Isotope Dilution Space Ratio Declines Above the Age of 60 Y, Potentially Impacting Estimates of Total Energy Expenditure by the Doubly Labeled Water Method.

Doubly labeled water is gold standard for measuring total energy expenditure (TEE). Measurements using the method are sensitive to the isotope dilution space ratio (DSR). Accuracy and precision of the method might be improved if we could identify factors influencing DSR. We evaluated the potential associations of age, sex, ethnicity, anthropometry, body composition, turnover rates of the isotopes, and geographical elevation with DSR. We used univariate regression analysis to explore the relationships between the continuous variables and analysis of variance to test the relationships between the categorical variables with DSR. Subsequently, we used general linear model (GLM) and 1-way analysis of variance to evaluate the simultaneous associations of age, sex, ethnicity, fat-free mass (FFM) and fat mass (FM) on DSR. From 5678 measurements complied from studies around the world with diverse ethnicity and living at various elevations, the mean DSR was 1.0364 ± 0.0141. No meaningful physiologic effect of any of the continuous and categorical variable on DSR was detected. General linear model analysis revealed no effect of FFM and FM (P > 0.33) on DSR, but DSR decreased with age (P < 0.001) among those aged 60 y and older regardless of sex. Among the Whites who were younger than 60 y, DSR was not related to FFM and FM (P = 0.73) but was affected by both age and sex (P < 0.001). Previous estimates of age-related decline in TEE may have overestimated TEE at age 90 y. Validation studies on older participants are required to confirm this finding.

iPSC-Derived LCHADD Retinal Pigment Epithelial Cells Are Susceptible to Lipid Peroxidation and Rescued by Transfection of a Wildtype AAV-HADHA Vector.

Purpose: Progressive choroid and retinal pigment epithelial (RPE) degeneration causing vision loss is a unique characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder caused by a common c.1528G>C pathogenic variant in HADHA, the α subunit of the mitochondrial trifunctional protein (TFP). We established and characterized an induced pluripotent stem cell (iPSC)-derived RPE cell model from cultured skin fibroblasts of patients with LCHADD and tested whether addition of wildtype (WT) HAHDA could rescue the phenotypes identified in LCHADD-RPE. Methods: We constructed an rAAV expression vector containing 3' 3xFLAG-tagged human HADHA cDNA under the transcriptional control of the cytomegalovirus (CMV) enhancer-chicken beta actin (CAG) promoter (CAG-HADHA-3XFLAG). LCHADD-RPE were cultured, matured, and transduced with either AAV-GFP (control) or AAV-HADHA-3XFLAG. Results: LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE. When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD. Transduced LCHADD-RPE expressing a WT copy of TFPα incorporated TFPα-FLAG into the TFP complex in the mitochondria and accumulated significantly less 3-hydroxy-acylcarnitines, released more ketones in response to palmitate, and were more resistant to oxidative stress following DHA exposure than control. Conclusions: iPSC-derived LCHADD-RPE are susceptible to lipid peroxidation mediated cell death and are rescued by exogenous HADHA delivered with rAAV. These results are promising for AAV-HADHA gene addition therapy as a possible treatment for chorioretinopathy in patients with LCHADD.

The LCHADD Mouse Model Recapitulates Early-Stage Chorioretinopathy in LCHADD Patients.

Purpose: Recent studies have shown that the retinal pigment epithelium (RPE) relies on fatty acid oxidation (FAO) for energy, however, its role in overall retinal health is unknown. The only FAO disorder that presents with chorioretinopathy is long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). Studying the molecular mechanisms can lead to new treatments for patients and elucidate the role of FAO in the RPE. This paper characterizes the chorioretinopathy progression in a recently reported LCHADD mouse model. Methods: Visual assessments, such as optokinetic tracking and fundus imaging, were performed in wildtype (WT) and LCHADD mice at 3, 6, 10, and 12 months of age. Retinal morphology was analyzed in 12-month retinal cross-sections using hematoxylin and eosin (H&E), RPE65, CD68, and TUNEL staining, whereas RPE structure was assessed using transmission electron microscopy (TEM). Acylcarnitine profiles were measured in isolated RPE/sclera samples to determine if FAO was blocked. Bulk RNA-sequencing of 12 month old male WT mice and LCHADD RPE/sclera samples assessed gene expression changes. Results: LCHADD RPE/sclera samples had a 5- to 7-fold increase in long-chain hydroxyacylcarnitines compared to WT, suggesting an impaired LCHAD step in long-chain FAO. LCHADD mice have progressively decreased visual performance and increased RPE degeneration starting at 6 months. LCHADD RPE have an altered structure and a two-fold increase in macrophages in the subretinal space. Finally, LCHADD RPE/sclera have differentially expressed genes compared to WT, including downregulation of genes important for RPE function and angiogenesis. Conclusions: Overall, this LCHADD mouse model recapitulates early-stage chorioretinopathy seen in patients with LCHADD and is a useful model for studying LCHADD chorioretinopathy.

