such as T2DM are distinct and special attention has been given to the predicting power of branched chain and aromatic amino acids, carnitines, and free fatty acids for IR and T2DM risk assessment. Our aim was to understand the metabolic differences between LS and GRS, which both have diminished insulin secretion but different GH counter-regulation as well as to compare these groups to normal controls. The metabolome of these 3 cohorts was assessed at the following instances: a) At the fasting state, and b) After an oral challenge of 1.5 mg/kg of glucose per kilogram of body weight, administered immediately after the fasting sample was drawn (samples were taken every 30 minutes for 5 hours [5h]). Preliminary results (by ANOVA) show a strong correlation, in the fasting state, between the control and the LS groups with clear discrimination from the GRS cohort, as determined by a heatmap of the top 100 features. Furthermore, the analysis of the 5h profile after the glucose challenge in the 3 groups revealed significant correlations in the levels of amino-acids that have been related to the genesis of IR and T2DM. This work represents the first deep-metabolome analysis in this unique study group. Disclosure V. Rubio: None. C.A. Chamberlain: None. C. Wasserfall: None. J. Guevara-Aguirre: None. A. Guevara: None. A.L. Rosenbloom: None. M.A. Atkinson: None. R.A. Yost: None. T.J. Garrett: None. Funding National Institutes of Health (U24DK097209)

Incidence of type 1 diabetes in 0 to 14 year olds in Australia from 2002 to 2017.

To determine the incidence of childhood onset type 1 diabetes in Australia from 2002 to 2017, and analyze incidence rate trends by calendar year, sex, and age at diagnosis. Children newly diagnosed with type 1 diabetes aged <15 years between 2002 and 2017 were identified from the National Diabetes Register, estimated to be ~99% complete. Data were obtained for diagnosis year, sex, age, and residential State/Territory at time of diagnosis. Population estimates by year, sex, single year of age, and State/Territory were obtained from the Australian Bureau of Statistics and Poisson regression used to examine incidence and trends by calendar year, sex, and age group at diagnosis. Between 2002 and 2017, there were 16 783 newly diagnosed cases of type 1 diabetes in children aged < 15 years (8684 boys: 8099 girls), giving a mean incidence of 25.0/1 00 000 person years (95%CI: 24.6, 25.4). A sinusoidal pattern in the incidence rate trend was observed with 5-yearly cycles providing the best model fit. No significant difference was observed in boys compared to girls (IRR 0.98 [95%CI: 0.95, 1.01]). Compared to 0 to 4 year olds, the mean incidence was 75% higher in 5 to 9 year olds, and 224% higher in 10 to 14 year olds. A decreasing incidence rate trend was observed in 0 to 4 year old boys and girls. This study reports updated incidence and incidence rate trends in children and adolescents diagnosed with type 1 diabetes in Australia. A cyclical pattern in incidence trend persists, with an overall decreasing trend observed only in the youngest age group.

Clinical profile and incidence of microvascular complications of childhood and adolescent onset type 1 and type 2 diabetes seen at a tertiary diabetes center in India.

To study the clinical characteristics and incidence of microvascular complications among childhood and adolescent onset type 1 (T1DM) and type 2 diabetes (T2DM) seen at a tertiary care diabetes center in India. From our electronic medical records, we retrieved clinical and biochemical details of 4555 individuals with childhood and adolescent onset diabetes (diagnosed below the age of 20 years) seen between 1992 and 2017. T1DM was diagnosed if there was history of ketoacidosis or fasting C-peptide <0.3 PMol/mL and stimulated C-peptide <0.6 PMol/mL or if insulin treatment was required from the time of diagnosis. T2DM was diagnosed based on absence of ketosis, or fasting C-peptide ≥0.6 PMol/mL and stimulated >1.0 PMoL/mL, or response to oral hypoglycemic agents for more than 2 years. We calculated the incidence rates of retinopathy (presence of at least one definite microaneurysm by retinal photography), nephropathy (urinary albumin excretion ≥30 μg/mg of creatinine) and neuropathy (vibration perception threshold ≥20 V) per 1000 person-years of follow up. Among the 4555 individuals with childhood and adolescent-onset diabetes, 71.4% had T1DM, 19.5% T2DM and 9.1% other forms of diabetes. Age at first visit and duration of diabetes were significantly higher in T2DM when compared to T1DM. The age adjusted incidence of retinopathy was 52.9/1000 person years (Confidence Intervals [CI]: 42.9-62.8) in T1DM and 49.8/1000 person years (CI 30.8-68.8) in T2DM; nephropathy, 6.2 (CI 3.3-9.0) and 13.8 (CI 5.6-22.0); and neuropathy, 8.8(CI 3.6-14.0) and 24.0 (CI 9.8-38.2) in T1DM and T2DM, respectively. The incidence of microvascular complications is high among childhood and adolescent-onset T1DM and T2DM and these calls for more aggressive control of diabetes.

Breast cancer and the black swan.

Most current research in cancer is attempting to find ways of preventing patients from dying after metastatic relapse. Driven by data and analysis, this project is an approach to solve the problem upstream, i.e., to prevent relapse.This project started with the unexpected observation of bimodal relapse patterns in breast and a number of other cancers. This was not explainable with the current cancer paradigm that has guided cancer therapy and early detection for many years. After much analysis using computer simulation and input from a number of medical specialties, we eventually came to the conclusion that the surgery to remove the primary tumour produced systemic inflammation for a week after surgery. This systemic inflammation apparently caused exits of cancer cells and micrometastases from dormant states and resulted in relapses in the first 3 years post-surgery.It was determined in a retrospective study that the common inexpensive perioperative non-steroidal anti-inflammatory drug (NSAID) ketorolac could curtail the early relapse events after breast cancer surgery. A second retrospective study strongly confirmed this but an apparently underpowered prospective study showed no advantage.We are analysing these data and are now proposing to test the perioperative NSAID at Beth Israel Deaconess Medical Centre with triple-negative breast cancer (TNBC) patients, the category that could respond best to the perioperative NSAID. If this works as well as we expect, we would then transfer this technology to low- and/or middle-incomes countries (LMICs), starting with Nigeria where early onset type of TNBC is common. There is an unmet need in LMICs, especially in countries like Nigeria (190 million population), for a means to prevent surgery induced relapse that we are attempting to resolve.This work aims, thus, to describe eventual mechanisms, and ways to test a solution addressing an unmet need. But first, we consider the context, including within an historical perspective, important to explain how and why a Kuhnian paradigm shift may be considered.