Visit 1 Research Articles

Are Questionnaires Helpful To Predict Exercise-Induced Bronchoconstriction (EIB) And Exercise-Induced Laryngeal Obstruction (EILO)?

Exercise induced laryngeal obstruction (EILO) is an important differential diagnosis to exercise induced bronchoconstriction (EIB) and diagnosed via continuous laryngoscopy while exercising (CLE). However, availability of CLE is limited to specialized centres. And without CLE EILO is often misdiagnosed as EIB. Therefore it is essential to carefully preselect potential EILO candidates. Aim of this study was to investigate whether two short questionnaires -Asthma Control Test (ACT) and Dyspnea Index (DI) evaluating upper airway-related dyspnea- can differentiate between EIB and EILO. Patients with dyspnea while exercising were analysed with an exercise challenge in the cold chamber (ECC) to diagnose EIB in visit 1 (V1), as appropriate a CLE in visit 2 (V2, 4-6 weeks after V1) and ACT and DI in V1 and V2. EIB patients were treated with asthma medication after V1. Complete dataset of 36 subjects were gathered. The ACT showed lower values in V2 in EILO compared to EIB patients. A lack of improvement in ACT in V2 after asthma medication of EIB patients is suspicious for additional EILO diagnosis. The DI showed higher values in V1 in EILO compared to EIB patients. A score≥30 can predict a positive CLE reaction. ACT and DI are valuable tools in preselecting CLE candidates to assure timely diagnostic despite limited diagnostic capabilities.

Palliative care in Autosomal Dominant Alzheimer’s disease due to PSEN1‐E280A genetic variant in Colombia

AbstractBackgroundAutosomal Dominant Alzheimer’s disease (ADAD) is a subtype of AD in which the symptoms begin before age 65. ADAD is an important subtype of AD as it affects people at productive and reproductive age, has a genetic origin in most of the cases and is one of the 10 causes of years lost to disability (YDLs) (1). Colombia has the largest kindred family with ADAD due to PSEN1‐E280A genetic variant, we aimed to characterize the palliative care need in a subsample of individuals from these families.MethodsWe performed an analytical observational study with one year follow‐up, data obtained from visit 1 (V1) is shown in this first report. Carriers of PSEN1‐E280A variant and GDS/FAST score above 4 were included. NECPAL and Edmonton surveys were conducted to the main carer to assess the need for palliative care and the frequency of symptoms. A complete medical evaluation was also performed.Results36 patients were included in V1. Median age was 53, most of the individuals were women (63.89%), lived in urban areas (88.89%) and the most common level of education was elementary‐middle school (47.22%). Clinical variables are listed in Table 2. Results of the poisson regression showed that dysphagia, pressure ulcers, asthenia perceived by the main carer, not being surprised if the patient died in the following 12 months (Surprise question of NECPAL scale), functional decline, use of medical services (2 visits in the past year), PAINAD scale and GDS/FAST scale were associated with the need for palliative care when adjusted by number of persons involved in caring, type of carer, hours of care per week and caregiver training.ConclusionADAD is a neurodegenerative disease that requires follow‐up by palliative care services. The health perception of the main carer should be taken into consideration when deciding the need for palliative care in these patients.

Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

Change in objective bulbar redness and symptoms after refit of weekly and monthly lenses into a water-gradient daily disposable lens material

Purpose. The purpose of this pilot study is to identify if fine graduated differences in objective redness of the eye exist in a cohort of non-symptomatic contact lens wearers. The pri- mary objective is the evaluation of change in bulbar redness when a non-symptomatic, 2-4 week contact lens wearer, is refitted to a Delefilcon A lens material. Secondary objectives include the determination of limbal redness, corneal and bulbar staining, and wearing comfort. Material and Methods. 52 habitual, asymptomatic, full time soft contact lens wearers were enrolled in a multicenter study. At the baseline visit, bulbar and limbal redness were measured objectively using the Redness-Scan of the Keratograph 5M (K5M). Habitual lenses, lens care type, comfort ratings and staining data were captured at baseline visit. A wash out phase of 6 ± 1 days was conducted in which the subjects did not wear any lenses before Delefilcon A lenses were dispensed at visit 2 (V2) for a wearing period of 26 ± 5 days. A follow up visit was planned after 6 ± 1 days from V2 and a final visit after additional 20 ± 4 days. During visits 2, 3 and 4, the same objective measurements were carried out and corresponding subjective data was captured. ANOVA, t-test for paired sam- ples, homogeneity test and Wilcoxon signed rank test were used for the statistical analyses. Results. A total number of 49 complete data sets were suc- cessfully evaluated. Objectively measured bulbar redness decreased by 0.121 (p = 0.003) from the baseline compared to the final visit. In the same period, limbal redness reduced by 0.151 (p = 0.000). In addition, an increase from 36 at baseline to 47 at V4 grade 0 ratings regarding corneal staining, and from 32 to 39 regarding bulbar staining was found, respec- tively. The averaged comfort rating with habitual lenses was 79.7 ± 16.6 compared to the final visit 89.0 ± 10.8. Conclusion. In the context of classic subjective grading hab- its which use fully grades in 1.0 steps, the objective Red- ness-Scan was able to detect finely graduated differences in the cohort of non-symptomatic wearers. The daily disposable test product delivers benefits to wearers in the form of re- duced bulbar and limbal redness, reduced corneal and bulbar staining, and statistically and clinically increased contact lens wearing comfort. Keywords contact lens, bulbar redness, wearing comfort