The Association Between Diet Quality and Glycemic Outcomes Among People with Type 1 Diabetes.

Background: The amount and type of food consumed impacts the glycemic response and insulin needs of people with type 1 diabetes mellitus (T1DM). Daily variability in consumption, reflected in diet quality, may acutely impact glycemic levels and insulin needs. Objective: Type 1 Diabetes Exercise Initiative (T1DEXI) data were examined to evaluate the impact of daily diet quality on near-term glycemic control and interaction with exercise. Methods: Using the Remote Food Photography Method, ≤8 d of dietary intake data were analyzed per participant. Diet quality was quantified with the Healthy Eating Index-2015 (HEI), where a score of 100 indicates the highest-quality diet. Each participant day was classified as low HEI (≤57) or high HEI (>57) based on the mean of nationally reported HEI data. Within participants, the relationship between diet quality and subsequent glycemia measured by continuous glucose monitoring (CGM) and total insulin dose usage was evaluated using a paired t-test and robust regression models. Results: Two hundred twenty-three adults (76% female) with mean ± SD age, HbA1c, and body mass index (BMI) of 37 ± 14 y, 6.6% ± 0.7%, and 25.1 ± 3.6 kg/m2, respectively, were included in these analyses. The mean HEI score was 56 across all participant days. On high HEI days (mean, 66 ± 4) compared with low HEI days (mean, 47 ± 5), total time in range (70-180 mg/dL) was greater (77.2% ± 14% compared with 75.7% ± 14%, respectively, P = 0.01), whereas time above 180 mg/dL (19% ± 14% compared with 21% ± 15%, respectively, P = 0.004), mean glucose (143 ± 22 compared with 145 ± 22 mg/dL, respectively, P = 0.02), and total daily insulin dose (0.52 ± 0.18 compared with 0.54 ± 0.18 U/kg/d, respectively, P = 0.009) were lower. The interaction between diet quality and exercise on glycemia was not significant. Conclusions: Higher HEI scores correlated with improved glycemia and lower insulin needs, although the impact of diet quality was modest and smaller than the previously reported impact of exercise.

Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy.

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.

A review of fatty acid oxidation disorder mouse models.

Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.

Associations between daily step count classifications and continuous glucose monitoring metrics in adults with type 1 diabetes: analysis of the Type 1 Diabetes Exercise Initiative (T1DEXI) cohort.

AIMS/HYPOTHESIS: Adults with type 1 diabetes should perform daily physical activity to help maintain health and fitness, but the influence of daily step counts on continuous glucose monitoring (CGM) metrics are unclear. This analysis used the Type 1 Diabetes Exercise Initiative (T1DEXI) dataset to investigate the effect of daily step count on CGM-based metrics. METHODS: In a 4 week free-living observational study of adults with type 1 diabetes, with available CGM and step count data, we categorised participants into three groups-below (<7000), meeting (7000-10,000) or exceeding (>10,000) the daily step count goal-to determine if step count category influenced CGM metrics, including per cent time in range (TIR: 3.9-10.0 mmol/l), time below range (TBR: <3.9 mmol/l) and time above range (TAR: >10.0 mmol/l). RESULTS: A total of 464 adults with type 1 diabetes (mean±SD age 37±14 years; HbA1c 48.8±8.1 mmol/mol [6.6±0.7%]; 73% female; 45% hybrid closed-loop system, 38% standard insulin pump, 17% multiple daily insulin injections) were included in the study. Between-participant analyses showed that individuals who exceeded the mean daily step count goal over the 4 week period had a similar TIR (75±14%) to those meeting (74±14%) or below (75±16%) the step count goal (p>0.05). In the within-participant comparisons, TIR was higher on days when the step count goal was exceeded or met (both 75±15%) than on days below the step count goal (73±16%; both p<0.001). The TBR was also higher when individuals exceeded the step count goals (3.1%±3.2%) than on days when they met or were below step count goals (difference in means -0.3% [p=0.006] and -0.4% [p=0.001], respectively). The total daily insulin dose was lower on days when step count goals were exceeded (0.52±0.18 U/kg; p<0.001) or were met (0.53±0.18 U/kg; p<0.001) than on days when step counts were below the current recommendation (0.55±0.18 U/kg). Step count had a larger effect on CGM-based metrics in participants with a baseline HbA1c ≥53 mmol/mol (≥7.0%). CONCLUSIONS/INTERPRETATION: Our results suggest that, compared with days with low step counts, days with higher step counts are associated with slight increases in both TIR and TBR, along with small reductions in total daily insulin requirements, in adults living with type 1 diabetes. DATA AVAILABILITY: The data that support the findings reported here are available on the Vivli Platform (ID: T1-DEXI; https://doi.org/10.25934/PR00008428 ).

Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.

PURPOSE: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) is a rare fatty acid oxidation disorder characterized by recurrent episodes of metabolic decompensation and rhabdomyolysis, as well as retinopathy, peripheral neuropathy, and cardiac involvement, such as infantile dilated cardiomyopathy. Because LCHADD patients are surviving longer, we sought to characterize LCHADD-associated major cardiac involvement in adolescence and young adulthood. METHODS: A retrospective cohort of 16 adolescent and young adult participants with LCHADD was reviewed for cardiac phenotype. RESULTS: Major cardiac involvement occurred in 9 of 16 participants, including sudden death, out-of-hospital cardiac arrest, acute cardiac decompensations with heart failure and/or in-hospital cardiac arrest, end-stage dilated cardiomyopathy, and moderate restrictive cardiomyopathy. Sudden cardiac arrest was more common in males and those with a history of infant cardiomyopathy. CONCLUSION: The cardiac manifestations of LCHADD in adolescence and early adulthood are complex and distinct from the phenotype seen in infancy. Life-threatening arrhythmia occurs at substantial rates in LCHADD, often in the absence of metabolic decompensation or rhabdomyolysis. The potential risk factors identified here-male sex and history of infant cardiomyopathy-may hint at strategies for risk stratification and possibly the prevention of these events.

Factors Affecting Reproducibility of Change in Glucose During Exercise: Results From the Type 1 Diabetes and EXercise Initiative.

AIMS: To evaluate factors affecting within-participant reproducibility in glycemic response to different forms of exercise. METHODS: Structured exercise sessions ~30 minutes in length from the Type 1 Diabetes Exercise Initiative (T1DEXI) study were used to assess within-participant glycemic variability during and after exercise. The effect of several pre-exercise factors on the within-participant glycemic variability was evaluated. RESULTS: Data from 476 adults with type 1 diabetes were analyzed. A participant's change in glucose during exercise was reproducible within 15 mg/dL of the participant's other exercise sessions only 32% of the time. Participants who exercised with lower and more consistent glucose level, insulin on board (IOB), and carbohydrate intake at exercise start had less variability in glycemic change during exercise. Participants with lower mean glucose (P < .001), lower glucose coefficient of variation (CV) (P < .001), and lower % time <70 mg/dL (P = .005) on sedentary days had less variable 24-hour post-exercise mean glucose. CONCLUSIONS: Reproducibility of change in glucose during exercise was low in this cohort of adults with T1D, but more consistency in pre-exercise glucose levels, IOB, and carbohydrates may increase this reproducibility. Mean glucose variability in the 24 hours after exercise is influenced more by the participant's overall glycemic control than other modifiable factors.

A proposal for an updated staging system for LCHADD retinopathy.

OBJECTIVE: To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging and electrophysiology. METHODS: We evaluated forty cases of patients with genetically confirmed LCHADD or trifunctional protein deficiency (TFPD) enrolled in a prospective natural history study. Wide-field fundus photographs, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ffERG) were reviewed and graded for severity. RESULTS: Two independent experts first graded fundus photos and electrophysiology to classify the stage of chorioretinopathy based upon an existing published system. With newer imaging modalities and improved electrophysiology, many patients did not fit cleanly into a single traditional staging group. Therefore, we developed a novel staging system that better delineated the progression of LCHADD retinopathy. We maintained the four previous delineated stages but created substages A and B in stages 2 to 3 to achieve better differentiation. DISCUSSION: Previous staging systems of LCHADD chorioretinopathy relied on only on the assessment of standard 30 to 45-degree fundus photographs, visual acuity, fluorescein angiography (FA), and ffERG. Advances in recordings of ffERG and multimodal imaging with wider fields of view, allow better assessment of retinal changes. Following these advanced assessments, seven patients did not fit neatly into the original classification system and were therefore recategorized under the new proposed system. CONCLUSION: The new proposed staging system improves the classification of LCHADD chorioretinopathy, with the potential to lead to a deeper understanding of the disease's progression and serve as a more reliable reference point for future therapeutic research.

