A systems biology approach to understand gut microbiota and host metabolism in morbid obesity: design of the BARIA Longitudinal Cohort Study.

INTRODUCTION: Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. METHODS: The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years. RESULTS: Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra-individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference. CONCLUSION: The BARIA study can add more understanding in how gut-microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity-associated disease epidemic.

Differences in the prevalence of intermediate hyperglycaemia and the associated incidence of type 2 diabetes mellitus by ethnicity: The HELIUS study.

AIMS: We aimed to describe differences in the prevalence of intermediate hyperglycaemia (IH) between six ethnic groups. Moreover, to investigate differences in the association of the classifications of IH with the incidence of T2DM between ethnic groups. METHODS: We included 3759 Dutch, 2826 African Surinamese, 1646 Ghanaian, 2571 Turkish, 2691 Moroccan and 1970 South Asian Surinamese origin participants of the HELIUS study. IH was measured by fasting plasma glucose (FPG) and HbA1c. We calculated age-, BMI and physical-activity-adjusted prevalence of IH by sex, and calculated age and sex-adjusted hazard ratios (HR)for the association between IH and T2DM in each ethnic group. RESULTS: The prevalence of IH was higher among ethnic minority groups (68.6-41.7%) than the Dutch majority (34.9%). The prevalence of IH categories varied across subgroups. Combined increased FPG and HbA1c was most prevalent in South-Asian Surinamese men (27.6%, 95 %CI: 24.5-30.9%), and in Dutch women (4.2%, 95 %CI: 3.4-5.1%). The HRs for T2DM for each IH-classification did not differ significantly between ethnic groups. HRs were highest for the combined classification, e.g., HR = 8.1, 95 %CI: 2.5-26.6 in the Dutch. CONCLUSION: We found a higher prevalence of IH in ethnic minority versus majority groups, but did not find evidence for a differential association of IH with incident T2DM.

The effects of laparoscopic Roux-en-Y gastric bypass and one-anastomosis gastric bypass on glycemic control and remission of type 2 diabetes mellitus: study protocol for a multi-center randomized controlled trial (the DIABAR-trial).

BACKGROUND: Metabolic surgery induces rapid remission of type 2 diabetes mellitus (T2DM). There is a paucity of high level evidence comparing the efficacy of the laparoscopic Roux-en-Y gastric bypass (RYGB) and the laparoscopic one-anastomosis gastric bypass (OAGB) in glycemic control. Also, the mechanisms that drive the conversion of T2DM in severe obese subjects to euglycemia are poorly understood. METHODS: The DIABAR-trial is an open, multi-center, randomized controlled clinical trial with 10 years follow-up which will be performed in 220 severely obese patients, diagnosed with T2DM and treated with glucose-lowering agents. Patients will be randomized in a 1:1 ratio to undergo RYGB or OAGB. The primary outcome is glycemic control at 12 months follow-up. Secondary outcome measures are diverse and include weight loss, surgical complications, psychologic status and quality of life, dietary behavior, gastrointestinal symptoms, repetitive bloodwork to identify changes over time, glucose tolerance and insulin sensitivity as measured by mixed meal tests, remission of T2DM, presence of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in liver biopsy, oral and fecal microbiome, cardiovascular performance, composition of bile acids, and the tendency to develop gallstones. DISCUSSION: The DIABAR-trial is one of the few randomized controlled trials primarily aimed to evaluate the glycemic response after the RYGB and OAGB in severe obese patients diagnosed with T2DM. Secondary aims of the trial are to contribute to a deeper understanding of the mechanisms that drive the remission of T2DM in severe obese patients by identification of microbial, immunological, and metabolic markers for metabolic response and to compare complications and side effects of RYGB and OAGB. TRIAL REGISTRATION: ClinicalTrials.gov NCT03330756 ; date first registered: October 13, 2017.

The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Screening for diabetic retinopathy in a clinical setting: a comparison of direct ophthalmoscopy by primary care physicians with fundus photography.