P39 Methotrexate induces epidermal DNA damage response and filaggrin in atopic eczema

Abstract Methotrexate (MTX) is an effective treatment for atopic eczema (AE), but its mechanism of action remains undefined. Our previous work identified keratinocytes as a direct target of MTX by increasing epidermal differentiation. Evidence supports the concept of DNA damage-induced keratinocyte differentiation; however, this has not been characterized in the context of MTX. We tested the hypothesis that MTX may act therapeutically in AE by inducing DNA damage and activating downstream DNA damage response signalling pathways. Patients with AE starting MTX (initial dose 10 mg weekly) were recruited (n = 12). The FLG status was determined by DNA genotyping. Clinical data and skin biopsies from lesional and nonlesional skin were collected at week 0 (baseline), week 2 [visit 1 (V1)] and week 12 [visit 2 (V2)] following MTX initiation. γH2A.X, a marker of DNA damage, was quantified to explore the relationship between DNA damage secondary to MTX treatment and FLG status. γH2A.X and filaggrin protein epidermal immunostaining were quantified. The male-to-female ratio was 8 : 4 and median participant age was 45 years. Median Eczema Area and Severity Index (EASI) score improved from 23.5 (baseline, n = 12) to 14.6 at V1 (n = 12) and 9.0 at V2 (n = 8). Median Dermatology Life Quality Index reduced from 15 (baseline, n = 12) to 10.5 (V2, n = 8). Four patients were FLG heterozygotes and eight were FLG wild type. In combined analysis of all patients, epidermal γH2A.X increased in lesional skin at both time points [n = 6 (V1: P = 0.022; V2: P = 0.009)] and in nonlesional skin by V2 (n = 6; P = 0.021). γH2A.X increased in lesional skin at V2 in both FLG heterozygotes (P = 0.044) and wild types (P = 0.038). Epidermal filaggrin in lesional and nonlesional skin increased at V1 and V2 in all patients combined (n = 5; P = 0.029). Filaggrin increased in the nonlesional skin of FLG heterozygotes (P = 0.044) and in the lesional skin of FLG wild-type patients (P = 0.009) by V2. Transcriptomic (RNAseq) analysis was performed on skin biopsies (n = 11 patients; n = 42 samples). We explored the relationship of gene expression with severity (EASI) and FLG status. AKR1B10, IL22 and LGALS7 expression increased with disease severity. The AKR1B10 (regulates keratinocyte differentiation) and LGALS7 expression (expressed during barrier dysfunction) response with EASI was enhanced in FLG heterozygotes vs. wild-type patients. Canonical pathways were upregulated in lesional skin at V2 vs. baseline. Through epidermal immunostaining and transcriptomic gene analysis, we demonstrated evidence of DNA damage and filaggrin induction in patients with AE following MTX therapy, with associated improved disease outcomes.

Development, sensitivity and reliability of a French version of the Leeds food preference questionnaire (LFPQ-fr) for the evaluation of food preferences and reward

BackgroundThere is a growing global interest in the evaluation of food reward, necessitating the adaptation of culturally appropriate instruments for use in empirical studies. This work presents the development and validation of a culturally adapted French version of the Leeds Food Preference Questionnaire (LFPQ-fr). MethodsThe LFPQ-fr was developed and validated in healthy-weight adults using the following systematic approach: i) selection and validation of appropriate food pictures; ii) linguistic translation of liking and wanting constructs in the target population (n = 430; 81% female; 42.2 ± 12.7 years); iii) validation of the sensitivity and reliability of the task performed in a fasted state and in response to a standardized test meal (n = 50; 50% female; 30.0 ± 8.4 years). ResultsDuring the first and second phases, the nutritional and perceptual validation of culturally appropriate food pictures and pertinent reward constructs, respectively, was demonstrated in a healthy-weight French sample. Findings from the third phase indicated that all food reward components were sensitive to the test meal and showed moderate to high agreement in both fasted (Lin's CCC =0.72–0.94) and fed (Lin's CCC = 0.53–0.80) appetitive states between visit 1 (V1) and visit (V2). Except for explicit liking fat bias, all primary outcomes were statistically consistent in fasted and fed states between V1 and V2. Changes in fat and taste biases in response to a standardized meal for all primary outcomes were also consistent between V1 and V2 except for explicit liking fat bias (Lin's CCC = 0.49- 0.72). ConclusionThe LFPQ-fr developed and tested in this study is a reproducible and reliable method to assess food reward in both the fasted and fed states in a healthy-weight French population.