Obesity alters the circadian profiles of energy metabolism and glucose regulation in humans.

OBJECTIVE: Given the complex interaction among the circadian system, energy metabolism, and obesity, the authors tested whether having obesity impacts the circadian variation in energy and glucose metabolism in humans. METHODS: Participants with BMI either in the healthy weight or obesity ranges were studied in a 5-day, in-laboratory protocol that equally distributed behaviors (i.e., sleep, eating, exercise) across 24 h. Energy metabolism was measured at rest and during a standardized exercise bout and blood was sampled before and after each identical study meal to assess glucose and insulin levels. RESULTS: In those with a healthy weight, the circadian nadir of energy expenditure, during both rest and exercise, occurred when participants would normally be asleep. However, in those with obesity, this nadir appears to occur during the habitual wake period. Differences in glucose regulation also depended on the circadian phase, such that individuals with obesity appeared to have relatively greater glucose intolerance during the circadian day and produced less insulin during the circadian night. CONCLUSIONS: Obesity is associated with altered circadian energy and glucose metabolism. Understanding and addressing these associations could lead to strategies that improve body weight and metabolic health in people with obesity.

Combining uncertainty-aware predictive modeling and a bedtime Smart Snack intervention to prevent nocturnal hypoglycemia in people with type 1 diabetes on multiple daily injections.

OBJECTIVE: Nocturnal hypoglycemia is a known challenge for people with type 1 diabetes, especially for physically active individuals or those on multiple daily injections. We developed an evidential neural network (ENN) to predict at bedtime the probability and timing of nocturnal hypoglycemia (0-4 vs 4-8 h after bedtime) based on several glucose metrics and physical activity patterns. We utilized these predictions in silico to prescribe bedtime carbohydrates with a Smart Snack intervention specific to the predicted minimum nocturnal glucose and timing of nocturnal hypoglycemia. MATERIALS AND METHODS: We leveraged free-living datasets collected from 366 individuals from the T1DEXI Study and Glooko. Inputs to the ENN used to model nocturnal hypoglycemia were derived from demographic information, continuous glucose monitoring, and physical activity data. We assessed the accuracy of the ENN using area under the receiver operating curve, and the clinical impact of the Smart Snack intervention through simulations. RESULTS: The ENN achieved an area under the receiver operating curve of 0.80 and 0.71 to predict nocturnal hypoglycemic events during 0-4 and 4-8 h after bedtime, respectively, outperforming all evaluated baseline methods. Use of the Smart Snack intervention reduced probability of nocturnal hypoglycemia from 23.9 ± 14.1% to 14.0 ± 13.3% and duration from 7.4 ± 7.0% to 2.4 ± 3.3% in silico. DISCUSSION: Our findings indicate that the ENN-based Smart Snack intervention has the potential to significantly reduce the frequency and duration of nocturnal hypoglycemic events. CONCLUSION: A decision support system that combines prediction of minimum nocturnal glucose and proactive recommendations for bedtime carbohydrate intake might effectively prevent nocturnal hypoglycemia and reduce the burden of glycemic self-management.

Greater male variability in daily energy expenditure develops through puberty.

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at different life stages, along with several morphological traits: height, fat free mass and fat mass. Total EE, and to some degree also activity EE, exhibit considerable greater male variation (GMV) in young adults, and then a decreasing GMV in progressively older individuals. Arguably, basal EE, and also morphometrics, do not exhibit this pattern. These findings suggest that single male sexual characteristics may not exhibit peak GMV in young adulthood, however total and perhaps also activity EE, associated with many morphological and physiological traits combined, do exhibit GMV most prominently during the reproductive life stages.