BACKGROUND: Type II diabetes mellitus is a major health problem among Native Americans, and diabetic retinopathy is a frequent complication of this disease. Screening for retinopathy can identify early disease and prevent major vision loss, but the most cost-effective screening method has not yet been determined. METHODS: In a rural clinic that served more than 400 Native Americans with diabetes, we compared the accuracy of referrals made based on two screening methods: ophthalmoscopy by trained primary care physicians and seven-view nonstereoscopic, mydriatic fundal photography read by two general ophthalmologists and a retinal specialist. Patients in whom abnormal findings were detected by either screening method were then referred to a general ophthalmologist for further evaluation. RESULTS: Two hundred forty-three examinations were performed and 83 referrals made. Both screening methods had high sensitivity for referring patients with retinopathy that required treatment or follow-up sooner than 1 year (100% for direct ophthalmoscopy by primary care physicians, 94% for the general ophthalmologist photography readers, and 100% for the retinal specialist reader). The calculated costs of screening by direct ophthalmoscopy and by retinal photography were 64% less and 44% to 35% less, respectively, than the cost of yearly ophthalmological examinations by ophthalmologists. CONCLUSIONS: Careful screening for treatable diabetic eye disease by trained primary care physicians proved to be a clinically acceptable, cost-effective strategy. Screening methods for diabetic retinopathy should be evaluated based on the absolute sensitivity, specificity, and predictive values of their ability to correctly refer patients rather than their diagnostic accuracy.

Proteinuria in early childhood due to familial LCAT deficiency caused by loss of a disulfide bond in lecithin:cholesterol acyl transferase.

INTRODUCTION: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare recessive disorder of cholesterol metabolism characterized by the absence of high density lipoprotein (HDL) and the triad of corneal opacification, hemolytic anemia and glomerulopathy. PATIENTS: We here report on FLD in three siblings of a kindred of Moroccan descent with HDL deficiency. In all cases (17, 12 and 3 years of age) corneal opacification and proteinuria were observed. In the 17-year-old female proband, anemia with target cells was observed. RESULTS: Homozygosity for a mutation in LCAT resulted in the exchange of cysteine to tyrosine at position 337, disrupting the second disulfide bond in LCAT. LCAT protein and activity were undetectable in the patients' plasma and in media of COS7 cells transfected with an expression vector with mutant LCAT cDNA. Upon treatment with an ACE inhibitor and a thiazide diuretic, proteinuria in the proband decreased from 6g to 2g/24h. CONCLUSION: This is the first report that FLD can cause nephropathy at a very early age.

Measuring tidal breathing parameters using a volumetric vest in neonates with and without lung disease.

Lung function measurement is difficult in unsedated infants; tidal breathing parameters are a useful non-invasive surrogate, but even these measurements cause disturbance from applying a facemask. We investigated a novel volumetric vest system (FloRight), which measures volume changes of the respiratory system from changes in the magnetic fields induced by current-carrying coils around the entire chest and abdomen. Using a facemask and ultrasonic flowmeter as comparator, we assessed the validity and repeatability of tidal breathing parameters measured by FloRight in 10 healthy newborn infants during natural sleep. We also assessed the effect of a facemask on tidal volume and tidal expiratory flow parameters. To assess the ability of the FloRight system to detect disease, we compared the healthy infants with 11 infants suffering from bronchopulmonary dysplasia. Tidal parameters with the FloRight vest corresponded closely with facemask measurements. Mean difference, mask minus vest, for tidal volume was 0.096 ml (P < 0.05), with limits of agreement +4.5 to -4.3 ml. Coefficient of repeatability was similar for mask and vest measurements. Tidal volume measured by FloRight with mask in place (20.6 ml) was significantly higher than without mask (16.1 ml), but tidal expiratory flow parameters were not altered. FloRight measurements of tidal parameters were markedly different between the two groups of infants, with tidal volume per Kg significantly higher and tidal expiratory flow parameters significantly lower. Our findings suggest that the FloRight system is able to measure tidal breathing parameters accurately, in healthy newborn infants, without prior calibration on the infant. It appears to have at least sufficient sensitivity to detect severe respiratory disease.