Abstract P181: Impact of Blood Pressure on Longitudinal Patterns of Pre-Heart Failure in a Hispanic/Latino Population-Based Cohort: Results From the Echocardiographic Study of Latinos (ECHO SOL)

Introduction: Hypertension (HTN) is a modifiable risk factor for heart failure (HF) and a common antecedent for pre-HF, but its effect on pre-HF is not well known. Hypothesis: Variations in blood pressure (BP) will be related to distinct patterns of pre-HF (prevalent and incident). Methods: Two echocardiograms were performed ∼4.3 years apart on 1643 adults in the Hispanic/Latino cohort ECHO SOL. Pre-HF was defined as systolic dysfunction (LVEF <50%/ global longitudinal strain >15%) or diastolic dysfunction (≥ Grade 1) or left ventricular remodeling (left ventricular mass index >115 for men, >95 for women/ relative wall thickness >0.42). At visit 1 (V1), 953 were normotensives, and 690 hypertensives [controlled and uncontrolled]. Groups were subdivided at visit 2 (V2) based on maintenance or changes from V1 BP status. Logistic regression models were used to determine the association of BP with pre-HF. All analyses were weighted due to complex survey design. Results: Higher BP at baseline (linear and by tertiles) was significantly associated with prevalent pre HF (table 1). Higher pulse pressure was significantly associated with incident pre-HF (table 1). Normotensives at V1 who later developed HTN (≥ 130/80 mmHg) at V2 had higher odds of having prevalent (2.05 [95% CI, 1.24 - 3.39]) and incident (2.42 [95% CI, 1.07 - 5.51]) pre-HF than those who remained with BP <130/80 mmHg at V2. When defining uncontrolled HTN as BP ≥ 130/80 mmHg, we found that uncontrolled hypertensives at V1 who remained uncontrolled at V2 had higher odds (2.75 [95% CI, 1.18 - 6.41]) of having prevalent pre-HF compared to uncontrolled hypertensives who progressed to controlled HTN at V2 (<130/80 mmHg). Conclusion A significant association exists between BP and prevalent/incident pre-HF in the Hispanic/Latino population. Additionally, those who progress from normal BP to hypertension face an increased risk of developing prevalent/incident pre-HF compared to those who remain normotensives. Blood pressure control of <130/80 mmHg could result in less prevalent pre-HF.

A closer look at yoga nidra- early randomized sleep lab investigations

ObjectivesWe aimed to examine trial feasibility plus physiological and psychological effects of a guided meditation practice, Yoga Nidra, in adults with self-reported insomnia. MethodsTwenty-two adults with self-reported insomnia were recruited to attend two visits at our research center. At Visit 1 (V1), participants were asked to lie quietly for ninety minutes. The primary outcome was change in electroencephalography (EEG). Heart rate variability (HRV), respiratory rate and self-reported mood and anxiety were also measured. At Visit 2 (V2), the same protocol was followed, except half of participants were randomized to practice Yoga Nidra for the first 30-min. ResultsThere were no between-group changes (V1-V2) in alpha EEG power at O1 (Intervention: 13 ± 70%; Control: −20 ± 40%), HRV or sleep onset latency in response to Yoga Nidra. Respiratory rate, however, showed statistically significant difference between groups (Yoga Nidra −1.4 breaths per minute (bpm) change during and − 2.1 bpm afterwards vs. Control +0.2 bpm during and + 0.4 bpm after; p = .03 for both during and after). The intervention displayed good acceptability (well-tolerated) and credibility (perceived benefit ratings) with implementation success (target sample size reached; 5% dropout rate). ConclusionsThis preliminary clinical trial provides early evidence that Yoga Nidra is a well-tolerated, feasible intervention for adults reporting insomnia. Decreased respiratory rate in response to Yoga Nidra needs to be confirmed in more definitive studies. Trial registration informationThis trial was registered on ClinicalTrials.gov as “A Closer Look at Yoga Nidra: Sleep Lab Analyses” (NCT#03685227).

Dynamics of human milk oligosaccharides in early lactation and relation with growth and appetitive traits of Filipino breastfed infants

Human milk oligosaccharides play a key role in the maturation of the infant gut microbiome and immune system and are hypothesized to affect growth. This study examined the temporal changes of 24 HMOs and their associations to infant growth and appetitive traits in an exploratory, prospective, observational, study of 41 Filipino mother-infant dyads. Exclusively breastfed, healthy, term infants were enrolled at 21–26 days of age (≈ 0.75 mo) and followed for 6 months. Infant growth measures and appetitive traits were collected at visit 1 (V1) (≈ 0.75 mo), V2 (≈ 1.5 mo), V3 (2.5 mo), V4 (2.75 mo), V5 (4 mo), and V6 (6 mo), while HMOs were measured at V1, V2, V3 and V5. Overall exposure to each HMO was summarized as area under the curve from baseline to 4 months of age and examined in association with each measure of growth at 6 months using linear regression adjusted for maternal age at birth, infant sex, birth weight, and mode of delivery. We saw modest associations between several HMOs and infant growth parameters. Our results suggest that specific HMOs, partly as proxy for milk groups (defined by Secretor and Lewis status), may be associated with head circumference and length, increasing their relevance especially in populations at the lower end of the WHO growth curve. We did not identify the same HMOs associated with infant appetitive traits, indicating that at least in our cohort, changes in appetite were not driving the observed associations between HMOs and growth.Clinical trial registration: NCT03387124.