A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder (FAOD) caused by a pathogenic variant, c.1528 G > C, in HADHA encoding the alpha subunit of trifunctional protein (TFPα). Individuals with LCHADD develop chorioretinopathy and peripheral neuropathy not observed in other FAODs in addition to the more ubiquitous symptoms of hypoketotic hypoglycemia, rhabdomyolysis and cardiomyopathy. We report a CRISPR/Cas9 generated knock-in murine model of G1528C in Hadha that recapitulates aspects of the human LCHADD phenotype. Homozygous pups are less numerous than expected from Mendelian probability, but survivors exhibit similar viability with wildtype (WT) littermates. Tissues of LCHADD homozygotes express TFPα protein, but LCHADD mice oxidize less fat and accumulate plasma 3-hydroxyacylcarnitines compared to WT mice. LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. In addition, LCHADD mice exhibit decreased visual performance, decreased cone function, and disruption of retinal pigment epithelium. Neurological function is affected, with impaired motor function during wire hang test and reduced open field activity. The G1528C knock-in mouse exhibits a phenotype similar to that observed in human patients; this model will be useful to explore pathophysiology and treatments for LCHADD in the future.

The Type 1 Diabetes and EXercise Initiative: Predicting Hypoglycemia Risk During Exercise for Participants with Type 1 Diabetes Using Repeated Measures Random Forest.

Objective: Exercise is known to increase the risk for hypoglycemia in type 1 diabetes (T1D) but predicting when it may occur remains a major challenge. The objective of this study was to develop a hypoglycemia prediction model based on a large real-world study of exercise in T1D. Research Design and Methods: Structured study-specified exercise (aerobic, interval, and resistance training videos) and free-living exercise sessions from the T1D Exercise Initiative study were used to build a model for predicting hypoglycemia, a continuous glucose monitoring value <70 mg/dL, during exercise. Repeated measures random forest (RMRF) and repeated measures logistic regression (RMLR) models were constructed to predict hypoglycemia using predictors at the start of exercise and baseline characteristics. Models were evaluated with area under the receiver operating characteristic curve (AUC) and balanced accuracy. Results: RMRF and RMLR had similar AUC (0.833 vs. 0.825, respectively) and both models had a balanced accuracy of 77%. The probability of hypoglycemia was higher for exercise sessions with lower pre-exercise glucose levels, negative pre-exercise glucose rates of change, greater percent time <70 mg/dL in the 24 h before exercise, and greater pre-exercise bolus insulin-on-board (IOB). Free-living aerobic exercises, walking/hiking, and physical labor had the highest probability of hypoglycemia, while structured exercises had the lowest probability of hypoglycemia. Conclusions: RMRF and RMLR accurately predict hypoglycemia during exercise and identify factors that increase the risk of hypoglycemia. Lower glucose, decreasing levels of glucose before exercise, and greater pre-exercise IOB largely predict hypoglycemia risk in adults with T1D.

Total daily energy expenditure has declined over the past three decades due to declining basal expenditure, not reduced activity expenditure.

Obesity is caused by a prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes is debated3,4. Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.

Examining the Acute Glycemic Effects of Different Types of Structured Exercise Sessions in Type 1 Diabetes in a Real-World Setting: The Type 1 Diabetes and Exercise Initiative (T1DEXI).

OBJECTIVE: Maintenance of glycemic control during and after exercise remains a major challenge for individuals with type 1 diabetes. Glycemic responses to exercise may differ by exercise type (aerobic, interval, or resistance), and the effect of activity type on glycemic control after exercise remains unclear. RESEARCH DESIGN AND METHODS: The Type 1 Diabetes Exercise Initiative (T1DEXI) was a real-world study of at-home exercise. Adult participants were randomly assigned to complete six structured aerobic, interval, or resistance exercise sessions over 4 weeks. Participants self-reported study and nonstudy exercise, food intake, and insulin dosing (multiple daily injection [MDI] users) using a custom smart phone application and provided pump (pump users), heart rate, and continuous glucose monitoring data. RESULTS: A total of 497 adults with type 1 diabetes (mean age ± SD 37 ± 14 years; mean HbA1c ± SD 6.6 ± 0.8% [49 ± 8.7 mmol/mol]) assigned to structured aerobic (n = 162), interval (n = 165), or resistance (n = 170) exercise were analyzed. The mean (± SD) change in glucose during assigned exercise was -18 ± 39, -14 ± 32, and -9 ± 36 mg/dL for aerobic, interval, and resistance, respectively (P < 0.001), with similar results for closed-loop, standard pump, and MDI users. Time in range 70-180 mg/dL (3.9-10.0 mmol/L) was higher during the 24 h after study exercise when compared with days without exercise (mean ± SD 76 ± 20% vs. 70 ± 23%; P < 0.001). CONCLUSIONS: Adults with type 1 diabetes experienced the largest drop in glucose level with aerobic exercise, followed by interval and resistance exercise, regardless of insulin delivery modality. Even in adults with well-controlled type 1 diabetes, days with structured exercise sessions contributed to clinically meaningful improvement in glucose time in range but may have slightly increased time below range.