Extracting respiratory data from pulse oximeter plethysmogram traces in newborn infants.

To investigate whether valid respiratory data can be extracted from the pulse oximeter plethysmographic (pleth) trace in healthy newborn infants, pleth data were collected from the foot, and respiratory airflow was simultaneously measured using a facemask. The pleth waveform was analysed using fast Fourier transform (FFT), low-pass filtering (LPF), and by plotting the peak-to-peak amplitude variation (PtP). Using FFT in 14 term infants, the median (range) respiratory rate from the pleth signal was 43 (30-65) breaths/min, and from the flow signal it was 44 (30-67) breaths/min (median difference 0.01 breaths/min, p>0.05). Both LPF and PtP analysis yielded waveforms with a frequency similar to the respiratory rate. Respiratory information, including respiratory rate and a respiratory-like waveform, can reliably be extracted from the pleth trace of a standard pulse oximeter in newborn infants. Such analysis may be clinically useful for non-invasive assessment of respiratory problems in infants and young children.

Measurement and repeatability of interrupter resistance in unsedated newborn infants.

Interrupter resistance (R(int)) is a useful measure of airway caliber in young children, but has not been well characterized in infants-in whom there are concerns about the accurate measurement of driving pressure. This study aimed to assess the feasibility and repeatability of measuring R(int) in unsedated newborn infants, and to explore alternative algorithms for calculating driving pressure. R(int) measurement was attempted in 28 healthy term newborn infants during natural sleep using the MicroRint device. Paired R(int) measurements were achieved in 24 infants, but after screening of waveforms only 15 infants had at least 5 technically acceptable waveforms on both measurements. R(int) values obtained were comparable with reported values for airflow resistance in newborns using other methods. However, the repeatability coefficient (CR) was much higher than reported values in preschool children using standard back-extrapolation algorithms, with CR 2.47 KPa L(-1) sec (unscreened) and 2.93 KPa L(-1) sec (screened). Other algorithms gave only marginally better repeatability, with all CR values over 50% of the mean R(int) value. Using current commercially available equipment, R(int) is too poorly repeatable to be a reliable measurement of airflow resistance in newborn infants. Lower deadspace equipment is needed, but anatomical and physiological factors in the infant are also important.

Comparing stepping-in-place and gait ability in adults with and without hemiplegia.

OBJECTIVE: To determine and compare select temporal-distance measures of stepping-in-place with gait ability in 2 age-matched groups. DESIGN: Repeated measures, matched research design. SETTING: Gait laboratory and hospital outpatient unit. PARTICIPANTS: Convenience sample recruited from within the community and the outpatient unit of a local rehabilitation hospital included 30 healthy adults (age range, 58.1 +/- 10.8yr) and 30 age-matched adults with hemiplegia (age range, 58.6 +/- 10.3yr), secondary to a cerebrovascular accident. INTERVENTIONS: Subjects were videotaped in the sagittal plane performing stepping-in-place and while walking. Select temporal-distance measures obtained by manual calculations from the video recordings were determined for 3 20-second trials of each activity. MAIN OUTCOME MEASURES: Single limb support duration (SLSD) of the lower extremities (LEs) and step frequency during stepping-in-place and during gait. RESULTS: A significant difference was found between the step frequency of each activity for the adults with hemiplegia (p <.05), but not for the healthy adults. A significant difference was also found between SLSD of the same LE across activities for each group (p <.05). SLSD of each LE during each individual activity, stepping-in-place, or gait, was not significantly different for the healthy adults, indicating LE symmetry; but it was significantly different for the adults with hemiplegia (p <.05), indicating LE asymmetry. CONCLUSIONS: Stepping-in-place incorporates reciprocal, rhythmic LE movement patterns similar to gait. And, although SLSD of the LEs was different between the activities in both groups, each group showed similar LE movement patterns during each individual activity. In addition, step frequency was consistent between the activities for the healthy adults. These results seem to indicate that the reciprocal, rhythmic LE movement patterns, which are invoked during gait, may also be invoked during stepping-in-place. However, further research is needed to enhance the data related to stepping-in-place and gait ability in clinical populations.