Effectiveness of wearable devices as a support strategy for maintaining physical activity after a structured exercise intervention for employees with metabolic syndrome: a randomized controlled trial

BackgroundMetabolic syndrome (MetS) is associated with an increased risk for cardiovascular events and high socioeconomic costs. Despite lifestyle interventions focusing on exercise are effective strategies to improve parameters of the above aspects, many programs fail to show sustained effects in the long-term.MethodsAt visit 2 (V2) 129 company employees with diagnosed MetS, who previously participated in a 6-month telemonitoring-supported exercise intervention, were randomized into three subgroups for a 6-month maintenance treatment phase. A wearable activity device was provided to subgroup A and B to assess and to track physical activity. Further subgroup A attended personal consultations with individual instructions for exercise activities. Subgroup C received neither technical nor personal support. 6 months later at visit (V3), changes in exercise capacity, MetS severity, work ability, health-related quality of life and anxiety and depression were compared between the subgroups with an analysis of variance with repeated measurements.ResultsThe total physical activity (in MET*h/week) declined between visit 2 and visit 3 (subgroup A: V2: 48.0 ± 33.6, V3: 37.1 ± 23.0; subgroup B: V2: 52.6 ± 35.7, V3: 43.8 ± 40.7, subgroup C: V2: 51.5 ± 29.7, V3: 36.9 ± 22.8, for all p = 0.00) with no between-subgroup differences over time (p = 0.68). In all three subgroups the initial improvements in relative exercise capacity and MetS severity were maintained. Work ability declined significantly in subgroup C (V2: 40.3 ± 5.0, V3: 39.1 ± 5.7; p < 0.05), but remained stable in the other subgroups with no between-subgroup differences over time (p = 0.38). Health-related quality of life and anxiety and depression severity also showed no significant differences over time.ConclusionsDespite the maintenance of physical activity could not be achieved, most of the health related outcomes remained stable and above baseline value, with no difference regarding the support strategy during the maintenance treatment phase.Trial registration The study was completed as a cooperation project between the Volkswagen AG and the Hannover Medical School (ClinicalTrials.gov Identifier: NCT02029131).

Long‐term progression of amyloid and tau biomarker profiles: Four‐year follow‐up imaging study

AbstractBackgroundTo investigate long‐term progression of amyloid (A) and tau (T) image‐based biomarker profiles in a cohort with wide range of cognitive status.MethodIn 273 participants [96 cognitively unimpaired (CU), 106 mild cognitive impairment (MCI), and 71 AD dementia (DEM)] who completed 18F‐florbetaben and 18F‐flortaucipir PET studies for visit 1 (V1), 167 participants (62 CU, 68 MCI, and 37 DEM) completed visit 2 (V2) PET studies at two years, and subsequently 66 participants (23 CU, 33 MCI, and 10 DEM) completed visit 3 (V3) PET studies at about four years (mean 4.5 years) after the V1 study. A/T biomarker profiles were determined by using the cut‐off standardized uptake value ratios of composite regions most vulnerable to each pathology.Result5.6% (5/90) of participants converted from A‐ to A+ at V2 and 18.5% (5/27) at V3. Likewise, 4.2% (5/118) of participants converted from T‐ to T+ at V2 and 17.4% (8/46) at V3. In comparison with lower conversion rate from T‐ to T+ in the A‐T‐ participants [2.3% (2 A‐T+ / 86 A‐T‐) at V2 and 7.4% (2 A+T+ / 27 A‐T‐) at V3], A+T‐ participants exhibited higher conversion rate from T‐ to T+ [9.4% (3 A+T+ / 32 A+T‐) at V2 and 31.6% (6 A+T+ / 19 A+T‐) at V3].ConclusionPositive conversion of A/T biomarkers occurs steadily throughout the long‐term period. Compared to A‐ individuals, positive conversion of T biomarker occurs four times more frequently in A+ individuals.

Towards clinical application of tau PET: Prognostics

AbstractBackgroundTau PET is now considered to be a disease stage biomarker for reflecting of Alzheimer’s disease (AD) severity. Recent longitudinal studies showed a progression of cortical tau burden and a predictability of baseline tau PET for further tau accumulation, cortical atrophy, and even clinical progression in the short term. In this study, we sought to investigate long‐term changes in tau burden and predictability of tau PET for long‐term disease progression.MethodIn a cohort with 273 participants who had completed visit 1 (V1) assessments including two PET scans (18F‐florbetaben and 18F‐flortaucipir), MR imaging studies and neuropsychological function tests, 77 Aβ+ participants [9 cognitively unimpaired (CU) and 38 mild cognitive impairment (MCI), and 30 AD dementia (DEM)] completed visit 2 (V2) assessments at two years, and subsequently 39 Aβ+ participants (6 CU, 24 MCI, and 9 DEM) completed visit 3 (V3) assessments at about four years (mean 4.6 years) after the V1 study. After correcting for partial volume effect, we measured regional standardized uptake value ratio (SUVR) values with cerebellar crus median as a reference and regional volumes, as well.ResultDuring the short‐ (V1 to V2) and long‐term (V1 to V3) periods, tau burden significantly increased in the widespread cortex, particularly in the medial and lateral temporal cortices. In 33 cognitively impaired patients who completed both V2 and V3 scans, DEM patients exhibited higher global cortical tau accumulation rates (V1 to V2 = 0.066 and V2 to V3 = 0.058 SUVR/year) than MCI patients (V1 to V2 = 0.044 and V2 to V3 = 0.051 SUVR/year). Tau burden at V1 correlated strongly with the tau accumulation and volume reduction rates, particularly in the lateral temporal cortex and also correlated with the global cognitive decline rate, particularly in the prefrontal and parietal cortices. Likewise, in both short‐ and long‐term data, tau accumulation rate correlated with the volume reduction and global cognitive decline rates.ConclusionTau accumulated progressively throughout a four year long‐term follow‐up period. Progression of tau pathology, cortical atrophy and cognitive decline can be predicted by baseline tau burden. Tau PET is a useful imaging biomarker in predicting long‐term disease progression.

Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele (55–200 CGG repeats; PM) in the fragile X mental retardation (FMR1) gene. It is currently unknown how the observed brain changes are associated with metabolic signatures in individuals who develop the disorder over time. The primary objective of this study was to investigate the correlation between longitudinal changes in the brain (area of the pons, midbrain, and MCP width) and the changes in the expression level of metabolic biomarkers of early diagnosis and progression of FXTAS in PM who, as part of an ongoing longitudinal study, emerged into two distinct categories. These included those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not meet the criteria of diagnosis (non-converters, NCON) and were compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Magnetic Resonance Imaging (MRIs) acquisition was obtained on a 3T Siemens Trio scanner and metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. Our findings indicate that differential metabolite levels are linked with the area of the pons between healthy control and premutation groups. More specifically, we observed a significant association of ceramides and mannonate metabolites with a decreased area of the pons, both at visit 1 (V1) and visit 2 (V2) only in the CON as compared to the NCON group suggesting their potential role in the development of the disorder. In addition, we found a significant correlation of these metabolic signatures with the FXTAS stage at V2 indicating their contribution to the progression and pathogenesis of FXTAS. Interestingly, these metabolites, as part of lipid and sphingolipid lipids pathways, provide evidence of the role that their dysregulation plays in the development of FXTAS and inform us as potential targets for personalized therapeutic development.

Clinical Benefit of Insulin Glargine 300 U/mL Among Patients with Type 2 Diabetes Mellitus Previously Uncontrolled on Basal or Premixed Insulin in Serbia: A Prospective, Observational, Single-Arm, Multicenter, Real-World Study.

IntroductionInsulin glargine 300 U/mL (Gla-300) is a novel glargine formulation which shows slower and more prolonged absorption following subcutaneous administration in comparison to insulin glargine 100 U/mL. In this prospective, observational, single-arm, multicenter, real-world study conducted in Serbia, we evaluated the effectiveness and safety of Gla-300 in patients with type 2 diabetes mellitus (T2DM) previously inadequately controlled with different basal or premix insulin therapy regimes.MethodsA total of 350 patients with T2DM were enrolled by 27 physicians, from date of the first patient in (12 December 2017) to the date of last patient completed/last patient out (30 October 2018), from both medical centers and general hospitals. Patients’ observation and data collection were performed at visit 1 (V1), i.e., the inclusion visit (3–6 months after Gla-300 introduction), including collection of retrospective data from the patients’ medical charts at the time of Gla-300 introduction, and at visit 2 (V2) (3–6 months after V1). The primary objective was to assess the change in glycated hemoglobin (HbA1c) level from day of the Gla-300 initiation to the end of the observational period, while the secondary objectives included other effectiveness, as well as safety and other clinically relevant data.ResultsThe mean age of the 350 patients was 63.4 ± 8.4 years and 56.3% were female. The mean duration of diabetes was 13.4 ± 7.4 years, while the mean duration of insulin therapy prior to Gla-300 initiation was 5.3 ± 3.9 years. There was a significant reduction in HbA1c level at each visit compared to the previous visit (8.63 ± 1.52% at baseline prior to Gla-300 initiation, 7.87 ± 1.13% at V1, 7.45 ± 1.05% at V2; p < 0.01 vs. previous visit) accompanied by significant reduction of all hypoglycemic events (p < 0.01).ConclusionInitiation of Gla-300 therapy significantly improved glycemic control and reduced the risk of hypoglycemia in patients with T2DM inadequately controlled with different basal or premix insulin therapy regimes.FundingSanofi Serbia.

Abstract P188: Anxiety Is Associated With Six-year Blood Pressure Change And Incident Hypertension: Findings From The Hispanic Community Health Study/ Study Of Latinos