Resting and total energy expenditure of patients with long-chain fatty acid oxidation disorders (LC-FAODs).

The basis of medical nutrition therapy for patients with LC-FAODs is to provide adequate energy to maintain anabolism and prevent catabolism. In practice, energy needs are estimated based on formulas derived from normal populations but it is unknown if energy expenditure among patients with LC-FAODs is similar to the normal population. We measured resting energy expenditure (REE), total energy expenditure (TEE) and body composition in 31 subjects with LC-FAODs ranging in age from 7 to 64 years. Measured REE was lower than estimated REE by various prediction equations and measured TEE was lower than estimated TEE. It is possible that the lower energy expenditure based on prediction formulas from the normal population is due to differences in body composition; we compared body composition to normal data from the 2017-18 National Health and Nutrition Examination Survey (NHANES). Fat free mass and fat mass was similar between subjects with an LC-FAOD and NHANES normal data suggesting no difference in body composition. We then compared measured REE and TEE to normal published data from the Dietary Reference Intakes (DRI). Measured REE and TEE were significantly lower among subjects with LC-FAODs compared to normal published energy expenditure data. Our results suggests patients with a LC-FAOD exhibit a lower REE and therefore actually have a slightly lower TEE than estimated. Current prediction equations may overestimate energy expenditure of patients with a LC-FAOD.

The Effect of Preoperative Carbohydrate Intake on Length of Stay and Postoperative Recovery Following Laparoscopic Living Donor Nephrectomy.

OBJECTIVE: Enhanced Recovery After Surgery (ERAS) protocols are applied in many surgical procedures and often involve preoperative carbohydrate intake. Research surrounding the utility of ERAS in living donor nephrectomy is limited. The objective of this study was to identify whether living kidney donors who received preoperative oral carbohydrates experienced a difference in length of hospital stay (LOS), duration of time required to resume regular oral food and fluid intake, and incidence of gastrointestinal (GI) complications following laparoscopic nephrectomy compared to historical control donors who underwent preoperative fasting. METHODS: This study was a retrospective analysis of data from adult subjects at one transplant center who underwent laparoscopic living donor nephrectomy. A total of 55 ERAS subjects who received preoperative carbohydrates and 93 historical control subjects who underwent preoperative fasting were included in the final analysis. The following variables were compared between groups: LOS, time to tolerating a regular oral diet postoperatively, time to meeting 50% of estimated fluid needs by oral intake postoperatively, and incidence of postoperative GI complications. RESULTS: No significant differences between the ERAS and historical control groups in age, weight, body mass index, sex distribution, or estimated fluid needs were identified. Both groups consisted of predominantly female subjects. ERAS subjects experienced a shorter LOS (2.8 days versus 3.9 days, P < .001), time to tolerating a regular oral diet (36.5 hours versus 68.2 hours, P < .001), and time to meeting 50% of estimated fluid needs (25.3 hours versus 44.6 hours, P < .001) after laparoscopic nephrectomy compared to historical control subjects. No significant difference between groups in the incidence of postoperative GI complications (nausea, vomiting, or ileus) was identified. CONCLUSION: Our findings demonstrate the advantages of ERAS in living kidney donors undergoing laparoscopic nephrectomy and support ERAS implementation within this patient population.

Optical coherence tomography angiography of choroidal neovascularization in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD).

Purpose: To report the clinical utility of optical coherence tomography angiography (OCTA) for demonstrating choroidal neovascularization (CNV) associated with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) retinopathy. Methods: Thirty-three participants with LCHADD (age 7-36 years; median 17) were imaged with OCTA and the Center for Ophthalmic Optics & Lasers Angiography Reading Toolkit (COOL-ART) software was implemented to process OCTA scans. Results: Seven participants (21 %; age 17-36 years; median 25) with LCHADD retinopathy demonstrated evidence of CNV by retinal examination or presence of CNV within outer retinal tissue on OCTA scans covering 3 × 3 and/or 6 × 6-mm. These sub-clinical CNVs are adjacent to hyperpigmented areas in the posterior pole. CNV presented at stage 2 or later of LCHADD retinopathy prior to the disappearance of RPE pigment in the macula. Conclusion: OCTA can be applied as a non-invasive method to evaluate the retinal and choroidal microvasculature. OCTA can reveal CNV in LCHADD even when the clinical exam is inconclusive. These data suggest that the incidence of CNV is greater than expected and can occur even in the early stages of LCHADD retinopathy.