Introduction: Prior research on the association of anxiety with hypertension has yielded mixed results. Despite the high burden of both conditions in Hispanics/Latinos, little is known about their association in this population. This study examined the longitudinal relationship of trait anxiety with changes in BP and incidence of hypertension. Hypothesis: Higher trait anxiety at Visit 1 (V1) will be associated with greater increases in BP and incident hypertension over 6 years. Methods: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multi-center prospective community-based study of 16,415 diverse Hispanics/Latinos ages 18-74 at V1 (2008-11). Data included 11,048 participants with complete information on BP, trait anxiety, and other variables at V1 and V2 (2014-17). Trait anxiety was measured at V1 using the 10-item Spielberger Trait Anxiety Scale, which was dichotomized into low and high using a cut-point of 20 points, the top quartile in the HCHS/SOL cohort. BP was measured using a standardized protocol and validated automated device. Hypertension was defined as systolic BP ≥ 140 or diastolic BP ≥ 90 mm Hg or self-reported antihypertensive medication use. Linear regressions were used to examine the association of anxiety with BP change; to account for medication use, 9 mmHg and 6 mmHg were added to systolic and diastolic BP of treated participants, respectively. The association of anxiety with incident hypertension at V2 was examined using Poisson regression among those without hypertension at V1 ( N = 7,878). Estimates were adjusted for complex survey design, sociodemographic factors, baseline BP, antidepressant/anxiolytic medication use, and health conditions. Results: Mean baseline age was 45.8 years and 60% were women. Mean change was 3.13 ( SE = 15.67) in systolic and 0.21 ( SE = 9.73) in diastolic BP. Individuals with high, compared to those with low, trait anxiety had greater increases in systolic ( B = 1.10, 95% CI = 0.28-1.93, p = 0.009) and diastolic BP ( B = 0.69, 95% CI = 0.11-1.27, p = 0.02) over 6 years, after adjusting for covariates. Individuals with high, relative to those with low, trait anxiety had an 18% higher risk of hypertension (RR = 1.18, 95% CI = 1.03-1.34, p = 0.012). Conclusions: Elevated trait anxiety is associated with small increases in BP over 6 years and an 18% higher risk of hypertension among diverse Hispanics/Latino adults. Research on the mechanisms underlying these relationships among Hispanics/Latinos is warranted to develop effective interventions to prevent and treat hypertension in this population.

472 Sleep Quality in Pregnancy: An Analysis of Cardiopulmonary Coupling in the nuMoM2b Cohort

Abstract Introduction The impact of pregnancy on sleep quality and sleep-breathing is of interest due to concerns of an impact on maternal, intra-uterine and neonatal health. The Sleep Disordered Breathing (SDB) sub-study of the Nulliparous Pregnancy Outcomes Study (NuMoM2b) provided a large cohort of single gestational women who underwent home sleep apnea testing (HSAT) to evaluate for SDB. To evaluate changes in sleep during pregnancy, we utilized publicly available data from http://www.sleepdata.org for cardiopulmonary coupling (CPC) analysis to evaluate SDB, as well as sleep duration and quality. No outcomes data is currently available. Methods Standardized Level 3 HSAT was performed after visit 1 (V1), (6–15 weeks’ gestation) and visit 3 (V3), (22 -31 weeks’ gestation) on 3702 women from the NuMoM2b cohort. CPC-analysis was performed using clinically validated algorithms based on CPC-method using ECG and oxygen saturation data (SpO2) as the input signals. SleepImage Apnea Hypopnea Index (sAHI) was calculated to evaluate for SDB (FDA; 182618). Additional calculations to determine sleep latency, sleep duration, wake after sleep onset, and sleep quality (SQI) were performed. The SQI-metric incorporates measures of sleep stability and instability and is then presented on a scale of 0 – 100 where a higher number is desirable. Results 3,261 &amp; 2,511 participants had data at visits 1 &amp; 3, respectively. A total of 3,012 and 2,332 individuals had ECG data of sufficient quality. The mean age of the analyzed cohort was 27 years old. SDB events were overall low, but significantly increased across visits, sAHI [(1.6 ± 2.5)/hour (V1) vs (2.9 ± 4.1) (V3)], p&amp;lt; 0.001. There was a statistically significant increase in sleep latency [7.4 ± 12.7 (V1) vs 18.7 ± 27.8 (V3)], p&amp;lt; 0.001 and reduction in total sleep time [401.2 ± 85.6 (V1) vs 348.5 ± 79.3 (V3)], p&amp;lt; 0.001. Most notably, there was a &amp;gt;10% reduction in the SQI, indicative of increased unstable, fragmented sleep as pregnancy progressed [72.1 ± 13.8 (V1), 60.5 ± 16.2 (V3)], p &amp;lt; 0.001. Conclusion Using objective measures based on CPC analysis from HSAT derived signals, sleep disordered breathing, sleep duration and sleep quality are all adversely impacted as gestation progresses. Support (if any):

Prospective Longitudinal Study Evaluating Comprehensive Metabolic and Life Style Characteristics of Pancreas Transplantation Recipients

Introduction: Pancreas Transplantation (PT) improves quality of life in Type 1 Diabetes (T1D) patients but limited longitudinal data are available regarding comprehensive metabolic assessment and lifestyle. Our objective was to comprehensively assess T1D patients who underwent PT (PTA and SPK) ≥ 1 year prior on two separate visits 1 year apart. Methodology: We studied 12 PT recipients ≥1 year post PT. Two assessments 1 year apart included comprehensive assessment of graft function using standard mixed meal tolerance test (MMTT), Continuous Glucose Monitoring (CGM) for 1 week, body composition using DEXA scan, physical activity using ActiGraph for 1 week and dietary assessment by VIOCARE®. Results: PT recipients (9F) were 55.5± 9.7 years old, 91.7 % Caucasian with 34.9 ± 12.3 years of diabetes, 6.7 ± 5.2 years (range-1.3–17.6 years) after PT. Ten participants underwent Pancreas Transplantation alone and two received Simultaneous Pancreas Kidney transplantation. Visit 1(V1) showed HbA1c 5.5 ± 0.7%, Fructosamine 238.4 ± 25.6 mcmol/L, BMI 31.2 ± 6.7 kg/m2, fasting plasma glucose (FPG) 95.2 ± 19.4mg/dL and C-peptide 2.6 ± 1.0 ng/ml and visit 2 (V2) HbA1c 5.5 ± 0.6%, Fructosamine 244.4 ± 41.3 mcmol/L, BMI 29.9 ± 5.1kg/m2, FPG 95.4 ± 27.7mg/dL, and C-peptide 2.5 ± 0.8 ng/ml (p-value not significant). One week CGM (n=9) showed excellent glucose control at both visits with mean glucose 117.8 ± 7.0 vs.112 ± 6.2 mg/dl and 96.3 ± 3.6 vs. 96.9±2.8 % time in target range (70-180mg/dl). Time >180mg/dl and >250mg/dl were 2.7 ± 3.0 vs. 1.3±1.7 % (p=0.0413) and 0.2 ± 0.6 vs. 0.1 ± 0.1 % respectively. Mild CGM hypoglycemia (<70 mg/dl) was observed during both visits (1.0 ± 1.0 vs. 1.7± 2 %). CV was 21.1 ± 5.5 and 20.1 ± 4.8 %. Eight recipients underwent MMTT and showed excellent response to Boost® with no significant difference between visits with exception of insulin concentrations at 60 mins (increased from V1) and 90 mins (decreased from V1) (p=0.0424 and 0.0235). DEXA (n=10) revealed similar total % mean fat, and fat distribution in arms, legs and trunk. ActiGraph (n=10) showed similar physical activity during both visits with 16761 ± 5176 and 14499 ± 4192 average steps/day respectively. Mean MET score was 1.6 ± 0.4 and 1.6 ± 0.2 indicating light intensity activity during both periods. Total mean sedentary bouts increased over 1 year (49.6 ± 39.1 vs. 60.8 ± 43.7, p=0.0038). Dietary assessment in 11 recipients showed no significant difference in dietary intake with calories intake 1.3± 0.4 vs. 1.2±0.5 daily Harris-Benedict and macronutrient intake with fat of 36.7 ± 4.3 % and 36.5 ± 5.7 %, CHO of 45.7 ± 5.5 % and 45.7 ± 5.5 % and Omega-3 of 0.1 ± 0.1 g and 0.05 ± 0.1 g respectively. Conclusion: PT recipients have excellent glucose control and pancreas graft function 1 or more years after PT when assessed over successive 2 years with suboptimal body composition and dietary intake and above average physical activity.

Longitudinal Investigation of Pubertal Milestones and Hormones as a Function of Body Fat in Girls

Background: Studies comparing the timing and pace of puberty in overweight/obese girls (OW/OB) vs normal weight girls (NW) have produced conflicting results; some suggest earlier activation of the central components of the reproductive axis in OB while others are more consistent with a peripheral source of estrogen (e.g. adipose tissue) driving puberty in OB. Importantly, there have been no longitudinal assessments of both clinical and biochemical pubertal markers in OB vs. NW. Methods: 90 healthy pre-menarchal girls (26 OW/OB, 54 NW) from the community, aged 8.2-14.7 years, completed 2.8 ± 1.7 (mean, SD) study visits over the course of 4 years. Visits included dual-energy x-ray absorptiometry to calculate percent total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; stages A-E), pelvic ultrasound, hand x-ray (bone age, BA), blood tests for reproductive hormones, and urine collection to determine a vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells. Menarchal status was determined at each visit and via follow-up questionnaires. The effect of TBF on hormones and markers of estrogen action, the pace of breast maturation, and age at menarche were determined using a mixed, multi-state, or Cox proportional hazards model, respectively. Mixed and Cox models controlled for BMORPH at visit 1 (V1) and race. Results: NW girls were older than OW/OB (11.3 vs. 10.2 yrs, p<0.01) at V1, more likely to be non-Hispanic White (66 vs. 40%, p=0.03), and had more advanced breast morphology BMORPH (p<0.01). LH, E2, VMI, BA, and ovarian and uterine volume increased with time with no effect of TBF. There was an interaction between time and TBF for FSH, INHB, E1, Total T, Free T, and A’dione (p<0.05): levels were initially similar in all TBF groups, but after 1 yr, levels increased in girls with higher TBF, plateaued in girls with mid-range TBF, and decreased in girls with lower TBF. Girls with higher TBF progressed through BMORPH stage D (corresponding to growth/arborization of the breast ductal system), more slowly than girls with lower TBF but achieved menarche at a younger age (risk 1.04x higher per 1 unit increase in TBF). Conclusions: Intensive reproductive phenotyping of girls during the pubertal transition reveals that both the neuroendocrine and ovarian components of the axis are generally preserved in girls with higher TBF but that the axis appears to be activated earlier than in girls with lower TBF. In late puberty, however, girls with higher TBF demonstrate subtle differences in standard hormonal (e.g. serum FSH, INHB, and androgen) and clinical (e.g. delayed growth of breast bud) markers of puberty. Investigation of the mechanistic basis for these differences and their potential clinical consequences for girls with higher TBF deserves further study.

Longitudinal Tracking of Autonomic and Cardiovascular Function in Individuals Previously Diagnosed with COVID‐19

BackgroundIndividuals infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) exhibit a wide variety of symptoms, indicating potential systemic effects of the virus. Anecdotally, many patients ‐ even those who experience only mild cases initially ‐ continue to suffer from symptoms months after diagnosis, including indicators of potential autonomic dysfunction like tachycardia upon standing. However, the long‐term impact of and recovery from COVID‐19 on autonomic and cardiovascular function in otherwise healthy individuals remains largely unclear.MethodsOtherwise healthy young adults (n=11, 6F) who had tested positive for SARS‐CoV‐2 came to the laboratory two times: Visit 1 (V1) was 3‐4 weeks post‐diagnosis, and Visit 2 (V2) was one month later. Muscle sympathetic nerve activity (MSNA; n=2) via microneurography, beat by beat systolic (SBP) and diastolic (DBP) arterial blood pressure via finger photoplethysmography, and heart rate (HR) were continuously measured in subjects at rest, during a 2‐min cold pressor test (CPT), and during 5 min each at 30° and 60° head up tilt (HUT; no MSNA). Paired sample t‐tests and two‐way ANOVA were used to determine differences in the cardiovascular outcome measures between visits.ResultsResting SBP (123 ± 18 vs. 119 ± 17 mmHg), DBP (73 ± 16 vs. 69 ± 7 mmHg), and HR (63 ± 10 vs. 62 ± 9 bpm) did not change from V1 to V2. Preliminary data (n=2) indicates MSNA may decrease from V1 to V2 (14.5 ± 4 vs. 9 ± 3 bursts·min‐1), but the study is currently not powered to examine statistical significance. During the 2‐minute CPT protocol, SBP (150 ± 10 vs. 145 ± 13 mmHg, p=0.08), DBP (94 ± 12 vs. 88 ± 12 mmHg, p=0.10), and HR (77 ± 19 vs. 71 ± 11 bpm, p=0.11) tended to be the same or lower from V1 to V2. Likewise, individual data from two subjects suggests MSNA reactivity during a painful stimulus (CPT) may decrease from V1 to V2 (16 ± 4 vs 10 ± 3 bursts·min‐1). These two subjects also exhibited reduced MSNA during the three‐minute CPT recovery period from V1 to V2 (14 ± 2 vs. 7 ± 1 bursts·min‐1). During both 30° and 60° HUT, SBP, DBP, and HR responses were similar between V1 and V2.ConclusionYoung, otherwise healthy individuals infected with SARS‐CoV‐2 may have exaggerated sympathetic neural and cardiovascular responses to physiological stress 3‐4 weeks post‐positive test date. However, preliminary data indicates that sympathetic and cardiovascular reactivity to painful stimuli is reduced from one‐ to two‐months post‐diagnosis. Continued monitoring of autonomic and cardiovascular function is warranted to determine the long‐term consequences of contracting SARS‐CoV‐2.

Sex steroids and adiposity in a prospective observational cohort of youth.

ObjectiveAdiposity, particularly visceral adipose tissue (VAT), predicts adverse cardiovascular risk factor profiles in children as well as adults. Although endogenous sex steroids likely influence VAT in adults, such an association has not been established in youth. The association between childhood and adolescent sex steroids with adiposity, specifically VAT, was examined before and after adjustment for other hormone changes.MethodsThese analyses examined longitudinal associations between sex steroids (testosterone, estradiol, dehydroepiandrosterone [DHEA]) and magnetic resonance imaging assessments of VAT in 418 children, 49% of whom were non‐White, at approximately 10 years old at Visit 1 (V1) and 17 years old at Visit 2 (V2). Linear mixed effects models adjusted for maternal education, household income, child caloric intake, physical activity, fasting insulin and leptin, and hepatic fat fraction. Differences in associations by race and pubertal stage were also assessed.ResultsAt V1, mean body mass index (BMI) for boys was 19.1 (4.7) kg/m2 and for girls was 18.5 (4.1) kg/m2. At V2, mean BMI for boys was 23.7 (5.5) kg/m2 and for girls was 23.6 (5.7) kg/m2. For each ng/dl (0.035 nmol/L) increase in testosterone at V1, there was a 0.25 cm2 increase in concurrent and future VAT in non‐White (p = 0.04) but not White girls (p = 0.78). Higher levels of testosterone and DHEA at V1 were associated with greater concurrent and future VAT at V2. These associations were consistent regardless of pubertal stage. In boys, higher testosterone predicted higher future VAT but lower concurrent VAT. Estradiol and DHEA did not predict future VAT in boys. In girls, DHEA predicted future subcutaneous adipose tissue (SAT), and no sex steroids predicted future SAT in boys.ConclusionsTestosterone levels predict VAT in boys and girls, and DHEA predicts VAT in girls, even after adjustment for other hormone changes.